Timely publication and sharing of trial data: opportunities and challenges for comparative effectiveness research in cardiovascular disease.

PubMed

Naci, Huseyin; Cooper, Jacob; Mossialos, Elias

2015-11-01

There is growing enthusiasm for the timely publication and sharing of clinical trial data. The rationale for open access includes greater transparency, reproducibility, and efficiency of the research enterprise. In cardiovascular diseases, routinely sharing clinical trial data would create opportunities for undertaking comparative effectiveness research, providing much needed evidence on how different interventions compare to each other on key outcomes. Access to individual patient-level data would strengthen the validity of such research. Novel methodological approaches like network meta-analyses using individual patient-level data could reliably compare interventions that have not been compared with each other in head-to-head trials. However, there are significant practical, methodological, financial, and legal challenges to this utopian open access that need to be continually addressed. Sharing clinical trial data openly will only occur when the previously tolerated process of clinical research involving direct ownership and secrecy is abandoned for a new culture in which medical science is open to all of its stakeholders. With this new culture, data will be accessible, reanalysis will be considered commonplace, and comparative effectiveness research through novel synthesis approaches, such as network meta-analyses, can thrive-as long as measures are taken to adequately ensure the goal remains to promote public health.

Cognitive enhancement treatments for bipolar disorder: A systematic review and methodological recommendations.

PubMed

Miskowiak, Kamilla W; Carvalho, André F; Vieta, Eduard; Kessing, Lars V

2016-10-01

Cognitive dysfunction is an emerging treatment target in bipolar disorder (BD). Several trials have assessed the efficacy of novel pharmacological and psychological treatments on cognition in BD but the findings are contradictory and unclear. A systematic search following the PRISMA guidelines was conducted on PubMed and PsychInfo. Eligible articles reported randomized, controlled or open-label trials investigating pharmacological or psychological treatments targeting cognitive dysfunction in BD. The quality of the identified randomized controlled trials (RCTs) was evaluated with the Cochrane Collaboration's Risk of Bias tool. We identified 19 eligible studies of which 13 were RCTs and six were open-label or non-randomized studies. The findings regarding efficacy on cognition were overall disappointing or preliminary, possibly due to several methodological challenges. For the RCTs, the risk of bias was high in nine cases, unclear in one case and low in three cases. Key reasons for the high risk of bias were lack of details on the randomization process, suboptimal handling of missing data and lack of a priori priority between cognition outcomes. Other challenges were the lack of consensus on whether and how to screen for cognitive impairment and on how to assess efficacy on cognition. In conclusion, methodological problems are likely to impede the success rates of cognition trials in BD. We recommend adherence to the CONSORT guidelines for RCTs, screening for cognitive impairment before inclusion of trial participants and selection of one primary cognition outcome. Future implementation of a 'neurocircuitry-based' biomarker model to evaluate neural target engagement is warranted. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Symptom research on chronic cough: a historical perspective.

PubMed

Irwin, R S; Madison, J M

2001-05-01

This review provides a perspective on how research on the management of cough has evolved, looks at key methodologic lessons that have been learned from this research and how they may relate to the management of other symptoms, identifies important methodologic challenges that remain to be solved, and lists important questions that still need to be answered. Three important methodologic lessons have been learned. First, cough must be evaluated systematically and according to a neuroanatomic framework. Second, the response to specific therapy must be noted to determine the cause or causes of cough and to characterize the strengths and limitations of diagnostic testing. Third, multiple conditions can simultaneously cause cough. Among the three methodologic challenges that still need to be solved are 1) definitively determining the diagnostic accuracy and reliability of 24-hour esophageal pH monitoring and how best to interpret pH test results, 2) definitively determining the role of nonacid reflux in cough due to gastroesophageal reflux disease, and 3) developing reliable and reproducible subjective and objective methods with which to assess the efficacy of cough therapy. Numerous important clinical questions are still unanswered: What role do empirical therapeutic trials play in diagnosing the cause of chronic cough? What is the most cost-effective approach to the diagnosis and treatment of chronic cough: empirical therapeutic trials or laboratory testing-directed therapeutic trials? How often is environmental air pollution, unrelated to allergies or smoking, responsible for chronic cough?

Designing trials for pressure ulcer risk assessment research: methodological challenges.

PubMed

Balzer, K; Köpke, S; Lühmann, D; Haastert, B; Kottner, J; Meyer, G

2013-08-01

For decades various pressure ulcer risk assessment scales (PURAS) have been developed and implemented into nursing practice despite uncertainty whether use of these tools helps to prevent pressure ulcers. According to current methodological standards, randomised controlled trials (RCTs) are required to conclusively determine the clinical efficacy and safety of this risk assessment strategy. In these trials, PURAS-aided risk assessment has to be compared to nurses' clinical judgment alone in terms of its impact on pressure ulcer incidence and adverse outcomes. However, RCTs evaluating diagnostic procedures are prone to specific risks of bias and threats to the statistical power which may challenge their validity and feasibility. This discussion paper critically reflects on the rigour and feasibility of experimental research needed to substantiate the clinical efficacy of PURAS-aided risk assessment. Based on reflections of the methodological literature, a critical appraisal of available trials on this subject and an analysis of a protocol developed for a methodologically robust cluster-RCT, this paper arrives at the following conclusions: First, available trials do not provide reliable estimates of the impact of PURAS-aided risk assessment on pressure ulcer incidence compared to nurses' clinical judgement alone due to serious risks of bias and insufficient sample size. Second, it seems infeasible to assess this impact by means of rigorous experimental studies since sample size would become extremely high if likely threats to validity and power are properly taken into account. Third, means of evidence linkages seem to currently be the most promising approaches for evaluating the clinical efficacy and safety of PURAS-aided risk assessment. With this kind of secondary research, the downstream effect of use of PURAS on pressure ulcer incidence could be modelled by combining best available evidence for single parts of this pathway. However, to yield reliable modelling results, more robust experimental research evaluating specific parts of the pressure ulcer risk assessment-prevention pathway is needed. Copyright © 2013 Elsevier Ltd. All rights reserved.

Fortuitous phenomena: on complexity, pragmatic randomised controlled trials, and knowledge for evidence-based practice.

PubMed

Thompson, Carl

2004-01-01

Many of the interventions that nurses develop and implement are in themselves complex and have to operate in situations of irreducible complexity and uncertainty. This article argues that the primary means of generating knowledge for the evidence-based deployment of complex interventions should be the pragmatic randomised controlled trial. Randomised controlled trials represent the only research design to adequately deal with that which we know and (far more importantly) that which we do not. Using the example of practice development as an exemplar for complexity, and drawing on the objections often voiced as a response to calls to make use of randomised controlled trials in nursing and nursing research, the article presents a developmental framework and some methodological solutions to problems often encountered. Randomised controlled trials, whilst undoubtedly methodologically and strategically challenging, offer the most robust basis for developing primary research knowledge on the effects of complex interventions in nursing and their active components.

Traditional chinese medicine: an update on clinical evidence.

PubMed

Xue, Charlie C L; Zhang, Anthony L; Greenwood, Kenneth M; Lin, Vivian; Story, David F

2010-03-01

As an alternative medical system, Traditional Chinese Medicine (TCM) has been increasingly used over the last several decades. Such a consumer-driven development has resulted in introduction of education programs for practitioner training, development of product and practitioner regulation systems, and generation of an increasing interest in research. Significant efforts have been made in validating the quality, effectiveness, and safety of TCM interventions evidenced by a growing number of published trials and systematic reviews. Commonly, the results of these studies were inconclusive due to the lack of quality and quantity of the trials to answer specific and answerable clinical questions. The methodology of a randomized clinical trial (RCT) is not free from bias, and the unique features of TCM (such as individualization and holism) further complicate effective execution of RCTs in TCM therapies. Thus, data from limited RCTs and systematic reviews need to be interpreted with great caution. Nevertheless, until new and specific methodology is developed that can adequately address these methodology challenges for RCTs in TCM, evidence from quality RCTs and systematic reviews still holds the credibility of TCM in the scientific community. This article summarizes studies on TCM utilization, and regulatory and educational development with a focus on updating the TCM clinical evidence from RCTs and systematic reviews over the last decade. The key issues and challenges associated with evidence-based TCM developments are also explored.

Confronting Challenges in Intervention Research with Ethnically Diverse Older Adults: The USC Well Elderly II Trial

PubMed Central

Jackson, Jeanne; Mandel, Deborah; Blanchard, Jeanine; Carlson, Mike; Cherry, Barbara; Azen, Stanley; Chou, Chih-Ping; Jordan-Marsh, Maryalice; Forman, Todd; White, Brett; Granger, Douglas; Knight, Bob; Clark, Florence

2011-01-01

Background Community-dwelling older adults are at risk for declines in physical health, cognition, and psychosocial well-being. However, their enactment of active and health-promoting lifestyles can reduce such declines. Purpose The purpose of this article is to describe the USC Well Elderly II study, a randomized clinical trial designed to test the effectiveness of a healthy lifestyle program for elders, and document how various methodological challenges were addressed during the course of the trial. Methods In the study, 460 ethnically diverse elders recruited from a variety of sites in the urban Los Angeles area were enrolled in a randomized experiment involving a crossover design component. Within either the first or second six month phase of their study involvement, each elder received a lifestyle intervention designed to improve a variety of aging outcomes. At 4–5 time points over an 18–24 month interval, the research participants were assessed on measures of healthy activity, coping, social support, perceived control, stress-related biomarkers, perceived physical health, psychosocial well-being, and cognitive functioning to test the effectiveness of the intervention and document the process mechanisms responsible for its effects. Results The study protocol was successfully implemented, including the enrollment of study sites, the recruitment of 460 older adults, administration of the intervention, adherence to the plan for assessment, and establishment of a large computerized data base. Limitations Methodological challenges were encountered in the areas of site recruitment, participant recruitment, testing, and intervention delivery. Conclusions The completion of clinical trials involving elders from numerous local sites requires careful oversight and anticipation of threats to the study design that stem from: (a) social situations that are particular to specific study sites; and (b) physical, functional, and social challenges pertaining to the elder population. PMID:19254939

Confronting challenges in intervention research with ethnically diverse older adults: the USC Well Elderly II Trial.

PubMed

Jackson, Jeanne; Mandel, Deborah; Blanchard, Jeanine; Carlson, Mike; Cherry, Barbara; Azen, Stanley; Chou, Chih-Ping; Jordan-Marsh, Maryalice; Forman, Todd; White, Brett; Granger, Douglas; Knight, Bob; Clark, Florence

2009-02-01

Community-dwelling older adults are at risk for declines in physical health, cognition, and psychosocial well-being. However, their enactment of active and health-promoting lifestyles can reduce such declines. The purpose of this article is to describe the USC Well Elderly II study, a randomized clinical trial designed to test the effectiveness of a healthy lifestyle program for elders, and document how various methodological challenges were addressed during the course of the trial. In the study, 460 ethnically diverse elders recruited from a variety of sites in the urban Los Angeles area were enrolled in a randomized experiment involving a crossover design component. Within either the first or second 6-month phase of their study involvement, each elder received a lifestyle intervention designed to improve a variety of aging outcomes. At 4-5 time points over an 18-24 month interval, the research participants were assessed on measures of healthy activity, coping, social support, perceived control, stress-related biomarkers, perceived physical health, psychosocial well-being, and cognitive functioning to test the effectiveness of the intervention and document the process mechanisms responsible for its effects. The study protocol was successfully implemented, including the enrollment of study sites, the recruitment of 460 older adults, administration of the intervention, adherence to the plan for assessment, and establishment of a large computerized data base. Methodological challenges were encountered in the areas of site recruitment, participant recruitment, testing, and intervention delivery. The completion of clinical trials involving elders from numerous local sites requires careful oversight and anticipation of threats to the study design that stem from: (a) social situations that are particular to specific study sites; and (b) physical, functional, and social challenges pertaining to the elder population.

Randomized controlled trials of simulation-based interventions in Emergency Medicine: a methodological review.

PubMed

Chauvin, Anthony; Truchot, Jennifer; Bafeta, Aida; Pateron, Dominique; Plaisance, Patrick; Yordanov, Youri

2018-04-01

The number of trials assessing Simulation-Based Medical Education (SBME) interventions has rapidly expanded. Many studies show that potential flaws in design, conduct and reporting of randomized controlled trials (RCTs) can bias their results. We conducted a methodological review of RCTs assessing a SBME in Emergency Medicine (EM) and examined their methodological characteristics. We searched MEDLINE via PubMed for RCT that assessed a simulation intervention in EM, published in 6 general and internal medicine and in the top 10 EM journals. The Cochrane Collaboration risk of Bias tool was used to assess risk of bias, intervention reporting was evaluated based on the "template for intervention description and replication" checklist, and methodological quality was evaluated by the Medical Education Research Study Quality Instrument. Reports selection and data extraction was done by 2 independents researchers. From 1394 RCTs screened, 68 trials assessed a SBME intervention. They represent one quarter of our sample. Cardiopulmonary resuscitation (CPR) is the most frequent topic (81%). Random sequence generation and allocation concealment were performed correctly in 66 and 49% of trials. Blinding of participants and assessors was performed correctly in 19 and 68%. Risk of attrition bias was low in three-quarters of the studies (n = 51). Risk of selective reporting bias was unclear in nearly all studies. The mean MERQSI score was of 13.4/18.4% of the reports provided a description allowing the intervention replication. Trials assessing simulation represent one quarter of RCTs in EM. Their quality remains unclear, and reproducing the interventions appears challenging due to reporting issues.

Methodological issues in the design and analyses of neonatal research studies: Experience of the NICHD Neonatal Research Network.

PubMed

Das, Abhik; Tyson, Jon; Pedroza, Claudia; Schmidt, Barbara; Gantz, Marie; Wallace, Dennis; Truog, William E; Higgins, Rosemary D

2016-10-01

Impressive advances in neonatology have occurred over the 30 years of life of The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN). However, substantial room for improvement remains in investigating and further developing the evidence base for improving outcomes among the extremely premature. We discuss some of the specific methodological challenges in the statistical design and analysis of randomized trials and observational studies in this population. Challenges faced by the NRN include designing trials for unusual or rare outcomes, accounting for and explaining center variations, identifying other subgroup differences, and balancing safety and efficacy concerns between short-term hospital outcomes and longer-term neurodevelopmental outcomes. In conclusion, the constellation of unique patient characteristics in neonates calls for broad understanding and careful consideration of the issues identified in this article for conducting rigorous studies in this population. Copyright © 2016 Elsevier Inc. All rights reserved.

Usual and Unusual Care: Existing Practice Control Groups In Randomized Controlled Trials of Behavioral Interventions

PubMed Central

Freedland, Kenneth E.; Mohr, David C.; Davidson, Karina W.; Schwartz, Joseph E.

2011-01-01

Objective To examine the use of existing practice control groups in randomized controlled trials of behavioral interventions, and the role of extrinsic healthcare services in the design and conduct of behavioral trials. Method Selective qualitative review. Results Extrinsic healthcare services, also known as nonstudy care, have important but under-recognized effects on the design and conduct of behavioral trials. Usual care, treatment as usual, standard of care, and other existing practice control groups pose a variety of methodological and ethical challenges, but they play a vital role in behavioral intervention research. Conclusion This review highlights the need for a scientific consensus statement on control groups in behavioral trials. PMID:21536837

Usual and unusual care: existing practice control groups in randomized controlled trials of behavioral interventions.

PubMed

Freedland, Kenneth E; Mohr, David C; Davidson, Karina W; Schwartz, Joseph E

2011-05-01

To evaluate the use of existing practice control groups in randomized controlled trials of behavioral interventions and the role of extrinsic health care services in the design and conduct of behavioral trials. Selective qualitative review. Extrinsic health care services, also known as nonstudy care, have important but under-recognized effects on the design and conduct of behavioral trials. Usual care, treatment-as-usual, standard of care, and other existing practice control groups pose a variety of methodological and ethical challenges, but they play a vital role in behavioral intervention research. This review highlights the need for a scientific consensus statement on control groups in behavioral trials.

Biomarker-Guided Non-Adaptive Trial Designs in Phase II and Phase III: A Methodological Review

PubMed Central

Antoniou, Miranta; Kolamunnage-Dona, Ruwanthi; Jorgensen, Andrea L.

2017-01-01

Biomarker-guided treatment is a rapidly developing area of medicine, where treatment choice is personalised according to one or more of an individual’s biomarker measurements. A number of biomarker-guided trial designs have been proposed in the past decade, including both adaptive and non-adaptive trial designs which test the effectiveness of a biomarker-guided approach to treatment with the aim of improving patient health. A better understanding of them is needed as challenges occur both in terms of trial design and analysis. We have undertaken a comprehensive literature review based on an in-depth search strategy with a view to providing the research community with clarity in definition, methodology and terminology of the various biomarker-guided trial designs (both adaptive and non-adaptive designs) from a total of 211 included papers. In the present paper, we focus on non-adaptive biomarker-guided trial designs for which we have identified five distinct main types mentioned in 100 papers. We have graphically displayed each non-adaptive trial design and provided an in-depth overview of their key characteristics. Substantial variability has been observed in terms of how trial designs are described and particularly in the terminology used by different authors. Our comprehensive review provides guidance for those designing biomarker-guided trials. PMID:28125057

Bridging the gap in complementary and alternative medicine research: manualization as a means of promoting standardization and flexibility of treatment in clinical trials of acupuncture.

PubMed

Schnyer, Rosa N; Allen, John J B

2002-10-01

An important methodological challenge encountered in acupuncture clinical research involves the design of treatment protocols that help ensure standardization and replicability while allowing for the necessary flexibility to tailor treatments to each individual. Manualization of protocols used in clinical trials of acupuncture and other traditionally-based complementary and alternative medicine (CAM) systems facilitates the systematic delivery of replicable and standardized, yet individually-tailored treatments. To facilitate high-quality CAM acupuncture research by outlining a method for the systematic design and implementation of protocols used in CAM clinical trials based on the concept of treatment manualization. A series of treatment manuals was developed to systematically articulate the Chinese medical theoretical and clinical framework for a given Western-defined illness, to increase the quality and consistency of treatment, and to standardize the technical aspects of the protocol. In all, three manuals were developed for National Institutes of Health (NIH)-funded clinical trials of acupuncture for depression, spasticity in cerebral palsy, and repetitive stress injury. In Part I, the rationale underlying these manuals and the challenges encountered in creating them are discussed, and qualitative assessments of their utility are provided. In Part II, a methodology to develop treatment manuals for use in clinical trials is detailed, and examples are given. A treatment manual provides a precise way to train and supervise practitioners, enable evaluation of conformity and competence, facilitate the training process, and increase the ability to identify the active therapeutic ingredients in clinical trials of acupuncture.

Randomised trials comparing different healthcare settings: an exploratory review of the impact of pre-trial preferences on participation, and discussion of other methodological challenges.

PubMed

Corbett, Mark S; Watson, Judith; Eastwood, Alison

2016-10-19

We recently published a systematic review of different healthcare settings (such as outpatient, community or home) for administering intravenous chemotherapy, and concluded that performing conventionally designed randomised trials was difficult. The main problems were achieving adequate trial accrual rates and recruiting a study population which adequately represented the target population of interest. These issues stemmed from the fact that potential participants may have had pre-trial perceptions about the trial settings they may be allocated; such preferences will sometimes be strong enough for patients to decline an invitation to participate in a trial. A patient preference trial design (in which patients can choose, or be randomised to, an intervention) may have obviated these recruitment issues, although none of the trials used such a design. In order to gain a better understanding of the broader prevalence and extent of these preference issues (and any other methodological challenges), we undertook an exploratory review of settings trials in any area of healthcare treatment research. We searched The Cochrane Library and Google Scholar and used snowballing methods to identify trials comparing different healthcare settings. Trial accrual was affected by patient preferences for a setting in 15 of the 16 identified studies; birth setting trials were the most markedly affected, with between 68 % and 85 % of eligible women declining to participate specifically because of preference for a particular healthcare setting. Recruitment into substance abuse and chemotherapy setting studies was also notably affected by preferences. Only four trials used a preference design: the proportion of eligible patients choosing to participate via a preference group ranged from between 33 % and 67 %. In trials of healthcare settings, accrual may be seriously affected by patient preferences. The use of trial designs which incorporate a preference component should therefore strongly be considered. When designing such trials, investigators should consider settings to be complex interventions, which are likely to have linked components which may be difficult to control for. Careful thought is also needed regarding the choice of comparator settings and the most appropriate outcome measures to be used.

Methodological challenges for the evaluation of clinical effectiveness in the context of accelerated regulatory approval: an overview.

PubMed

Woolacott, Nerys; Corbett, Mark; Jones-Diette, Julie; Hodgson, Robert

2017-10-01

Regulatory authorities are approving innovative therapies with limited evidence. Although this level of data is sufficient for the regulator to establish an acceptable risk-benefit balance, it is problematic for downstream health technology assessment, where assessment of cost-effectiveness requires reliable estimates of effectiveness relative to existing clinical practice. Some key issues associated with a limited evidence base include using data, from nonrandomized studies, from small single-arm trials, or from single-center trials; and using surrogate end points. We examined these methodological challenges through a pragmatic review of the available literature. Methods to adjust nonrandomized studies for confounding are imperfect. The relative treatment effect generated from single-arm trials is uncertain and may be optimistic. Single-center trial results may not be generalizable. Surrogate end points, on average, overestimate treatment effects. Current methods for analyzing such data are limited, and effectiveness claims based on these suboptimal forms of evidence are likely to be subject to significant uncertainty. Assessments of cost-effectiveness, based on the modeling of such data, are likely to be subject to considerable uncertainty. This uncertainty must not be underestimated by decision makers: methods for its quantification are required and schemes to protect payers from the cost of uncertainty should be implemented. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Evaluation Study Design--A Pluralist Approach to Evidence

ERIC Educational Resources Information Center

Fives, Allyn; Canavan, John; Dolan, Pat

2017-01-01

There is significant controversy over what counts as evidence in the evaluation of social interventions. It is increasingly common to use methodological criteria to rank evidence types in a hierarchy, with Randomised Controlled Trials (RCTs) at or near the highest level. Because of numerous challenges to a hierarchical approach, this article…

Methodological challenges collecting parent phone-call healthcare utilization data.

PubMed

Moreau, Paula; Crawford, Sybil; Sullivan-Bolyai, Susan

2016-02-01

Recommendations by the National Institute of Nursing Research and other groups have strongly encouraged nurses to pay greater attention to cost-effectiveness analysis when conducting research. Given the increasing prominence of translational science and comparative effective research, cost-effective analysis has become a basic tool in determining intervention value in research. Tracking phone-call communication (number of calls and context) with cross-checks between parents and healthcare providers is an example of this type of healthcare utilization data collection. This article identifies some methodological challenges that have emerged in the process of collecting this type of data in a randomized controlled trial: Parent education Through Simulation-Diabetes (PETS-D). We also describe ways in which those challenges have been addressed with comparison data results, and make recommendations for future research. Copyright © 2015 Elsevier Inc. All rights reserved.

Bayesian network meta-analysis for cluster randomized trials with binary outcomes.

PubMed

Uhlmann, Lorenz; Jensen, Katrin; Kieser, Meinhard

2017-06-01

Network meta-analysis is becoming a common approach to combine direct and indirect comparisons of several treatment arms. In recent research, there have been various developments and extensions of the standard methodology. Simultaneously, cluster randomized trials are experiencing an increased popularity, especially in the field of health services research, where, for example, medical practices are the units of randomization but the outcome is measured at the patient level. Combination of the results of cluster randomized trials is challenging. In this tutorial, we examine and compare different approaches for the incorporation of cluster randomized trials in a (network) meta-analysis. Furthermore, we provide practical insight on the implementation of the models. In simulation studies, it is shown that some of the examined approaches lead to unsatisfying results. However, there are alternatives which are suitable to combine cluster randomized trials in a network meta-analysis as they are unbiased and reach accurate coverage rates. In conclusion, the methodology can be extended in such a way that an adequate inclusion of the results obtained in cluster randomized trials becomes feasible. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Post-trial follow-up methodology in large randomized controlled trials: a systematic review protocol.

PubMed

Llewellyn-Bennett, Rebecca; Bowman, Louise; Bulbulia, Richard

2016-12-15

Clinical trials typically have a relatively short follow-up period, and may both underestimate potential benefits of treatments investigated, and fail to detect hazards, which can take much longer to emerge. Prolonged follow-up of trial participants after the end of the scheduled trial period can provide important information on both efficacy and safety outcomes. This protocol describes a systematic review to qualitatively compare methods of post-trial follow-up used in large randomized controlled trials. A systematic search of electronic databases and clinical trial registries will use a predefined search strategy. All large (more than 1000 adult participants) randomized controlled trials will be evaluated. Two reviewers will screen and extract data according to this protocol with the aim of 95% concordance of papers checked and discrepancies will be resolved by a third reviewer. Trial methods, participant retention rates and prevalence of missing data will be recorded and compared. The potential for bias will be evaluated using the Cochrane Risk of Bias tool (applied to the methods used during the in-trial period) with the aim of investigating whether the quality of the post-trial follow-up methodology might be predicted by the quality of the methods used for the original trial. Post-trial follow-up can provide valuable information about the long-term benefits and hazards of medical interventions. However, it can be logistically challenging and costly. The aim of this systematic review is to describe how trial participants have been followed-up post-trial in order to inform future post-trial follow-up designs. Not applicable for PROSPERO registration.

Statistical Frequency-Dependent Analysis of Trial-to-Trial Variability in Single Time Series by Recurrence Plots.

PubMed

Tošić, Tamara; Sellers, Kristin K; Fröhlich, Flavio; Fedotenkova, Mariia; Beim Graben, Peter; Hutt, Axel

2015-01-01

For decades, research in neuroscience has supported the hypothesis that brain dynamics exhibits recurrent metastable states connected by transients, which together encode fundamental neural information processing. To understand the system's dynamics it is important to detect such recurrence domains, but it is challenging to extract them from experimental neuroscience datasets due to the large trial-to-trial variability. The proposed methodology extracts recurrent metastable states in univariate time series by transforming datasets into their time-frequency representations and computing recurrence plots based on instantaneous spectral power values in various frequency bands. Additionally, a new statistical inference analysis compares different trial recurrence plots with corresponding surrogates to obtain statistically significant recurrent structures. This combination of methods is validated by applying it to two artificial datasets. In a final study of visually-evoked Local Field Potentials in partially anesthetized ferrets, the methodology is able to reveal recurrence structures of neural responses with trial-to-trial variability. Focusing on different frequency bands, the δ-band activity is much less recurrent than α-band activity. Moreover, α-activity is susceptible to pre-stimuli, while δ-activity is much less sensitive to pre-stimuli. This difference in recurrence structures in different frequency bands indicates diverse underlying information processing steps in the brain.

Statistical Frequency-Dependent Analysis of Trial-to-Trial Variability in Single Time Series by Recurrence Plots

PubMed Central

Tošić, Tamara; Sellers, Kristin K.; Fröhlich, Flavio; Fedotenkova, Mariia; beim Graben, Peter; Hutt, Axel

2016-01-01

For decades, research in neuroscience has supported the hypothesis that brain dynamics exhibits recurrent metastable states connected by transients, which together encode fundamental neural information processing. To understand the system's dynamics it is important to detect such recurrence domains, but it is challenging to extract them from experimental neuroscience datasets due to the large trial-to-trial variability. The proposed methodology extracts recurrent metastable states in univariate time series by transforming datasets into their time-frequency representations and computing recurrence plots based on instantaneous spectral power values in various frequency bands. Additionally, a new statistical inference analysis compares different trial recurrence plots with corresponding surrogates to obtain statistically significant recurrent structures. This combination of methods is validated by applying it to two artificial datasets. In a final study of visually-evoked Local Field Potentials in partially anesthetized ferrets, the methodology is able to reveal recurrence structures of neural responses with trial-to-trial variability. Focusing on different frequency bands, the δ-band activity is much less recurrent than α-band activity. Moreover, α-activity is susceptible to pre-stimuli, while δ-activity is much less sensitive to pre-stimuli. This difference in recurrence structures in different frequency bands indicates diverse underlying information processing steps in the brain. PMID:26834580

Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

PubMed Central

Bogaerts, Jan; Sydes, Matthew R.; Keat, Nicola; McConnell, Andrea; Benson, Al; Ho, Alan; Roth, Arnaud; Fortpied, Catherine; Eng, Cathy; Peckitt, Clare; Coens, Corneel; Pettaway, Curtis; Arnold, Dirk; Hall, Emma; Marshall, Ernie; Sclafani, Francesco; Hatcher, Helen; Earl, Helena; Ray-Coquard, Isabelle; Paul, James; Blay, Jean-Yves; Whelan, Jeremy; Panageas, Kathy; Wheatley, Keith; Harrington, Kevin; Licitra, Lisa; Billingham, Lucinda; Hensley, Martee; McCabe, Martin; Patel, Poulam M.; Carvajal, Richard; Wilson, Richard; Glynne-Jones, Rob; McWilliams, Rob; Leyvraz, Serge; Rao, Sheela; Nicholson, Steve; Filiaci, Virginia; Negrouk, Anastassia; Lacombe, Denis; Dupont, Elisabeth; Pauporté, Iris; Welch, John J.; Law, Kate; Trimble, Ted; Seymour, Matthew

2015-01-01

Background The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. Settings The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional – usually randomised – clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. Results The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. Interpretation Trials can be designed using a wide array of possibilities. There is no ‘one size fits all’ solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases. PMID:25542058

Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative.

PubMed

Bogaerts, Jan; Sydes, Matthew R; Keat, Nicola; McConnell, Andrea; Benson, Al; Ho, Alan; Roth, Arnaud; Fortpied, Catherine; Eng, Cathy; Peckitt, Clare; Coens, Corneel; Pettaway, Curtis; Arnold, Dirk; Hall, Emma; Marshall, Ernie; Sclafani, Francesco; Hatcher, Helen; Earl, Helena; Ray-Coquard, Isabelle; Paul, James; Blay, Jean-Yves; Whelan, Jeremy; Panageas, Kathy; Wheatley, Keith; Harrington, Kevin; Licitra, Lisa; Billingham, Lucinda; Hensley, Martee; McCabe, Martin; Patel, Poulam M; Carvajal, Richard; Wilson, Richard; Glynne-Jones, Rob; McWilliams, Rob; Leyvraz, Serge; Rao, Sheela; Nicholson, Steve; Filiaci, Virginia; Negrouk, Anastassia; Lacombe, Denis; Dupont, Elisabeth; Pauporté, Iris; Welch, John J; Law, Kate; Trimble, Ted; Seymour, Matthew

2015-02-01

The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Smartphone app design for the wireless control of a neuromuscular electrical stimulator device with integrated randomization allocation process for RCT applications.

PubMed

Sweeney, Dean; Quinlan, Leo R; OLaighin, Gearoid

2015-08-01

The use of NMES has evolved over the last five decades. Technological advancements have transformed these once complex systems into user-friendly devices with enhanced control functions, leading to new applications of NMES being investigated. The use of Randomized Control Trial (RCT) methodology in evaluating the effectiveness of new and existing applications of NMES is a demanding process adding time and cost to a translation into clinical practice. Poor quality trials may result in poor evidence of NMES effectiveness. In this paper some of the key challenges encountered in NMES clinical trials are identified with the aim of purposing a solution to address these challenges through the adoption of Smartphone technology. The design and evaluation of a smartphone application to provide automatic blind randomization control and facilitating the wireless temporal control of a portable Bluetooth enabled NMES is presented.

Quality and methodological challenges in Internet-based mental health trials.

PubMed

Ye, Xibiao; Bapuji, Sunita Bayyavarapu; Winters, Shannon; Metge, Colleen; Raynard, Mellissa

2014-08-01

To review the quality of Internet-based mental health intervention studies and their methodological challenges. We searched multiple literature databases to identify relevant studies according to the Population, Interventions, Comparators, Outcomes, and Study Design framework. Two reviewers independently assessed selection bias, allocation bias, confounding bias, blinding, data collection methods, and withdrawals/dropouts, using the Quality Assessment Tool for Quantitative Studies. We rated each component as strong, moderate, or weak and assigned a global rating (strong, moderate, or weak) to each study. We discussed methodological issues related to the study quality. Of 122 studies included, 31 (25%), 44 (36%), and 47 (39%) were rated strong, moderate, and weak, respectively. Only five studies were rated strong for all of the six quality components (three of them were published by the same group). Lack of blinding, selection bias, and low adherence were the top three challenges in Internet-based mental health intervention studies. The overall quality of Internet-based mental health intervention needs to improve. In particular, studies need to improve sample selection, intervention allocation, and blinding.

Methodology for a trial of brain-centered versus anticholinergic therapy in women with urgency urinary incontinence.

PubMed

Komesu, Yuko M; Rogers, Rebecca G; Sapien, Robert E; Schrader, Ronald M; Simmerman-Sierra, Timothy; Mayer, Andrew R; Ketai, Loren H

2017-06-01

We describe the rationale and methodology for a study comparing mind-body treatment and pharmacotherapy in women with urgency urinary incontinence (UUI). To explore brain associations in UUI, a subset of patients will also undergo functional magnetic resonance imaging (fMRI). We hypothesize that hypnotherapy, a mind-body intervention, will be at least as effective as pharmacotherapy in treating UUI. We also hypothesize that fMRI findings will change following treatment, with changes potentially differing between groups. We describe the development and design challenges of a study comparing the efficacy of hypnotherapy and conventional pharmacotherapy in the treatment of UUI. The study randomizes women to either of these treatments, and outcome measures include bladder diaries and validated questionnaires. Sample size estimates, based on a noninferiority test (alpha = 0.025, beta = 0.20), after considering dropout subjects and subjects lost to follow-up, indicated that approximately 150 woman would be required to test the hypothesis that hypnotherapy is not inferior to pharmacotherapy within a 5 % noninferiority margin. The study will also evaluate fMRI changes in a subset of participants before and after therapy. Challenges included designing a study with a mind-body therapy and a comparison treatment equally acceptable to participants, standardizing the interventions, and confronting the reality that trials are time-consuming for participants who have to make appropriate accommodations in their schedule. Study enrollment began in March 2013 and is ongoing. We describe the design of a randomized controlled trial comparing mind-body therapy and pharmacotherapy in the treatment of UUI and the challenges encountered in its implementation.

Methodology for astronaut reconditioning research.

PubMed

Beard, David J; Cook, Jonathan A

2017-01-01

Space medicine offers some unique challenges, especially in terms of research methodology. A specific challenge for astronaut reconditioning involves identification of what aspects of terrestrial research methodology hold and which require modification. This paper reviews this area and presents appropriate solutions where possible. It is concluded that spaceflight rehabilitation research should remain question/problem driven and is broadly similar to the terrestrial equivalent on small populations, such as rare diseases and various sports. Astronauts and Medical Operations personnel should be involved at all levels to ensure feasibility of research protocols. There is room for creative and hybrid methodology but careful systematic observation is likely to be more achievable and fruitful than complex trial based comparisons. Multi-space agency collaboration will be critical to pool data from small groups of astronauts with the accepted use of standardised outcome measures across all agencies. Systematic reviews will be an essential component. Most limitations relate to the inherent small sample size available for human spaceflight research. Early adoption of a co-operative model for spaceflight rehabilitation research is therefore advised. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Non-pharmacological, non-technical treatments for musculoskeletal disease: methodological challenges of clinical trials using the example of knee osteoarthritis and falls in the elderly].

PubMed

Thiem, Ulrich; Trampisch, Ulrike; Trampisch, Hans-Joachim

2013-01-01

Physical therapy modalities are regarded as an integral part of the treatment of musculoskeletal diseases like osteoarthritis of the knee or falls in the elderly. Guidelines and treatment recommendations promote such interventions. However, the evidence supporting physical therapy modalities is often weaker than that found for drug treatments. One reason is that a simple blinding of treatment assignments by means of a placebo is usually not possible. Another issue is patient preferences that have an impact on the conduct of the study and the interpretation of the results. This article highlights methodological challenges of studies investigating physical therapy modalities, and points out some possible solutions. (As supplied by publisher). Copyright © 2013. Published by Elsevier GmbH.

Methodological Challenges of Multiple-Component Intervention: Lessons Learned from a Randomized Controlled Trial of Functional Recovery After Hip Fracture

PubMed Central

Peterson, Margaret G.E.; Cornell, Charles N.; MacKenzie, C. Ronald; Robbins, Laura; Horton, Roberta; Ganz, Sandy B.; Ruchlin, Hirsch S.; Russo, Pamela Williams; Paget, Stephen A.; Charlson, Mary E.

2006-01-01

We conducted a randomized controlled trial to assess the efficacy and safety of a multiple-component intervention designed to improve functional recovery after hip fracture. One hundred seventy-six patients who underwent surgery for a primary unilateral hip fracture were assigned randomly to receive usual care (control arm, n = 86) or a brief motivational videotape, supportive peer counseling, and high-intensity muscle-strength training (intervention arm, n = 90). Between-group differences on the physical functioning, role-physical, and social functioning domains of the SF-36 were assessed postoperatively at 6 months. At the end of the trial, 32 intervention and 27 control patients (34%) completed the 6-month outcome assessment. Although patient compliance with all three components of the intervention was uneven, over 90% of intervention patients were exposed to the motivational videotape. Intervention patients experienced a significant (P = 0.03) improvement in the role-physical domain (mean change, −11 ± 33) compared to control patients (mean change, −37 ± 41). Change in general health (P = 0.2) and mental health (P = 0.1) domain scores was also directionally consistent with the study hypothesis. Although our findings are consistent with previous reports of comprehensive rehabilitation efforts for hip fracture patients, the trial was undermined by high attrition and the possibility of self-selection bias at 6-month follow-up. We discuss the methodological challenges and lessons learned in conducting a randomized controlled trial that sought to implement and assess the impact of a complex intervention in a population that proved difficult to follow up once they had returned to the community. PMID:18751772

Methodological and Ethical Issues in Pediatric Medication Safety Research.

PubMed

Carpenter, Delesha; Gonzalez, Daniel; Retsch-Bogart, George; Sleath, Betsy; Wilfond, Benjamin

2017-09-01

In May 2016, the Eshelman School of Pharmacy at The University of North Carolina at Chapel Hill convened the PharmSci conference to address the topic of "methodological and ethical issues in pediatric medication safety research." A multidisciplinary group of experts representing a diverse array of perspectives, including those of the US Food and Drug Administration, children's hospitals, and academia, identified important considerations for pediatric medication safety research and opportunities to advance the field. This executive summary describes current challenges that clinicians and researchers encounter related to pediatric medication safety research and identifies innovative and ethically sound methodologies to address these challenges to improve children's health. This article addresses 5 areas: (1) pediatric drug development and drug trials; (2) conducting comparative effectiveness research in pediatric populations; (3) child and parent engagement on study teams; (4) improving communication with children and parents; and (5) assessing child-reported outcomes and adverse drug events. Copyright © 2017 by the American Academy of Pediatrics.

Design and methodological considerations of an effectiveness trial of a computer-assisted intervention: an example from the NIDA Clinical Trials Network.

PubMed

Campbell, Aimee N C; Nunes, Edward V; Miele, Gloria M; Matthews, Abigail; Polsky, Daniel; Ghitza, Udi E; Turrigiano, Eva; Bailey, Genie L; VanVeldhuisen, Paul; Chapdelaine, Rita; Froias, Autumn; Stitzer, Maxine L; Carroll, Kathleen M; Winhusen, Theresa; Clingerman, Sara; Perez, Livangelie; McClure, Erin; Goldman, Bruce; Crowell, A Rebecca

2012-03-01

Computer-assisted interventions hold the promise of minimizing two problems that are ubiquitous in substance abuse treatment: the lack of ready access to treatment and the challenges to providing empirically-supported treatments. Reviews of research on computer-assisted treatments for mental health and substance abuse report promising findings, but study quality and methodological limitations remain an issue. In addition, relatively few computer-assisted treatments have been tested among illicit substance users. This manuscript describes the methodological considerations of a multi-site effectiveness trial conducted within the National Institute on Drug Abuse's (NIDA's) National Drug Abuse Treatment Clinical Trials Network (CTN). The study is evaluating a web-based version of the Community Reinforcement Approach, in addition to prize-based contingency management, among 500 participants enrolled in 10 outpatient substance abuse treatment programs. Several potential effectiveness trial designs were considered and the rationale for the choice of design in this study is described. The study uses a randomized controlled design (with independent treatment arm allocation), intention-to-treat primary outcome analysis, biological markers for the primary outcome of abstinence, long-term follow-up assessments, precise measurement of intervention dose, and a cost-effectiveness analysis. Input from community providers during protocol development highlighted potential concerns and helped to address issues of practicality and feasibility. Collaboration between providers and investigators supports the utility of infrastructures that enhance research partnerships to facilitate effectiveness trials and dissemination of promising, technologically innovative treatments. Outcomes from this study will further the empirical knowledge base on the effectiveness and cost-effectiveness of computer-assisted treatment in clinical treatment settings. Copyright © 2011 Elsevier Inc. All rights reserved.

Design and Methodological Considerations of an Effectiveness Trial of a Computer-assisted Intervention: An Example from the NIDA Clinical Trials Network

PubMed Central

Campbell, Aimee N. C.; Nunes, Edward V.; Miele, Gloria M.; Matthews, Abigail; Polsky, Daniel; Ghitza, Udi E.; Turrigiano, Eva; Bailey, Genie L.; VanVeldhuisen, Paul; Chapdelaine, Rita; Froias, Autumn; Stitzer, Maxine L.; Carroll, Kathleen M.; Winhusen, Theresa; Clingerman, Sara; Perez, Livangelie; McClure, Erin; Goldman, Bruce; Crowell, A. Rebecca

2011-01-01

Computer-assisted interventions hold the promise of minimizing two problems that are ubiquitous in substance abuse treatment: the lack of ready access to treatment and the challenges to providing empirically-supported treatments. Reviews of research on computer-assisted treatments for mental health and substance abuse report promising findings, but study quality and methodological limitations remain an issue. In addition, relatively few computer-assisted treatments have been tested among illicit substance users. This manuscript describes the methodological considerations of a multi-site effectiveness trial conducted within the National Institute on Drug Abuse's (NIDA's) National Drug Abuse Treatment Clinical Trials Network (CTN). The study is evaluating a web-based version of the Community Reinforcement Approach, in addition to prize-based contingency management, among 500 participants enrolled in 10 outpatient substance abuse treatment programs. Several potential effectiveness trial designs were considered and the rationale for the choice of design in this study is described. The study uses a randomized controlled design (with independent treatment arm allocation), intention-to-treat primary outcome analysis, biological markers for the primary outcome of abstinence, long-term follow-up assessments, precise measurement of intervention dose, and a cost-effectiveness analysis. Input from community providers during protocol development highlighted potential concerns and helped to address issues of practicality and feasibility. Collaboration between providers and investigators supports the utility of infrastructures that enhance research partnerships to facilitate effectiveness trials and dissemination of promising, technologically innovative treatments. Outcomes from this study will further the empirical knowledge base on the effectiveness and cost-effectiveness of computer-assisted treatment in clinical treatment settings. PMID:22085803

Directions for new developments on statistical design and analysis of small population group trials.

PubMed

Hilgers, Ralf-Dieter; Roes, Kit; Stallard, Nigel

2016-06-14

Most statistical design and analysis methods for clinical trials have been developed and evaluated where at least several hundreds of patients could be recruited. These methods may not be suitable to evaluate therapies if the sample size is unavoidably small, which is usually termed by small populations. The specific sample size cut off, where the standard methods fail, needs to be investigated. In this paper, the authors present their view on new developments for design and analysis of clinical trials in small population groups, where conventional statistical methods may be inappropriate, e.g., because of lack of power or poor adherence to asymptotic approximations due to sample size restrictions. Following the EMA/CHMP guideline on clinical trials in small populations, we consider directions for new developments in the area of statistical methodology for design and analysis of small population clinical trials. We relate the findings to the research activities of three projects, Asterix, IDeAl, and InSPiRe, which have received funding since 2013 within the FP7-HEALTH-2013-INNOVATION-1 framework of the EU. As not all aspects of the wide research area of small population clinical trials can be addressed, we focus on areas where we feel advances are needed and feasible. The general framework of the EMA/CHMP guideline on small population clinical trials stimulates a number of research areas. These serve as the basis for the three projects, Asterix, IDeAl, and InSPiRe, which use various approaches to develop new statistical methodology for design and analysis of small population clinical trials. Small population clinical trials refer to trials with a limited number of patients. Small populations may result form rare diseases or specific subtypes of more common diseases. New statistical methodology needs to be tailored to these specific situations. The main results from the three projects will constitute a useful toolbox for improved design and analysis of small population clinical trials. They address various challenges presented by the EMA/CHMP guideline as well as recent discussions about extrapolation. There is a need for involvement of the patients' perspective in the planning and conduct of small population clinical trials for a successful therapy evaluation.

Methodology for a Trial of Brain-Centered versus Anti-cholinergic Therapy for Women with Urgency Urinary Incontinence

PubMed Central

Komesu, Yuko M.; Ketai, Loren H.; Sapien, Robert E.; Rogers, Rebecca G.; Schrader, Ronald M.; Simmerman-Sierra, Timothy; Mayer, Andrew R.

2016-01-01

Introduction This paper describes the rationale and methodology a study which investigates mind-body treatment versus pharmacotherapy for women with urgency urinary incontinence (UUI). To explore brain associations in UUI, a subset of patients will also undergo functional magnetic resonance imaging (fMRI). We hypothesize that hypnotherapy a mind-body intervention, will be at least as effective pharmacotherapy in treating UUI. We also hypothesize that fMRI findings will change following treatment, with changes potentially differing between groups. Methods The purpose of this manuscript is to recount the development and design challenges of a study evaluating the efficacy of hypnotherapy compared to conventional pharmacotherapy in UUI treatment. The study randomizes women to either of these treatments and outcome measures include bladder diaries and validated questionnaires. Sample size estimates, based on a non-inferiority test (alpha=.025, beta=0.20), after considering drop-out/loss to follow-up, indicated approximately 150 woman would be required to test the hypothesis that hypnotherapy is non-inferior to pharmacotherapy within a 5% non-inferiority margin. The study will also evaluate fMRI change in a subset of participants before and after therapy. Study challenges included designing a study with a mind-body therapy and a comparison treatment equally acceptable to participants, standardizing the interventions, confronting the reality that trials are time-consuming for participants and making appropriate accommodations. Results Study enrollment began March 2013 and is ongoing. Conclusions This manuscript details the design a of randomized controlled trial (RCT) comparing mind-body therapy to medications in treatment of UUI and describes the challenges encountered in its planning. PMID:27752750

Regulatory Scientific Advice on Non-Inferiority Drug Trials

PubMed Central

Knol, Mirjam J.; Klungel, Olaf H.; Gispen-De Wied, Christine C.; de Boer, Antonius; Hoes, Arno W.; Leufkens, Hubert G.; Mantel-Teeuwisse, Aukje K.

2013-01-01

The active-controlled trial with a non-inferiority design has gained popularity in recent years. However, non-inferiority trials present some methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how a non-inferiority trial should be conducted. Moreover, in a scientific advice procedure, regulators give companies the opportunity to discuss critical trial issues prior to the start of the trial. The aim of this study was to identify potential issues that may benefit from more explicit guidance by regulators. To achieve this, we collected and analyzed questions about non-inferiority trials posed by applicants for scientific advice in Europe in 2008 and 2009, as well as the responses given by the European Medicines Agency (EMA). In our analysis we included 156 final letters of advice from 2008 and 2009, addressed to 94 different applicants (manufacturers). Our analysis yielded two major findings: (1) applicants frequently asked questions ‘whether’ and ‘how’ to conduct a non-inferiority trial, 26% and 74%, respectively, and (2) the EMA regulators seem mainly concerned about the choice of the non-inferiority margin in non-inferiority trials (36% of total regulatory answers). In 40% of the answers, the EMA recommended using a stricter margin, and in 10% of the answers regarding non-inferiority margins, the EMA questioned the justification of the proposed non-inferiority margin. We conclude that there are still difficulties in selecting the appropriate methodology for non-inferiority trials. Straightforward and harmonized guidance regarding non-inferiority trials is required, for example on whether it is necessary to conduct such a trial and how the non-inferiority margin is determined. It is unlikely that regulatory guidelines can cover all therapeutic areas; therefore, in some cases regulatory scientific advice may be used as an opportunity for tailored advice. PMID:24040346

Emerging and recurrent issues in drug development.

PubMed

Anello, C

This paper reviews several emerging and recurrent issues relating to the drug development process. These emerging issues include changes to the FDA regulatory environment, internationalization of drug development, advances in computer technology and visualization tools, and efforts to incorporate meta-analysis methodology. Recurrent issues include: renewed interest in statistical methods for handling subgroups in the design and analysis of clinical trials; renewed interest in alternatives to the 'intention-to-treat' analysis in the presence of non-compliance in randomized clinical trials; renewed interest in methodology to address the multiplicities resulting from a variety of sources inherent in the drug development process, and renewed interest in methods to assure data integrity. These emerging and recurrent issues provide a continuing challenge to the international community of statisticians involved in drug development. Moreover, the involvement of statisticians with different perspectives continues to enrich the field and contributes to improvement in the public health.

Guiding Blind Pedestrians with a Personal Navigation System

NASA Astrophysics Data System (ADS)

Dodson, A. H.; Moon, G. V.; Moore, T.; Jones, D.

With the assistance provided by the white cane or guide dog, most blind pedestrians can find their way to known destinations along familiar routes. Finding new or known destinations along unfamiliar routes is more challenging. Before such a journey is attempted, detailed instructions must be acquired. The difficulty of obtaining and then reliably following such instructions deters many blind pedestrians from travelling alone in unknown areas. This paper demonstrates a technological approach, by way of field trials, that supplements the existing aids and eliminates the need for sighted guides. The approach has the potential to offer greater independence to the blind person. The investigation suggests that the methodology used in personal navigation systems for the sighted is sub-optimal for guiding the blind pedestrian. Suitable extensions are introduced, and the results show the proposed methodology is efficient for guiding the blind individual to unknown destinations in the chosen field trial environment.

Optimizing Clinical Trial Enrollment Methods Through "Goal Programming"

PubMed Central

Davis, J.M.; Sandgren, A.J.; Manley, A.R.; Daleo, M.A.; Smith, S.S.

2014-01-01

Introduction Clinical trials often fail to reach desired goals due to poor recruitment outcomes, including low participant turnout, high recruitment cost, or poor representation of minorities. At present, there is limited literature available to guide recruitment methodology. This study, conducted by researchers at the University of Wisconsin Center for Tobacco Research and Intervention (UW-CTRI), provides an example of how iterative analysis of recruitment data may be used to optimize recruitment outcomes during ongoing recruitment. Study methodology UW-CTRI’s research team provided a description of methods used to recruit smokers in two randomized trials (n = 196 and n = 175). The trials targeted low socioeconomic status (SES) smokers and involved time-intensive smoking cessation interventions. Primary recruitment goals were to meet required sample size and provide representative diversity while working with limited funds and limited time. Recruitment data was analyzed repeatedly throughout each study to optimize recruitment outcomes. Results Estimates of recruitment outcomes based on prior studies on smoking cessation suggested that researchers would be able to recruit 240 low SES smokers within 30 months at a cost of $72,000. With employment of methods described herein, researchers were able to recruit 374 low SES smokers over 30 months at a cost of $36,260. Discussion Each human subjects study presents unique recruitment challenges with time and cost of recruitment dependent on the sample population and study methodology. Nonetheless, researchers may be able to improve recruitment outcomes though iterative analysis of recruitment data and optimization of recruitment methods throughout the recruitment period. PMID:25642125

Antidepressant Efficacy for Depression in Children and Adolescents: Industry- and NIMH-Funded Studies.

PubMed

Walkup, John T

2017-05-01

Significant controversy surrounds the efficacy of the newer antidepressants for children and adolescents with depression. The controversy largely hinges on meta-analyses of studies that suggest that antidepressants are minimally effective, not effective, or equivalent to placebo. In this review, the author discusses several scientific and clinical complexities that are important to understand in reviewing the antidepressant literature: the strengths and weaknesses of meta-analyses; the scientific and regulatory context for the large number of antidepressant trials in the late 1990s and early 2000s; and the distinction between a negative trial, where the treatment does not demonstrate efficacy, and a failed trial, where methodological problems make it impossible to draw any conclusion about efficacy. It is the premise of this review that meta-analyses that include the large number of industry-sponsored antidepressant trials distort the picture of antidepressant efficacy for teen depression. Industry-sponsored child and adolescent depression trials suffer from a number of implementation challenges and should be considered failed trials that are largely uninformative and not eligible to be included in efficacy meta-analyses. In contrast to the industry-sponsored trials, depression trials funded by the National Institute of Mental Health (NIMH) (N=2) are characterized by many methodological strengths, lower placebo response rates (30%-35%), and meaningful between-group differences (25%-30%) that support antidepressant efficacy. The NIMH-funded trials, taken together with the demonstrated efficacy of the serotonin reuptake inhibitors for childhood-onset obsessive-compulsive disorder and the anxiety disorders, suggest a broad and important role for antidepressant medications in pediatric internalizing conditions.

New scoring methodology improves the sensitivity of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) in clinical trials.

PubMed

Verma, Nishant; Beretvas, S Natasha; Pascual, Belen; Masdeu, Joseph C; Markey, Mia K

2015-11-12

As currently used, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) has low sensitivity for measuring Alzheimer's disease progression in clinical trials. A major reason behind the low sensitivity is its sub-optimal scoring methodology, which can be improved to obtain better sensitivity. Using item response theory, we developed a new scoring methodology (ADAS-CogIRT) for the ADAS-Cog, which addresses several major limitations of the current scoring methodology. The sensitivity of the ADAS-CogIRT methodology was evaluated using clinical trial simulations as well as a negative clinical trial, which had shown an evidence of a treatment effect. The ADAS-Cog was found to measure impairment in three cognitive domains of memory, language, and praxis. The ADAS-CogIRT methodology required significantly fewer patients and shorter trial durations as compared to the current scoring methodology when both were evaluated in simulated clinical trials. When validated on data from a real clinical trial, the ADAS-CogIRT methodology had higher sensitivity than the current scoring methodology in detecting the treatment effect. The proposed scoring methodology significantly improves the sensitivity of the ADAS-Cog in measuring progression of cognitive impairment in clinical trials focused in the mild-to-moderate Alzheimer's disease stage. This provides a boost to the efficiency of clinical trials requiring fewer patients and shorter durations for investigating disease-modifying treatments.

Suspected Nonceliac Gluten Sensitivity Confirmed in Few Patients After Gluten Challenge in Double-Blind, Placebo-Controlled Trials.

PubMed

Molina-Infante, Javier; Carroccio, Antonio

2017-03-01

A double-blind, placebo-controlled, gluten challenge has been proposed to confirm a diagnosis of nonceliac gluten sensitivity (NCGS) in patients without celiac disease who respond to a gluten-free diet. To determine the accuracy of this approach, we analyzed data from 10 double-blind, placebo-controlled, gluten-challenge trials, comprising 1312 adults. The studies varied in the duration of the challenge (range, 1 d to 6 wk), daily doses for the gluten challenge (range, 2-52 g; 3 studies administered <8 g/d), and composition of the placebo (gluten-free products, xylose, whey protein, rice, or corn starch containing fermentable carbohydrates). Most of the studies found gluten challenge to significantly increase symptom scores compared with placebo. However, only 38 of 231 NCGS patients (16%) showed gluten-specific symptoms. Furthermore, 40% of these subjects had a nocebo response (similar or increased symptoms in response to placebo). These findings reveal heterogeneity and potential methodology flaws among studies of gluten challenge, cast doubt on gluten as the culprit food component in most patients with presumptive NCGS, and highlight the importance of the nocebo effect in these types of studies. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Challenges with cost-utility analyses of behavioural interventions among older adults at risk for dementia.

PubMed

Davis, Jennifer C; Bryan, Stirling; Marra, Carlo A; Hsiung, Ging-Yuek R; Liu-Ambrose, Teresa

2015-10-01

Cognitive decline is one of the most prominent healthcare issues of the 21st century. Within the context of combating cognitive decline through behavioural interventions, physical activity is a promising approach. There is a dearth of health economic data in the area of behavioural interventions for dementia prevention. Yet, economic evaluations are essential for providing information to policy makers for resource allocation. It is essential we first address population and intervention-specific methodological challenges prior to building a larger evidence base. We use a cost-utility analysis conducted alongside the exercise for cognition and everyday living (EXCEL) study to illustrate methodological challenges specific to assessing the cost-effectiveness of behavioural interventions aimed at older adults at risk of cognitive decline. A cost-utility analysis conducted concurrently with a 6-month, three-arm randomised controlled trial (ie, the EXCEL study) was used as an example to identify and discuss methodological challenges. Both the aerobic training and resistance training interventions were less costly than twice weekly balance and tone classes. In critically evaluating the economic evaluation of the EXCEL study we identified four category-specific challenges: (1) analysing costs; (2) assessing quality-adjusted life-years; (3) Incomplete data; and (4) 'Intervention' activities of the control group. Resistance training and aerobic training resulted in healthcare cost saving and were equally effective to balance and tone classes after only 6 months of intervention. To ensure this population is treated fairly in terms of claims on resources, we first need to identify areas for methodological improvement. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

An overview of the impact of rare disease characteristics on research methodology.

PubMed

Whicher, Danielle; Philbin, Sarah; Aronson, Naomi

2018-01-19

About 30 million individuals in the United States are living with a rare disease, which by definition have a prevalence of 200,000 or fewer cases in the United States ([National Organization for Rare Disorders], [About NORD], [2016]). Disease heterogeneity and geographic dispersion add to the difficulty of completing robust studies in small populations. Improving the ability to conduct research on rare diseases would have a significant impact on population health. The purpose of this paper is to raise awareness of methodological approaches that can address the challenges to conducting robust research on rare diseases. We conducted a landscape review of available methodological and analytic approaches to address the challenges of rare disease research. Our objectives were to: 1. identify algorithms for matching study design to rare disease attributes and the methodological approaches applicable to these algorithms; 2. draw inferences on how research communities and infrastructure can contribute to the efficiency of research on rare diseases; and 3. to describe methodological approaches in the rare disease portfolio of the Patient-Centered Outcomes Research Institute (PCORI), a funder promoting both rare disease research and research infrastructure. We identified three algorithms for matching study design to rare disease or intervention characteristics (Gagne, et.al, BMJ 349:g6802, 2014); (Gupta, et.al, J Clin Epidemiol 64:1085-1094, 2011); (Cornu, et. al, Orphet J Rare Dis 8:48,2012) and summarized the applicable methodological and analytic approaches. From this literature we were also able to draw inferences on how an effective research infrastructure can set an agenda, prioritize studies, accelerate accrual, catalyze patient engagement and terminate poorly performing studies. Of the 24 rare disease projects in the PCORI portfolio, 11 are randomized controlled trials (RCTs) using standard designs. Thirteen are observational studies using case-control, prospective cohort, or natural history designs. PCORI has supported the development of 9 Patient-Powered Research Networks (PPRNs) focused on rare diseases. Matching research design to attributes of rare diseases and interventions can facilitate the completion of RCTs that are adequately powered. An effective research infrastructure can improve efficiency and avoid waste in rare disease research. Our review of the PCORI research portfolio demonstrates that it is feasible to conduct RCTs in rare disease. However, most of these studies are using standard RCT designs. This suggests that use of a broader array of methodological approaches to RCTs --such as adaptive trials, cross-over trials, and early escape designs can improve the productivity of robust research in rare diseases.

Methods for a multicenter randomized trial for mixed urinary incontinence: rationale and patient-centeredness of the ESTEEM trial.

PubMed

Sung, Vivian W; Borello-France, Diane; Dunivan, Gena; Gantz, Marie; Lukacz, Emily S; Moalli, Pamela; Newman, Diane K; Richter, Holly E; Ridgeway, Beri; Smith, Ariana L; Weidner, Alison C; Meikle, Susan

2016-10-01

Mixed urinary incontinence (MUI) can be a challenging condition to manage. We describe the protocol design and rationale for the Effects of Surgical Treatment Enhanced with Exercise for Mixed Urinary Incontinence (ESTEEM) trial, designed to compare a combined conservative and surgical treatment approach versus surgery alone for improving patient-centered MUI outcomes at 12 months. ESTEEM is a multisite, prospective, randomized trial of female participants with MUI randomized to a standardized perioperative behavioral/pelvic floor exercise intervention plus midurethral sling versus midurethral sling alone. We describe our methods and four challenges encountered during the design phase: defining the study population, selecting relevant patient-centered outcomes, determining sample size estimates using a patient-reported outcome measure, and designing an analysis plan that accommodates MUI failure rates. A central theme in the design was patient centeredness, which guided many key decisions. Our primary outcome is patient-reported MUI symptoms measured using the Urogenital Distress Inventory (UDI) score at 12 months. Secondary outcomes include quality of life, sexual function, cost-effectiveness, time to failure, and need for additional treatment. The final study design was implemented in November 2013 across eight clinical sites in the Pelvic Floor Disorders Network. As of 27 February 2016, 433 total/472 targeted participants had been randomized. We describe the ESTEEM protocol and our methods for reaching consensus for methodological challenges in designing a trial for MUI by maintaining the patient perspective at the core of key decisions. This trial will provide information that can directly impact patient care and clinical decision making.

Patient-Reported Outcomes and Survivorship in Radiation Oncology: Overcoming the Cons

PubMed Central

Siddiqui, Farzan; Liu, Arthur K.; Watkins-Bruner, Deborah; Movsas, Benjamin

2014-01-01

Purpose Although patient-reported outcomes (PROs) have become a key component of clinical oncology trials, many challenges exist regarding their optimal application. The goal of this article is to methodically review these barriers and suggest strategies to overcome them. This review will primarily focus on radiation oncology examples, will address issues regarding the “why, how, and what” of PROs, and will provide strategies for difficult problems such as methods for reducing missing data. This review will also address cancer survivorship because it closely relates to PROs. Methods Key articles focusing on PROs, quality of life, and survivorship issues in oncology trials are highlighted, with an emphasis on radiation oncology clinical trials. Publications and Web sites of various governmental and regulatory agencies are also reviewed. Results The study of PROs in clinical oncology trials has become well established. There are guidelines provided by organizations such as the US Food and Drug Administration that clearly indicate the importance of and methodology for studying PROs. Clinical trials in oncology have repeatedly demonstrated the value of studying PROs and suggested ways to overcome some of the key challenges. The Radiation Therapy Oncology Group (RTOG) has led some of these efforts, and their contributions are highlighted. The current state of cancer survivorship guidelines is also discussed. Conclusion The study of PROs presents significant benefits in understanding and treating toxicities and enhancing quality of life; however, challenges remain. Strategies are presented to overcome these hurdles, which will ultimately improve cancer survivorship. PMID:25113760

Meeting the Challenge of Doing an RCT Evaluation of Youth Mentoring in Ireland: A Journey in Mixed Methods

ERIC Educational Resources Information Center

Brady, Bernadine; O'Regan, Connie

2009-01-01

The youth mentoring program Big Brothers Big Sisters is one of the first social interventions involving youth in Ireland to be evaluated using a randomized controlled trial methodology. This article sets out the design process undertaken, describing how the research team came to adopt a concurrent embedded mixed methods design as a means of…

Methodological quality of randomized trials published in the Journal of the American Podiatric Medical Association, 1999-2013.

PubMed

Landorf, Karl B; Menz, Hylton B; Armstrong, David G; Herbert, Robert D

2015-07-01

Randomized trials must be of high methodological quality to yield credible, actionable findings. The main aim of this project was to evaluate whether there has been an improvement in the methodological quality of randomized trials published in the Journal of the American Podiatric Medical Association (JAPMA). Randomized trials published in JAPMA during a 15-year period (January 1999 to December 2013) were evaluated. The methodological quality of randomized trials was evaluated using the PEDro scale (scores range from 0 to 10, with 0 being lowest quality). Linear regression was used to assess changes in methodological quality over time. A total of 1,143 articles were published in JAPMA between January 1999 and December 2013. Of these, 44 articles were reports of randomized trials. Although the number of randomized trials published each year increased, there was only minimal improvement in their methodological quality (mean rate of improvement = 0.01 points per year). The methodological quality of the trials studied was typically moderate, with a mean ± SD PEDro score of 5.1 ± 1.5. Although there were a few high-quality randomized trials published in the journal, most (84.1%) scored between 3 and 6. Although there has been an increase in the number of randomized trials published in JAPMA, there is substantial opportunity for improvement in the methodological quality of trials published in the journal. Researchers seeking to publish reports of randomized trials should seek to meet current best-practice standards in the conduct and reporting of their trials.

METHODOLOGICAL QUALITY OF ECONOMIC EVALUATIONS ALONGSIDE TRIALS OF KNEE PHYSIOTHERAPY.

PubMed

García-Pérez, Lidia; Linertová, Renata; Arvelo-Martín, Alejandro; Guerra-Marrero, Carolina; Martínez-Alberto, Carlos Enrique; Cuéllar-Pompa, Leticia; Escobar, Antonio; Serrano-Aguilar, Pedro

2017-01-01

The methodological quality of an economic evaluation performed alongside a clinical trial can be underestimated if the paper does not report key methodological features. This study discusses methodological assessment issues on the example of a systematic review on cost-effectiveness of physiotherapy for knee osteoarthritis. Six economic evaluation studies included in the systematic review and related clinical trials were assessed using the 10-question check-list by Drummond and the Physiotherapy Evidence Database (PEDro) scale. All economic evaluations were performed alongside a clinical trial but the studied interventions were too heterogeneous to be synthesized. Methodological quality of the economic evaluations reported in the papers was not free of drawbacks, and in some cases, it improved when information from the related clinical trial was taken into account. Economic evaluation papers dedicate little space to methodological features of related clinical trials; therefore, the methodological quality can be underestimated if evaluated separately from the trials. Future economic evaluations should follow more strictly the recommendations about methodology and the authors should pay special attention to the quality of reporting.

Challenges in evaluating surgical innovation.

PubMed

Ergina, Patrick L; Cook, Jonathan A; Blazeby, Jane M; Boutron, Isabelle; Clavien, Pierre-Alain; Reeves, Barnaby C; Seiler, Christoph M; Altman, Douglas G; Aronson, Jeffrey K; Barkun, Jeffrey S; Campbell, W Bruce; Cook, Jonathan A; Feldman, Liane S; Flum, David R; Glasziou, Paul; Maddern, Guy J; Marshall, John C; McCulloch, Peter; Nicholl, Jon; Strasberg, Steven M; Meakins, Jonathan L; Ashby, Deborah; Black, Nick; Bunker, John; Burton, Martin; Campbell, Marion; Chalkidou, Kalipso; Chalmers, Iain; de Leval, Marc; Deeks, Jon; Grant, Adrian; Gray, Muir; Greenhalgh, Roger; Jenicek, Milos; Kehoe, Sean; Lilford, Richard; Littlejohns, Peter; Loke, Yoon; Madhock, Rajan; McPherson, Kim; Rothwell, Peter; Summerskill, Bill; Taggart, David; Tekkis, Parris; Thompson, Matthew; Treasure, Tom; Trohler, Ulrich; Vandenbroucke, Jan

2009-09-26

Research on surgical interventions is associated with several methodological and practical challenges of which few, if any, apply only to surgery. However, surgical evaluation is especially demanding because many of these challenges coincide. In this report, the second of three on surgical innovation and evaluation, we discuss obstacles related to the study design of randomised controlled trials and non-randomised studies assessing surgical interventions. We also describe the issues related to the nature of surgical procedures-for example, their complexity, surgeon-related factors, and the range of outcomes. Although difficult, surgical evaluation is achievable and necessary. Solutions tailored to surgical research and a framework for generating evidence on which to base surgical practice are essential.

Methodological issues in the design of clinical trials for the treatment of multidrug-resistant tuberculosis: challenges and opportunities.

PubMed

Lienhardt, C; Davies, G

2010-05-01

The burden of multidrug-resistant tuberculosis (MDR-TB) is increasing dramatically in the world today, severely hampering global TB control. Treatment of MDR-TB is complex, prolonged, expensive and requires appropriate clinical and laboratory infrastructure. The majority of MDR-TB patients still do not have access to adequate diagnostic services or quality assured second-line drugs, leading to high levels of morbidity and mortality. More effective and efficient MDR-TB treatment with reduced toxicity that could be safely delivered to patients co-infected with human immunodeficiency virus (HIV) is an urgent research priority that could be cost-saving for health systems overall. In this context, understanding how best to design and execute randomised controlled trials to improve MDR-TB treatment has taken on new urgency, to identify the optimal combination(s) of existing and new drugs to assemble in efficient and safe regimen(s), preferably of short duration, that can be easily delivered to patients and safely combined with antiretroviral treatment. In the present report, we address the methodological issues in the design and execution of Phase II and Phase III trials arising from this goal. We suggest that a rational selection of appropriate designs and outcome measures, associated with the application of new diagnostic technology, could overcome many of the methodological and logistical problems. These advances could be key to historic improvements in the treatment of patients suffering from MDR-TB, and perhaps ultimately drug-susceptible TB. As with HIV, clinical trials in patients with drug-resistant disease may provide a quicker and less expensive path to licensure than trials for treatment of drug-susceptible disease.

Methodological developments in searching for studies for systematic reviews: past, present and future?

PubMed

Lefebvre, Carol; Glanville, Julie; Wieland, L Susan; Coles, Bernadette; Weightman, Alison L

2013-09-25

The Cochrane Collaboration was established in 1993, following the opening of the UK Cochrane Centre in 1992, at a time when searching for studies for inclusion in systematic reviews was not well-developed. Review authors largely conducted their own searches or depended on medical librarians, who often possessed limited awareness and experience of systematic reviews. Guidance on the conduct and reporting of searches was limited. When work began to identify reports of randomized controlled trials (RCTs) for inclusion in Cochrane Reviews in 1992, there were only approximately 20,000 reports indexed as RCTs in MEDLINE and none indexed as RCTs in Embase. No search filters had been developed with the aim of identifying all RCTs in MEDLINE or other major databases. This presented The Cochrane Collaboration with a considerable challenge in identifying relevant studies.Over time, the number of studies indexed as RCTs in the major databases has grown considerably and the Cochrane Central Register of Controlled Trials (CENTRAL) has become the best single source of published controlled trials, with approximately 700,000 records, including records identified by the Collaboration from Embase and MEDLINE. Search filters for various study types, including systematic reviews and the Cochrane Highly Sensitive Search Strategies for RCTs, have been developed. There have been considerable advances in the evidence base for methodological aspects of information retrieval. The Cochrane Handbook for Systematic Reviews of Interventions now provides detailed guidance on the conduct and reporting of searches. Initiatives across The Cochrane Collaboration to improve the quality inter alia of information retrieval include: the recently introduced Methodological Expectations for Cochrane Intervention Reviews (MECIR) programme, which stipulates 'mandatory' and 'highly desirable' standards for various aspects of review conduct and reporting including searching, the development of Standard Training Materials for Cochrane Reviews and work on peer review of electronic search strategies. Almost all Cochrane Review Groups and some Cochrane Centres and Fields now have a Trials Search Co-ordinator responsible for study identification and medical librarians and other information specialists are increasingly experienced in searching for studies for systematic reviews.Prospective registration of clinical trials is increasing and searching trials registers is now mandatory for Cochrane Reviews, where relevant. Portals such as the WHO International Clinical Trials Registry Platform (ICTRP) are likely to become increasingly attractive, given concerns about the number of trials which may not be registered and/or published. The importance of access to information from regulatory and reimbursement agencies is likely to increase. Cross-database searching, gateways or portals and improved access to full-text databases will impact on how searches are conducted and reported, as will services such as Google Scholar, Scopus and Web of Science. Technologies such as textual analysis, semantic analysis, text mining and data linkage will have a major impact on the search process but efficient and effective updating of reviews may remain a challenge.In twenty years' time, we envisage that the impact of universal social networking, as well as national and international legislation, will mean that all trials involving humans will be registered at inception and detailed trial results will be routinely available to all. Challenges will remain, however, to ensure the discoverability of relevant information in diverse and often complex sources and the availability of metadata to provide the most efficient access to information. We envisage an ongoing role for information professionals as experts in identifying new resources, researching efficient ways to link or mine them for relevant data and managing their content for the efficient production of systematic reviews.

Methodological developments in searching for studies for systematic reviews: past, present and future?

PubMed Central

2013-01-01

The Cochrane Collaboration was established in 1993, following the opening of the UK Cochrane Centre in 1992, at a time when searching for studies for inclusion in systematic reviews was not well-developed. Review authors largely conducted their own searches or depended on medical librarians, who often possessed limited awareness and experience of systematic reviews. Guidance on the conduct and reporting of searches was limited. When work began to identify reports of randomized controlled trials (RCTs) for inclusion in Cochrane Reviews in 1992, there were only approximately 20,000 reports indexed as RCTs in MEDLINE and none indexed as RCTs in Embase. No search filters had been developed with the aim of identifying all RCTs in MEDLINE or other major databases. This presented The Cochrane Collaboration with a considerable challenge in identifying relevant studies. Over time, the number of studies indexed as RCTs in the major databases has grown considerably and the Cochrane Central Register of Controlled Trials (CENTRAL) has become the best single source of published controlled trials, with approximately 700,000 records, including records identified by the Collaboration from Embase and MEDLINE. Search filters for various study types, including systematic reviews and the Cochrane Highly Sensitive Search Strategies for RCTs, have been developed. There have been considerable advances in the evidence base for methodological aspects of information retrieval. The Cochrane Handbook for Systematic Reviews of Interventions now provides detailed guidance on the conduct and reporting of searches. Initiatives across The Cochrane Collaboration to improve the quality inter alia of information retrieval include: the recently introduced Methodological Expectations for Cochrane Intervention Reviews (MECIR) programme, which stipulates 'mandatory’ and 'highly desirable’ standards for various aspects of review conduct and reporting including searching, the development of Standard Training Materials for Cochrane Reviews and work on peer review of electronic search strategies. Almost all Cochrane Review Groups and some Cochrane Centres and Fields now have a Trials Search Co-ordinator responsible for study identification and medical librarians and other information specialists are increasingly experienced in searching for studies for systematic reviews. Prospective registration of clinical trials is increasing and searching trials registers is now mandatory for Cochrane Reviews, where relevant. Portals such as the WHO International Clinical Trials Registry Platform (ICTRP) are likely to become increasingly attractive, given concerns about the number of trials which may not be registered and/or published. The importance of access to information from regulatory and reimbursement agencies is likely to increase. Cross-database searching, gateways or portals and improved access to full-text databases will impact on how searches are conducted and reported, as will services such as Google Scholar, Scopus and Web of Science. Technologies such as textual analysis, semantic analysis, text mining and data linkage will have a major impact on the search process but efficient and effective updating of reviews may remain a challenge. In twenty years’ time, we envisage that the impact of universal social networking, as well as national and international legislation, will mean that all trials involving humans will be registered at inception and detailed trial results will be routinely available to all. Challenges will remain, however, to ensure the discoverability of relevant information in diverse and often complex sources and the availability of metadata to provide the most efficient access to information. We envisage an ongoing role for information professionals as experts in identifying new resources, researching efficient ways to link or mine them for relevant data and managing their content for the efficient production of systematic reviews. PMID:24066664

Methodological idiosyncracies, frameworks and challenges of non-pharmaceutical and non-technical treatment interventions.

PubMed

Schünemann, Holger J

2013-01-01

In this brief article which summarises a presentation given at the "6. Diskussionsforum zur Nutzenbewertung im Gesundheitswesen" of the German Ministry of Education and Research "Gesundheitsforschungsrat (GFR)" and the Institute for Quality and Efficiency in Healthcare (IQWiG) I will analyse some methodological idiosyncrasies of studies evaluating non-pharmacological non-technical interventions (NPNTI). I will focus on how the methodological framework of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group may support design and appraisal of NPNTI. Specific design features that may be of particular value in NPNTI research, such as expertise-based randomised controlled trials, will be briefly described. Finally, based on an example, I will argue that - despite the methodological idiosyncrasies - there is neither a sufficient reason to accept different standards for the assessment of the confidence in the evidence from NPNTI nor for using study designs that are less rigorous compared to "simpler" interventions but that special measures have to be taken to reduce the risk of bias. The example that will be used in this article will primarily come from the field of respiratory rehabilitation, a typical multi-component or complex intervention and by definition a complex NPNTI, which has been evaluated in many randomised controlled trials. (As supplied by publisher). Copyright © 2013. Published by Elsevier GmbH.

Quality of reporting in clinical trials of preharvest food safety interventions and associations with treatment effect.

PubMed

Sargeant, Jan M; Saint-Onge, Jacqueline; Valcour, James; Thompson, Adam; Elgie, Robyn; Snedeker, Kate; Marcynuk, Pasha

2009-10-01

Randomized controlled trials (RCTs) are the gold standard for evaluating treatment efficacy. Therefore, it is important that RCTs are conducted with methodological rigor to prevent biased results and report results in a manner that allows the reader to evaluate internal and external validity. Most human health journals now require manuscripts to meet the Consolidated Standards of Reporting Trials (CONSORT) criteria for reporting of RCTs. Our objective was to evaluate preharvest food safety trials using a modification of the CONSORT criteria to assess methodological quality and completeness of reporting, and to investigate associations between reporting and treatment effects. One hundred randomly selected trials were evaluated using a modified CONSORT statement. The majority of the selected trials (84%) used a deliberate disease challenge, with the remainder representing natural pathogen exposure. There were widespread deficiencies in the reporting of many trial features. Randomization, double blinding, and the number of subjects lost to follow-up were reported in only 46%, 0%, and 43% of trials, respectively. The inclusion criteria for study subjects were only described in 16% of trials, and the number of animals housed together was only stated in 52% of the trials. Although 91 trials had more than one outcome, no trials specified the primary outcome of interest. There were significant bivariable associations between the proportion of positive treatment effects and failure to report the number of subjects lost to follow-up, the number of animals housed together in a group, the level of treatment allocation, and possible study limitations. The results suggest that there are substantive deficiencies in reporting of preharvest food safety trials, and that these deficiencies may be associated with biased treatment effects. The creation and adoption of standards for reporting in preharvest food safety trials will help to ensure the inclusion of important trial details in all publications.

Understanding Nutritional Epidemiology and Its Role in Policy12

PubMed Central

Satija, Ambika; Yu, Edward; Willett, Walter C; Hu, Frank B

2015-01-01

Nutritional epidemiology has recently been criticized on several fronts, including the inability to measure diet accurately, and for its reliance on observational studies to address etiologic questions. In addition, several recent meta-analyses with serious methodologic flaws have arrived at erroneous or misleading conclusions, reigniting controversy over formerly settled debates. All of this has raised questions regarding the ability of nutritional epidemiologic studies to inform policy. These criticisms, to a large degree, stem from a misunderstanding of the methodologic issues of the field and the inappropriate use of the drug trial paradigm in nutrition research. The exposure of interest in nutritional epidemiology is human diet, which is a complex system of interacting components that cumulatively affect health. Consequently, nutritional epidemiology constantly faces a unique set of challenges and continually develops specific methodologies to address these. Misunderstanding these issues can lead to the nonconstructive and sometimes naive criticisms we see today. This article aims to clarify common misunderstandings of nutritional epidemiology, address challenges to the field, and discuss the utility of nutritional science in guiding policy by focusing on 5 broad questions commonly asked of the field. PMID:25593140

Design and challenges for a randomized, multi-site clinical trial comparing the use of service dogs and emotional support dogs in Veterans with post-traumatic stress disorder (PTSD).

PubMed

Saunders, Gabrielle H; Biswas, Kousick; Serpi, Tracey; McGovern, Stephanie; Groer, Shirley; Stock, Eileen M; Magruder, Kathryn M; Storzbach, Daniel; Skelton, Kelly; Abrams, Thad; McCranie, Mark; Richerson, Joan; Dorn, Patricia A; Huang, Grant D; Fallon, Michael T

2017-11-01

Posttraumatic stress disorder (PTSD) is a leading cause of impairments in quality of life and functioning among Veterans. Service dogs have been promoted as an effective adjunctive intervention for PTSD, however published research is limited and design and implementation flaws in published studies limit validated conclusions. This paper describes the rationale for the study design, a detailed methodological description, and implementation challenges of a multisite randomized clinical trial examining the impact of service dogs on the on the functioning and quality of life of Veterans with PTSD. Trial design considerations prioritized participant and intervention (dog) safety, selection of an intervention comparison group that would optimize enrollment in all treatment arms, pragmatic methods to ensure healthy well-trained dogs, and the selection of outcomes for achieving scientific and clinical validity in a Veteran PTSD population. Since there is no blueprint for conducting a randomized clinical trial examining the impact of dogs on PTSD of this size and scope, it is our primary intent that the successful completion of this trial will set a benchmark for future trial design and scientific rigor, as well as guiding researchers aiming to better understand the role that dogs can have in the management of Veterans experiencing mental health conditions such as PTSD. Published by Elsevier Inc.

Perspective: Randomized Controlled Trials Are Not a Panacea for Diet-Related Research12

PubMed Central

Hébert, James R; Frongillo, Edward A; Adams, Swann A; Turner-McGrievy, Gabrielle M; Hurley, Thomas G; Miller, Donald R; Ockene, Ira S

2016-01-01

Research into the role of diet in health faces a number of methodologic challenges in the choice of study design, measurement methods, and analytic options. Heavier reliance on randomized controlled trial (RCT) designs is suggested as a way to solve these challenges. We present and discuss 7 inherent and practical considerations with special relevance to RCTs designed to study diet: 1) the need for narrow focus; 2) the choice of subjects and exposures; 3) blinding of the intervention; 4) perceived asymmetry of treatment in relation to need; 5) temporal relations between dietary exposures and putative outcomes; 6) strict adherence to the intervention protocol, despite potential clinical counter-indications; and 7) the need to maintain methodologic rigor, including measuring diet carefully and frequently. Alternatives, including observational studies and adaptive intervention designs, are presented and discussed. Given high noise-to-signal ratios interjected by using inaccurate assessment methods in studies with weak or inappropriate study designs (including RCTs), it is conceivable and indeed likely that effects of diet are underestimated. No matter which designs are used, studies will require continued improvement in the assessment of dietary intake. As technology continues to improve, there is potential for enhanced accuracy and reduced user burden of dietary assessments that are applicable to a wide variety of study designs, including RCTs. PMID:27184269

Implications of the licensure of a partially efficacious malaria vaccine on evaluating second-generation vaccines.

PubMed

Fowkes, Freya J I; Simpson, Julie A; Beeson, James G

2013-10-30

Malaria is a leading cause of morbidity and mortality, with approximately 225 million clinical episodes and >1.2 million deaths annually attributed to malaria. Development of a highly efficacious malaria vaccine will offer unparalleled possibilities for disease prevention and remains a key priority for long-term malaria control and elimination. The Malaria Vaccine Technology Roadmap's goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%'. To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%). However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future. In this opinion piece we discuss the methodological, logistical and ethical issues that may impact on the feasibility and implementation of superiority, non-inferiority and equivalence trials to assess second generation malaria vaccines in the advent of the licensure of a partially efficacious malaria vaccine. Selecting which new malaria vaccines go forward, and defining appropriate methodology for assessment in logistically challenging clinical trials, is crucial. It is imperative that the scientific community considers all the issues and starts planning how second-generation malaria vaccines will advance in the advent of licensure of a partially effective vaccine.

Efficacy and toxicity differences in lung cancer populations in the era of clinical trials globalization: the 'common arm' approach.

PubMed

Mack, Philip C; Gandara, David R; Lara, Primo N

2012-12-01

Historically, notable variability has been observed in clinical trial outcomes between different regions and populations worldwide, even when employing the same cytotoxic regimen in lung cancer. These divergent results underscore the inherent challenges in interpreting trials conducted abroad and raise questions regarding the general applicability of transnational clinical trials. Various reasons have been postulated to account for these differences in efficacy and toxicity, including trial design, eligibility criteria, patient demographics and, perhaps most intriguingly, population-related pharmacogenomics. However, without methodology to control for such variables, these hypotheses remain largely untested. The authors previously developed the 'common arm' approach in order to directly compare efficacy and toxicity results of trials simultaneously performed in different countries. By standardizing clinical trial-associated variables such as treatment regimens (dose, schedule, and so on), eligibility, staging, response and toxicity criteria, this approach has the potential to determine the underlying reasons for divergences in trial outcomes across countries, and whether population-associated polymorphisms contribute to these differences. In the past decade, Japanese and US investigators have applied the common arm analytic method to trials in both extensive-stage small-cell lung cancer (SCLC) and advanced nonSCLC. In the SCLC analysis, a comparison of the cisplatin/irinotecan arms from both trials revealed significant differences in response rates and overall survival. Significant differences were also observed in the distribution of gender and performance status. The common arm analysis in nonSCLC included two trials from Japan and one from the USA, each containing a 'common' carboplatin/paclitaxel arm. Clinical results were similar in the two Japanese trials, but were significantly different from the US trial with regard to survival, neutropenia, febrile neutropenia and anemia. The underlying basis for these divergent outcomes is discussed. The common arm methodology provides a template for identifying and interpreting patient outcome differences across populations, and is an instructive lesson in the burgeoning era of clinical trials globalization.

Observational Studies: Cohort and Case-Control Studies

PubMed Central

Song, Jae W.; Chung, Kevin C.

2010-01-01

Observational studies are an important category of study designs. To address some investigative questions in plastic surgery, randomized controlled trials are not always indicated or ethical to conduct. Instead, observational studies may be the next best method to address these types of questions. Well-designed observational studies have been shown to provide results similar to randomized controlled trials, challenging the belief that observational studies are second-rate. Cohort studies and case-control studies are two primary types of observational studies that aid in evaluating associations between diseases and exposures. In this review article, we describe these study designs, methodological issues, and provide examples from the plastic surgery literature. PMID:20697313

Conducting pilot and feasibility studies.

PubMed

Cope, Diane G

2015-03-01

Planning a well-designed research study can be tedious and laborious work. However, this process is critical and ultimately can produce valid, reliable study findings. Designing a large-scale randomized, controlled trial (RCT)-the gold standard in quantitative research-can be even more challenging. Even the most well-planned study potentially can result in issues with research procedures and design, such as recruitment, retention, or methodology. One strategy that may facilitate sound study design is the completion of a pilot or feasibility study prior to the initiation of a larger-scale trial. This article will discuss pilot and feasibility studies, their advantages and disadvantages, and implications for oncology nursing research. 
.

A data grid for imaging-based clinical trials

NASA Astrophysics Data System (ADS)

Zhou, Zheng; Chao, Sander S.; Lee, Jasper; Liu, Brent; Documet, Jorge; Huang, H. K.

2007-03-01

Clinical trials play a crucial role in testing new drugs or devices in modern medicine. Medical imaging has also become an important tool in clinical trials because images provide a unique and fast diagnosis with visual observation and quantitative assessment. A typical imaging-based clinical trial consists of: 1) A well-defined rigorous clinical trial protocol, 2) a radiology core that has a quality control mechanism, a biostatistics component, and a server for storing and distributing data and analysis results; and 3) many field sites that generate and send image studies to the radiology core. As the number of clinical trials increases, it becomes a challenge for a radiology core servicing multiple trials to have a server robust enough to administrate and quickly distribute information to participating radiologists/clinicians worldwide. The Data Grid can satisfy the aforementioned requirements of imaging based clinical trials. In this paper, we present a Data Grid architecture for imaging-based clinical trials. A Data Grid prototype has been implemented in the Image Processing and Informatics (IPI) Laboratory at the University of Southern California to test and evaluate performance in storing trial images and analysis results for a clinical trial. The implementation methodology and evaluation protocol of the Data Grid are presented.

Do systematic reviews on pediatric topics need special methodological considerations?

PubMed

Farid-Kapadia, Mufiza; Askie, Lisa; Hartling, Lisa; Contopoulos-Ioannidis, Despina; Bhutta, Zulfiqar A; Soll, Roger; Moher, David; Offringa, Martin

2017-03-06

Systematic reviews are key tools to enable decision making by healthcare providers and policymakers. Despite the availability of the evidence based Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA-2009 and PRISMA-P 2015) statements that were developed to improve the transparency and quality of reporting of systematic reviews, uncertainty on how to deal with pediatric-specific methodological challenges of systematic reviews impairs decision-making in child health. In this paper, we identify methodological challenges specific to the design, conduct and reporting of pediatric systematic reviews, and propose a process to address these challenges. One fundamental decision at the outset of a systematic review is whether to focus on a pediatric population only, or to include both adult and pediatric populations. Both from the policy and patient care point of view, the appropriateness of interventions and comparators administered to pre-defined pediatric age subgroup is critical. Decisions need to be based on the biological plausibility of differences in treatment effects across the developmental trajectory in children. Synthesis of evidence from different trials is often impaired by the use of outcomes and measurement instruments that differ between trials and are neither relevant nor validated in the pediatric population. Other issues specific to pediatric systematic reviews include lack of pediatric-sensitive search strategies and inconsistent choices of pediatric age subgroups in meta-analyses. In addition to these methodological issues generic to all pediatric systematic reviews, special considerations are required for reviews of health care interventions' safety and efficacy in neonatology, global health, comparative effectiveness interventions and individual participant data meta-analyses. To date, there is no standard approach available to overcome this problem. We propose to develop a consensus-based checklist of essential items which researchers should consider when they are planning (PRISMA-PC-Protocol for Children) or reporting (PRISMA-C-reporting for Children) a pediatric systematic review. Available guidelines including PRISMA do not cover the complexity associated with the conduct and reporting of systematic reviews in the pediatric population; they require additional and modified standards for reporting items. Such guidance will facilitate the translation of knowledge from the literature to bedside care and policy, thereby enhancing delivery of care and improving child health outcomes.

Effectiveness of vocational rehabilitation intervention on the return to work and employment of persons with multiple sclerosis.

PubMed

Khan, Fary; Ng, Louisa; Turner-Stokes, Lynne

2009-01-21

Multiple sclerosis is a neurological disease that frequently affects adults of working age, resulting in a range of physical, cognitive and psychosocial deficits that impact on workforce participation. Although, the literature supports vocational rehabilitation (VR) approaches in persons with multiple sclerosis (pwMS), the evidence for its effectiveness is yet to be established. To evaluate the effectiveness of VR programs compared to alternative programs or care as usual on return to work, workability and employment in pwMS; to evaluate the cost effectiveness of these programs. Electronic searches included: Cochrane Central Register of Controlled Trials "CENTRAL" 2008 issue 3, MEDLINE (PubMed) (1966- 2008), EMBASE (1988- 2008), CINAHL (1982- 2008), PEDro (1990- 2008), the Cochrane Rehabilitation and Related Therapies Field trials Register and the National Health Service National Research Register. Randomized and controlled clinical trials, including before - after controlled trials, that compare VR rehabilitation with alternative intervention such as standard or a lesser form of intervention or waitlist controls. Two reviewers selected trials and rated their methodological quality independently. A 'best evidence' synthesis was performed, based on methodological quality. Trials were grouped in terms of type and setting of VR programs. Two trials (one RCT and one CCT) (total 80 participants) met the review criteria. Both trials scored poorly on the methodological quality assessment. There was 'insufficient evidence' for VR programs for (a)'competitive employment', in altering rates of job retention, changes in employment, improvement in rates of re-entry into the labour force; (b) for altering 'work ability' by improving participants' confidence in the accommodation request process, or employability maturity or job seeking activity. No evidence could be assimilated for changes in proportions of persons in supported employment or on disability pensions, nor for cost-effectiveness. There was inconclusive evidence to support VR for pwMS. However, the review highlights some of the challenges in providing VR for pwMS. Clinicians need to be aware of vocational issues, and to understand and manage barriers for maintaining employment. Proactive and timely VR programs should incorporate practical solutions to deal with work disability, workplace accommodation and educate employers, and the wider community. Liaison with policy makers is imperative for government initiatives that encourage work focused VR programs. Future research in VR should focus on improving methodological and scientific rigour of clinical trials; on the development of appropriate and valid outcome measures; and on cost effectiveness of VR programs.

The Cooking and Pneumonia Study (CAPS) in Malawi: A Nested Pilot of Photovoice Participatory Research Methodology

PubMed Central

Ardrey, Jane; Desmond, Nicola

2016-01-01

The Cooking and Pneumonia Study (CAPS) is a village-level randomised controlled trial of an advanced cookstove intervention to prevent pneumonia in children under the age of 5 in rural Malawi (www.capstudy.org). The trial offers a unique opportunity to gain understanding about the social and cultural factors that may facilitate sustained use of improved cookstoves. In January 2015, the use of Photovoice as a participatory research methodology was piloted at the CAPS Chikhwawa site. Photovoice is a photographic technique that allows communities (including women and marginalised groups) to share knowledge about their perspectives and priorities. Four households were given digital cameras and asked to collect images over 24–48 hours and were then interviewed on film about their selection. This resulted in over 400 images and a one hour long film that revealed community concerns and could be thematically analysed. The collection of interview data through film was useful for capturing discussion and was acceptable to participants. Photovoice is a feasible participatory research methodology that can play a valuable role in qualitative studies of improved cookstove adoption in challenging resource poor settings. PMID:27254291

Microbicide research in developing countries: have we given the ethical concerns due consideration?

PubMed

Moodley, Keymanthri

2007-09-19

HIV prevention research has been fraught with ethical concerns since its inception. These concerns were highlighted during HIV vaccine research and have been elaborated in microbicide research. A host of unique ethical concerns pervade the microbicide research process from trial design to post-trial microbicide availability. Given the urgency of research and development in the face of the devastating HIV pandemic, these ethical concerns represent an enormous challenge for investigators, sponsors and Research Ethics Committees (RECs) both locally and internationally. Ethical concerns relating to safety in microbicide research are a major international concern. However, in the urgency to develop a medically efficacious microbicide, some of these concerns may not have been anticipated. In the risk-benefit assessment of research protocols, both medical and psycho-social risk must be considered. In this paper four main areas that have a potential for medical and/or psycho-social harm are examined. Male partner involvement is controversial in the setting of covert use of microbicides. However, given the long-term exposure of men to experimental products, this may be methodologically, ethically and legally important. Covert use of microbicides may impact negatively on relationship dynamics leading to psychosocial harm to varying extents. The unexpectedly high rates of pregnancy during clinical trials raise important methodological and ethical concerns. Enrollment of adolescents without parental consent generates ethical and legal concerns that must be carefully considered by RECs and trial sites. Finally, paradoxical outcomes in recent trials internationally have advanced the debate on the nature of informed consent and responsibility of researchers to participants who become HIV positive during or after trials. Phase 3 microbicide trials are an undisputed research and ethical priority in developing countries. However, such trials must be conducted with attention to both methodological and ethical detail. It is imperative that guidelines are formulated to ensure that high ethical standards are maintained despite the scientific urgency of microbicide development. Given the controversy raised by emergent ethical issues during the course of microbicide development, it is important that international consensus is reached amongst the various ethics and regulatory agencies in developing and developed countries alike.

Assessing Cognitive Function in Bipolar Disorder: Challenges and Recommendations for Clinical Trial Design

PubMed Central

Burdick, Katherine E.; Ketter, Terence A.; Goldberg, Joseph F.; Calabrese, Joseph R.

2015-01-01

OBJECTIVE Neurocognitive impairment in schizophrenia has been recognized for more than a century. In contrast, only recently have significant neurocognitive deficits been recognized in bipolar disorder. Converging data suggest the importance of cognitive problems in relation to quality of life in bipolar disorder, highlighting the need for treatment and prevention efforts targeting cognition in bipolar patients. Future treatment trials targeting cognitive deficits will be met with methodological challenges due to the inherent complexity and heterogeneity of the disorder, including significant diagnostic comorbidities, the episodic nature of the illness, frequent use of polypharmacy, cognitive heterogeneity, and a lack of consensus regarding measurement of cognition and outcome in bipolar patients. Guidelines for use in designing future trials are needed. PARTICIPANTS The members of the consensus panel (each of the bylined authors) were selected based upon their expertise in bipolar disorder. Dr. Burdick is a neuropsychologist who has studied cognition in this illness for 15 years; Drs. Ketter, Calabrese, and Goldberg each bring considerable expertise in the treatment of bipolar disorder both within and outside of controlled clinical trials. This consensus statement was derived from work together at scientific meetings (e.g. symposium presention at the 2014 Annual meeting of the American Society of Clinical Psychopharmacology, among others) and ongoing discussions by conference call. With the exception of the public presentations on this topic, these meetings were closed to outside participants. EVIDENCE A literature review was undertaken by the authors to identify illness-specific challenges relevant to the design and conduct of treatment trials targeting neurocognition in bipolar disorder. Expert opinion from each of the authors guided the consensus recommendations. CONSENSUS PROCESS Consensus recommendations, reached by unanimous opinion of the authors, are provided here as a preliminary guide for future trial design. Recommendations comprise exclusion of certain syndromal level comorbid diagnoses and current affective instability, restrictions on numbers and types of medications, and use of pre-screening assessment to ensure enrollment of subjects with adequate objective evidence of baseline cognitive impairment. CONCLUSIONS Clinical trials to address cognitive deficits in bipolar disorder face distinctive design challenges. As such trials move from proof-of-concept to confirmation of clinical efficacy, it will be important to incorporate distinctive design modifications to adequately address these challenges and increase the likelihood of demonstrating cognitive remediation effects. The field is now primed to address these challenges and a comprehensive effort to formalize best practice guidelines will be a critically important next step. PMID:25830456

Methodological challenges in conducting a multi-site randomized clinical trial of massage therapy in hospice.

PubMed

Kutner, Jean; Smith, Marlaine; Mellis, Karen; Felton, Sue; Yamashita, Traci; Corbin, Lisa

2010-06-01

Researchers conducting multi-site studies of interventions for end-of-life symptom management face significant challenges with respect to obtaining an adequate sample and training and retaining on-site study teams. The purpose of this paper is to describe the strategies and responses to these challenges in a multi-site randomized clinical trial (RCT) of the efficacy of massage therapy for decreasing pain among patients with advanced cancer in palliative care/hospice settings. Over a period of 36 months, we enrolled 380 participants across 15 sites; 27% of whom withdrew prior to study completion (less than the anticipated 30% rate). We saw an average of 68% turnover amongst study staff. Three key qualities characterized successful on-site study teams: (1) organizational commitment; (2) strong leadership from on-site study coordinators; and (3) effective lines of communication between the on-site study coordinators and both their teams and the university-based research team. Issues of recruitment, retention and training should be accounted for in hospice-based research study design and budgeting.

Monitoring safety in a phase III real‐world effectiveness trial: use of novel methodology in the Salford Lung Study

PubMed Central

Harvey, Catherine; Brewster, Jill; Bakerly, Nawar Diar; Elkhenini, Hanaa F.; Stanciu, Roxana; Williams, Claire; Brereton, Jacqui; New, John P.; McCrae, John; McCorkindale, Sheila; Leather, David

2016-01-01

Abstract Background The Salford Lung Study (SLS) programme, encompassing two phase III pragmatic randomised controlled trials, was designed to generate evidence on the effectiveness of a once‐daily treatment for asthma and chronic obstructive pulmonary disease in routine primary care using electronic health records. Objective The objective of this study was to describe and discuss the safety monitoring methodology and the challenges associated with ensuring patient safety in the SLS. Refinements to safety monitoring processes and infrastructure are also discussed. The study results are outside the remit of this paper. The results of the COPD study were published recently and a more in‐depth exploration of the safety results will be the subject of future publications. Achievements The SLS used a linked database system to capture relevant data from primary care practices in Salford and South Manchester, two university hospitals and other national databases. Patient data were collated and analysed to create daily summaries that were used to alert a specialist safety team to potential safety events. Clinical research teams at participating general practitioner sites and pharmacies also captured safety events during routine consultations. Confidence in the safety monitoring processes over time allowed the methodology to be refined and streamlined without compromising patient safety or the timely collection of data. The information technology infrastructure also allowed additional details of safety information to be collected. Conclusion Integration of multiple data sources in the SLS may provide more comprehensive safety information than usually collected in standard randomised controlled trials. Application of the principles of safety monitoring methodology from the SLS could facilitate safety monitoring processes for future pragmatic randomised controlled trials and yield important complementary safety and effectiveness data. © 2016 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd. PMID:27804174

The research gap in chronic paediatric pain: A systematic review of randomised controlled trials.

PubMed

Boulkedid, R; Abdou, A Y; Desselas, E; Monégat, M; de Leeuw, T G; Avez-Couturier, J; Dugue, S; Mareau, C; Charron, B; Alberti, C; Kaguelidou, F

2018-02-01

Chronic pain is associated with significant functional and social impairment. The objective of this review was to assess the characteristics and quality of randomized controlled trials (RCTs) evaluating pain management interventions in children and adolescents with chronic pain. We performed a systematic search of PubMed, Embase and the Cochrane Library up to July 2017. We included RCTs that involved children and adolescents (3 months-18 years) and evaluated the use of pharmacological or non-pharmacological intervention(s) in the context of pain persisting or re-occurring for more than 3 months. Methodological quality was evaluated using the Cochrane Risk of Bias (ROB) Tool. A total of 58 RCTs were identified and numbers steadily increased over time. The majority were conducted in single hospital institutions, with no information on study funding. Median sample size was 47.5 participants (Q1,Q3: 32, 70). Forty-five percent of RCTs included both adults and children and the median of the mean ages at inclusion was 12.9 years (Q1,Q3: 11, 15). Testing of non-pharmacological interventions was predominant and only 5 RCTs evaluated analgesics or co-analgesics. Abdominal pain, headache/migraine and musculoskeletal pain were the most common types of chronic pain among participants. Methodological quality was poor with 90% of RCTs presenting a high or unclear ROB. Evaluation of analgesics targeting chronic pain relief in children and adolescents through RCTs is marginal. Infants and children with long-lasting painful conditions are insufficiently represented in RCTs. We discuss possible research constraints and challenges as well as methodologies to circumvent them. There is a substantial research gap regarding analgesic interventions for children and adolescents with chronic pain. Most clinical trials in the field focus on the evaluation of non-pharmacological interventions and are of low methodological quality. There is also a specific lack of trials involving infants and children and adolescents with long-lasting diseases. © 2017 European Pain Federation - EFIC®.

Why European and United States drug regulators are not speaking with one voice on anti-influenza drugs: regulatory review methodologies and the importance of 'deep' product reviews.

PubMed

Mulinari, Shai; Davis, Courtney

2017-11-09

Relenza represents the first neuraminidase inhibitor (NI), a class of drugs that also includes the drug Tamiflu. Although heralded as breakthrough treatments in influenza, NI efficacy has remained highly controversial. A key unsettled question is why the United States Food and Drug Administration (FDA) has approved more cautious efficacy statements in labelling than European regulators for both drugs. We conducted a qualitative analysis of United States and European Union regulatory appraisals for Relenza to investigate the reasons for divergent regulatory interpretations, pertaining to Relenza's capacity to alleviate symptoms and reduce frequency of complications of influenza. In Europe, Relenza was evaluated via the so-called national procedure with Sweden as the reference country. We show that FDA reviewers, unlike their European (i.e. Swedish) counterpart, (1) rejected the manufacturer's insistence on pooling efficacy data, (2) remained wary of subgroup analyses, and (3) insisted on stringent statistical analyses. These differences meant that the FDA was less likely to depart from prevailing regulatory and scientific standards in interpreting trial results. We argue that the differences are explained largely by divergent institutionalised review methodologies, i.e. the European regulator's reliance on manufacturer-compiled summaries compared to the FDA's examination of original data and documentation from trials. The FDA's more probing and meticulous evaluative methodology allowed its reviewers to develop 'deep' knowledge concerning the clinical and statistical facets of trials, and more informed opinions regarding suitable methods for analysing trial results. These findings challenge the current emphasis on evaluating regulatory performance mainly in terms of speed of review. We propose that persistent uncertainty and knowledge deficits regarding NIs could have been ameliorated had regulators engaged in the public debates over the drugs' efficacy and explained their contrasting methodologies and judgments. Regulators use major resources to evaluate drugs, but if regulators' assessments are not effectively disseminated and used, resources are used inefficiently.

Monitoring safety in a phase III real-world effectiveness trial: use of novel methodology in the Salford Lung Study.

PubMed

Collier, Sue; Harvey, Catherine; Brewster, Jill; Bakerly, Nawar Diar; Elkhenini, Hanaa F; Stanciu, Roxana; Williams, Claire; Brereton, Jacqui; New, John P; McCrae, John; McCorkindale, Sheila; Leather, David

2017-03-01

The Salford Lung Study (SLS) programme, encompassing two phase III pragmatic randomised controlled trials, was designed to generate evidence on the effectiveness of a once-daily treatment for asthma and chronic obstructive pulmonary disease in routine primary care using electronic health records. The objective of this study was to describe and discuss the safety monitoring methodology and the challenges associated with ensuring patient safety in the SLS. Refinements to safety monitoring processes and infrastructure are also discussed. The study results are outside the remit of this paper. The results of the COPD study were published recently and a more in-depth exploration of the safety results will be the subject of future publications. The SLS used a linked database system to capture relevant data from primary care practices in Salford and South Manchester, two university hospitals and other national databases. Patient data were collated and analysed to create daily summaries that were used to alert a specialist safety team to potential safety events. Clinical research teams at participating general practitioner sites and pharmacies also captured safety events during routine consultations. Confidence in the safety monitoring processes over time allowed the methodology to be refined and streamlined without compromising patient safety or the timely collection of data. The information technology infrastructure also allowed additional details of safety information to be collected. Integration of multiple data sources in the SLS may provide more comprehensive safety information than usually collected in standard randomised controlled trials. Application of the principles of safety monitoring methodology from the SLS could facilitate safety monitoring processes for future pragmatic randomised controlled trials and yield important complementary safety and effectiveness data. © 2016 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd. © 2016 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Tailored Communication Within Mobile Apps for Diabetes Self-Management: A Systematic Review

PubMed Central

Wahl, Astrid Klopstad; Cvancarova Småstuen, Milada; Ribu, Lis

2017-01-01

Background The prevalence of diabetes is increasing and with the requirements for self-management and risk of late complications, it remains a challenge for the individual and society. Patients can benefit from support from health care personnel in their self-management, and the traditional communication between patients and health care personnel is changing. Smartphones and apps offer a unique platform for communication, but apps with integrated health care personnel communication based on patient data are yet to be investigated to provide evidence of possible effects. Objective Our goal was to systematically review studies that aimed to evaluate integrated communication within mobile apps for tailored feedback between patients with diabetes and health care personnel in terms of (1) study characteristics, (2) functions, (3) study outcomes, (4) effects, and (5) methodological quality. Methods A systematic literature search was conducted following our International Prospective Register of Systematic Reviews (PROSPERO) protocol, searching for apps with integrated communication for persons with diabetes tested in a controlled trial in the period 2008 to 2016. We searched the databases PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central, Excerpta Medica database (EMBASE), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform. The search was closed in September 2016. Reference lists of primary articles and review papers were assessed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and we applied the Cochrane risk of bias tool to assess methodological quality. Results We identified 2822 citations and after duplicate removal, we assessed 1128 citations. A total of 6 papers were included in this systematic review, reporting on data from 431 persons participating in small trials of short duration. The integrated communication features were mostly individualized as written non–real-time feedback. The number of functions varied from 2 to 9, and blood glucose tracking was the most common. HbA1c was the most common primary outcome, but the remaining reported outcomes were not standardized and comparable. Because of both the heterogeneity of the included trials and the poor methodological quality of the studies, a meta-analysis was not possible. A statistically significant improvement in the primary measure of outcome was found in 3 of the 6 included studies, of which 2 were HbA1c and 1 was mean daytime ambulatory blood pressure. Participants in the included trials reported positive usability or feasibility postintervention in 5 out of 6 trials. The overall methodological quality of the trials was, however, scored as an uncertain risk of bias. Conclusions This systematic review highlights the need for more trials of higher methodological quality. Few studies offer an integrated function for communication and feedback from health care personnel, and the research field represents an area of heterogeneity with few studies of highly rigorous methodological quality. This, in combination with a low number of participants and a short follow-up, is making it difficult to provide reliable evidence of effects for stakeholders. PMID:28645890

Establishing CASA as an evidence-based practice.

PubMed

Lawson, Jennifer; Berrick, Jill Duerr

2013-01-01

In this article the authors examine the evidentiary status of the Court Appointed Special Advocates (CASA) program through a review of current research findings and a critical analysis of the study methodologies used to produce those findings. Due to the equivocal research findings and widespread methodological weaknesses (most notably selection bias) in the literature base, it is determined that there is not currently enough evidence to establish CASA as an evidence-based practice. In spite of the challenges to the feasibility of such research, a future research agenda is suggested that calls for the execution of large randomized controlled trials in order to produce findings that will inform a deeper understanding of CASA effectiveness in improving child outcomes.

Methodological issues associated with clinical trials in epilepsy.

PubMed

Ferlazzo, Edoardo; Sueri, Chiara; Gasparini, Sara; Russo, Emilio; Cianci, Vittoria; Ascoli, Michele; De Sarro, Giovambattista; Aguglia, Umberto

2017-10-01

despite methodological advances in epilepsy clinical trials, the proportion of patients reaching seizure-freedom has not substantially changed over the years. We review the main methodological limitations of current trials, the possible strategies to overcome these limits, and the issues that need to be addressed in next future. Area covered: references were identified by PubMed search until March 2017 and unpublished literature was searched on ClinicalTrials.gov. Add-on trials mainly involve refractory epilepsy subjects, reducing overall response to the investigational drug. The inclusion of subjects with earlier disease from less developed countries has partially allowed overcoming this limitation, but has introduced more random variability of results. Monotherapy trials rise methodological, economical, and ethical concerns with different regulatory requirements in European Union and in the United States of America. Newer trial designs, such as futility trials or 'time-to-event' design, have been implemented. Moreover, both add-on and monotherapy trials results might be affected by patient's ability to recognize and record seizures, and by randomness of seizures occurrence over time. Possible strategies to achieve more reliable outcomes are detailed. Expert commentary: clinical trial methodology needs to be optimized to better address regulatory agencies requirements and to encounter both patients' and clinicians' needs.

Implementation of an Ebola virus disease vaccine clinical trial during the Ebola epidemic in Liberia: Design, procedures, and challenges.

PubMed

Kennedy, Stephen B; Neaton, James D; Lane, H Clifford; Kieh, Mark W S; Massaquoi, Moses B F; Touchette, Nancy A; Nason, Martha C; Follmann, Dean A; Boley, Fatorma K; Johnson, Melvin P; Larson, Gregg; Kateh, Francis N; Nyenswah, Tolbert G

2016-02-01

The index case of the Ebola virus disease epidemic in West Africa is believed to have originated in Guinea. By June 2014, Guinea, Liberia, and Sierra Leone were in the midst of a full-blown and complex global health emergency. The devastating effects of this Ebola epidemic in West Africa put the global health response in acute focus for urgent international interventions. Accordingly, in October 2014, a World Health Organization high-level meeting endorsed the concept of a phase 2/3 clinical trial in Liberia to study Ebola vaccines. As a follow-up to the global response, in November 2014, the Government of Liberia and the US Government signed an agreement to form a research partnership to investigate Ebola and to assess intervention strategies for treating, controlling, and preventing the disease in Liberia. This agreement led to the establishment of the Joint Liberia-US Partnership for Research on Ebola Virus in Liberia as the beginning of a long-term collaborative partnership in clinical research between the two countries. In this article, we discuss the methodology and related challenges associated with the implementation of the Ebola vaccines clinical trial, based on a double-blinded randomized controlled trial, in Liberia. © The Author(s) 2016.

Investigating the association between medication adherence and health-related quality of life in COPD: Methodological challenges when using a proxy measure of adherence.

PubMed

Boland, Melinde R S; van Boven, Job F M; Kruis, Annemarije L; Chavannes, Niels H; van der Molen, Thys; Goossens, Lucas M A; Rutten-van Mölken, Maureen P M H

2016-01-01

The association between non-adherence to medication and health-related quality-of-life (HRQoL) in Chronic Obstructive Pulmonary Disease (COPD) remains poorly understood. Different ways to deal with methodological challenges to estimate this association have probably contributed to conflicting results. To investigate the association between medication adherence and HRQoL, thereby illustrating methodological challenges that need to be addressed. We used longitudinal patient-level data from a cluster-randomized controlled trial (i.e. RECODE) including three-year data on type and dose of COPD maintenance medication prescribed and HRQoL (Clinical COPD Questionnaire [CCQ], st. George Respiratory Questionnaire [SGRQ], EuroQol 5-dimensions [EQ-5D]) of 511 patients. A linear mixed model was used to assess the association between adherence and HRQoL using a fixed cut-off of 80% of the proportion of days covered (PDC) to define adherence. Subsequently, we investigated the impact of differences in disease severity; lifestyle; and reversed causality, representing the methodological challenges. Additionally, we investigated the impact of changing the definition of adherence. In unadjusted analyses, and analyses adjusting for demographic characteristics only, SGRQ score was worse in the adherent compared to the non-adherent group. This association disappeared when correcting for disease severity and/or lifestyle. A better SGRQ score was predictive of decreased adherence in the following year. However, accounting for the previous HRQoL did not result in positive associations between adherence and HRQoL. When defining four categories of adherence, patients with a PDC between 80 and 99% had a significantly worse SGRQ score compared to patients with a PDC <60%, even after correction for lifestyle. There was no significant association between adherence and CCQ or EQ-5D. This study showed persistent methodological challenges in the investigation of the effect of medication adherence on HRQoL in COPD. A positive association of adherence and HRQoL was not found, even after adjusting for lifestyle, disease severity, and previous HRQoL. Copyright © 2015. Published by Elsevier Ltd.

Design and analysis of group-randomized trials in cancer: A review of current practices.

PubMed

Murray, David M; Pals, Sherri L; George, Stephanie M; Kuzmichev, Andrey; Lai, Gabriel Y; Lee, Jocelyn A; Myles, Ranell L; Nelson, Shakira M

2018-06-01

The purpose of this paper is to summarize current practices for the design and analysis of group-randomized trials involving cancer-related risk factors or outcomes and to offer recommendations to improve future trials. We searched for group-randomized trials involving cancer-related risk factors or outcomes that were published or online in peer-reviewed journals in 2011-15. During 2016-17, in Bethesda MD, we reviewed 123 articles from 76 journals to characterize their design and their methods for sample size estimation and data analysis. Only 66 (53.7%) of the articles reported appropriate methods for sample size estimation. Only 63 (51.2%) reported exclusively appropriate methods for analysis. These findings suggest that many investigators do not adequately attend to the methodological challenges inherent in group-randomized trials. These practices can lead to underpowered studies, to an inflated type 1 error rate, and to inferences that mislead readers. Investigators should work with biostatisticians or other methodologists familiar with these issues. Funders and editors should ensure careful methodological review of applications and manuscripts. Reviewers should ensure that studies are properly planned and analyzed. These steps are needed to improve the rigor and reproducibility of group-randomized trials. The Office of Disease Prevention (ODP) at the National Institutes of Health (NIH) has taken several steps to address these issues. ODP offers an online course on the design and analysis of group-randomized trials. ODP is working to increase the number of methodologists who serve on grant review panels. ODP has developed standard language for the Application Guide and the Review Criteria to draw investigators' attention to these issues. Finally, ODP has created a new Research Methods Resources website to help investigators, reviewers, and NIH staff better understand these issues. Published by Elsevier Inc.

Yoga-based exercise improves balance and mobility in people aged 60 and over: a systematic review and meta-analysis.

PubMed

Youkhana, Sabrina; Dean, Catherine M; Wolff, Moa; Sherrington, Catherine; Tiedemann, Anne

2016-01-01

one-third of community-dwelling older adults fall annually. Exercise that challenges balance is proven to prevent falls. We conducted a systematic review with meta-analysis to determine the impact of yoga-based exercise on balance and physical mobility in people aged 60+ years. searches for relevant trials were conducted on the following electronic databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, Allied and Complementary Medicine Database and the Physiotherapy Evidence Database (PEDro) from inception to February 2015. Trials were included if they evaluated the effect of physical yoga (excluding meditation and breathing exercises alone) on balance in people aged 60+ years. We extracted data on balance and the secondary outcome of physical mobility. Standardised mean differences and 95% confidence intervals (CI) were calculated using random-effects models. Methodological quality of trials was assessed using the 10-point Physiotherapy Evidence Database (PEDro) Scale. six trials of relatively high methodological quality, totalling 307 participants, were identified and had data that could be included in a meta-analysis. Overall, yoga interventions had a small effect on balance performance (Hedges' g = 0.40, 95% CI 0.15-0.65, 6 trials) and a medium effect on physical mobility (Hedges' g = 0.50, 95% CI 0.06-0.95, 3 trials). yoga interventions resulted in small improvements in balance and medium improvements in physical mobility in people aged 60+ years. Further research is required to determine whether yoga-related improvements in balance and mobility translate to prevention of falls in older people. PROSPERO Registration number CRD42015015872. © The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Challenges in designing, conducting, and reporting oral health behavioral intervention studies in primary school age children: methodological issues

PubMed Central

Cooper, Anna Mary; Coffey, Margaret; Dugdill, Lindsey

2014-01-01

Often within oral health, clinical outcome measures dominate trial design rather than behavioral outcome measures, and often there is a reliance on proxy self-reporting of children’s behavior with no corroboration through triangulation of measures. The complexity of the interventions involved in oral health intervention is often overlooked in trial design, and more flexible pragmatic designs that take account of the research context may be more appropriate. Some of the limitations in oral health behavioral intervention studies (trials) in primary school age children were reported in a recently published Cochrane review. This paper aims to critically discuss the findings of a recent Cochrane review in terms of the methodological implications that arise for future design, development, measurement, and reporting of oral health trials in primary school age children. Key components of the UK Medical Research Council’s framework for the design and evaluation of complex interventions are discussed in relation to using taxonomies of behavior change. This paper is not designed to be a definitive guide but aims to bring learning from other areas of public health and health promotion into dental public health. Ultimately, the aim is to aid the design of more successful interventions that produce long-term behavioral changes in children in relation to toothbrushing and nighttime sugar snacking. PMID:27774028

Understanding nutritional epidemiology and its role in policy.

PubMed

Satija, Ambika; Yu, Edward; Willett, Walter C; Hu, Frank B

2015-01-01

Nutritional epidemiology has recently been criticized on several fronts, including the inability to measure diet accurately, and for its reliance on observational studies to address etiologic questions. In addition, several recent meta-analyses with serious methodologic flaws have arrived at erroneous or misleading conclusions, reigniting controversy over formerly settled debates. All of this has raised questions regarding the ability of nutritional epidemiologic studies to inform policy. These criticisms, to a large degree, stem from a misunderstanding of the methodologic issues of the field and the inappropriate use of the drug trial paradigm in nutrition research. The exposure of interest in nutritional epidemiology is human diet, which is a complex system of interacting components that cumulatively affect health. Consequently, nutritional epidemiology constantly faces a unique set of challenges and continually develops specific methodologies to address these. Misunderstanding these issues can lead to the nonconstructive and sometimes naive criticisms we see today. This article aims to clarify common misunderstandings of nutritional epidemiology, address challenges to the field, and discuss the utility of nutritional science in guiding policy by focusing on 5 broad questions commonly asked of the field. © 2015 American Society for Nutrition.

Implications of the licensure of a partially efficacious malaria vaccine on evaluating second-generation vaccines

PubMed Central

2013-01-01

Background Malaria is a leading cause of morbidity and mortality, with approximately 225 million clinical episodes and >1.2 million deaths annually attributed to malaria. Development of a highly efficacious malaria vaccine will offer unparalleled possibilities for disease prevention and remains a key priority for long-term malaria control and elimination. Discussion The Malaria Vaccine Technology Roadmap’s goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%’. To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%). However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future. In this opinion piece we discuss the methodological, logistical and ethical issues that may impact on the feasibility and implementation of superiority, non-inferiority and equivalence trials to assess second generation malaria vaccines in the advent of the licensure of a partially efficacious malaria vaccine. Conclusions Selecting which new malaria vaccines go forward, and defining appropriate methodology for assessment in logistically challenging clinical trials, is crucial. It is imperative that the scientific community considers all the issues and starts planning how second-generation malaria vaccines will advance in the advent of licensure of a partially effective vaccine. PMID:24228861

Methodological challenges in evaluating the effectiveness of women's crisis houses compared with psychiatric wards: findings from a pilot patient preference RCT.

PubMed

Howard, Louise M; Leese, Morven; Byford, Sarah; Killaspy, Helen; Cole, Laura; Lawlor, Caroline; Johnson, Sonia

2009-10-01

There are several methodological difficulties to address when evaluating acute psychiatric services. This study explored potential methods in evaluating the effectiveness of women's crisis houses compared with psychiatric wards in a pilot patient preference randomized controlled trial. Women requiring voluntary admission to a psychiatric hospital or women's crisis house were asked to enter this pilot and different options for recruitment were explored, including different recruitment sites in the pathway to admission and methods for including women without capacity. Forty-one percent (n = 42) of women entering the study agreed to be randomized and 59% (n = 61) entered patient preference arms. Only 7% of women were recruited before admission and 1 woman without capacity entered the study, despite procedures to facilitate this. Recruitment of patients with acute psychiatric crises is therefore challenging; researchers evaluating acute services should establish a consensus on how ethically and practically to recruit patients in this setting.

No child left behind: Enrolling children and adults simultaneously in critical care randomized trials*

PubMed Central

Halpern, Scott D.; Randolph, Adrienne G.; Angus, Derek C.

2010-01-01

Objective Randomized clinical trials of novel critical care interventions are currently tested in children only after documenting their safety in adults. Although this practice may protect children from research risks, it may paradoxically threaten children’s well-being by depriving them of evidence to guide their care. We sought to evaluate the ethical, methodologic, and practical arguments for and against studying critical care interventions in adults and children simultaneously rather than sequentially. Data Source Empirical studies and conceptual arguments germane to the objective were reviewed. Data Extraction and Synthesis Children are traditionally viewed as “participants of last resort” due to their vulnerability and decisional incapacity. However, critically ill adults commonly share similar features. Thus, structured risk assessments used by Institutional Review Boards to determine the adequacy of research protections for critically ill adults can also help protect children. From a methodologic perspective, interventions may be tested simultaneously in children and adults by enrolling children as a prespecified subgroup within a larger adult randomized clinical trial or by enrolling children in a separate trial conducted in parallel. Both approaches raise practical and analytical challenges that can frequently be met. For example, investigators might choose outcome measures that are appropriate for both adults and children. Additionally, using Bayesian approaches to link the estimates of treatment effects in children to the values observed in adults may enhance the statistical power to detect pediatric-specific effects. Finally, centralized Institutional Review Boards and data monitoring centers may alleviate practical concerns with conducting trials among adults and children simultaneously. Conclusions The current standard of testing critical care interventions in adults before children rests on tenuous ethical arguments and is entrenched by the methodologic and logistic barriers encountered with alternative approaches. However, these barriers will frequently be surmountable. We therefore propose that the default paradigm be changed such that interventions are examined routinely in critically ill children and adults simultaneously unless unique reasons exist to the contrary. PMID:19602971

How to write a surgical clinical research protocol: literature review and practical guide.

PubMed

Rosenthal, Rachel; Schäfer, Juliane; Briel, Matthias; Bucher, Heiner C; Oertli, Daniel; Dell-Kuster, Salome

2014-02-01

The study protocol is the core document of every clinical research project. Clinical research in studies involving surgical interventions presents some specific challenges, which need to be accounted for and described in the study protocol. The aim of this review is to provide a practical guide for developing a clinical study protocol for surgical interventions with a focus on methodologic issues. On the basis of an in-depth literature search of methodologic literature and on some cardinal published surgical trials and observational studies, the authors provides a 10-step guide for developing a clinical study protocol in surgery. This practical guide outlines key methodologic issues important when planning an ethically and scientifically sound research project involving surgical interventions, with the ultimate goal of providing high-level evidence relevant for health care decision making in surgery. Copyright © 2014 Elsevier Inc. All rights reserved.

Pretesting Qualitative Data Collection Procedures to Facilitate Methodological Adherence and Team Building in Nigeria.

PubMed

Hurst, Samantha; Arulogun, Oyedunni S; Owolabi, Ayowa O; Akinyemi, Rufus; Uvere, Ezinne; Warth, Stephanie; Ovbiagele, Bruce

Qualitative methods are becoming widely used and increasingly accepted in biomedical research involving teams formed by experts from developing and developed practice environments. Resources are rare in offering guidance on how to surmount challenges of team integration and resolution of complicated logistical issues in a global setting. In this article we present a critical reflection of lessons learned and necessary steps taken to achieve methodological coherence and international team synergy. A series of 10 pretest interviews were conducted to assess instrumentation rigor and formulate measures to address any limitations or threats to bias and management procedures before carrying out the formal phase of qualitative research, contributing to an evidence-based stroke-preventive care clinical trial study. The experience of pretesting notably helped to identify obstacles and thus increase the methodological and social reliability central to conducting credible qualitative research, while also ensuring both personal and professional fulfillment of our team members.

Association between bibliometric parameters, reporting and methodological quality of randomised controlled trials in vascular and endovascular surgery.

PubMed

Hajibandeh, Shahab; Hajibandeh, Shahin; Antoniou, George A; Green, Patrick A; Maden, Michelle; Torella, Francesco

2017-04-01

Purpose We aimed to investigate association between bibliometric parameters, reporting and methodological quality of vascular and endovascular surgery randomised controlled trials. Methods The most recent 75 and oldest 75 randomised controlled trials published in leading journals over a 10-year period were identified. The reporting quality was analysed using the CONSORT statement, and methodological quality with the Intercollegiate Guidelines Network checklist. We used exploratory univariate and multivariable linear regression analysis to investigate associations. Findings Bibliometric parameters such as type of journal, study design reported in title, number of pages; external funding, industry sponsoring and number of citations are associated with reporting quality. Moreover, parameters such as type of journal, subject area and study design reported in title are associated with methodological quality. Conclusions The bibliometric parameters of randomised controlled trials may be independent predictors for their reporting and methodological quality. Moreover, the reporting quality of randomised controlled trials is associated with their methodological quality and vice versa.

Completeness of reporting in abstracts from clinical trials of pre-harvest interventions against foodborne pathogens.

PubMed

Snedeker, Kate G; Canning, Paisley; Totton, Sarah C; Sargeant, Jan M

2012-04-01

Abstracts are the most commonly read part of a journal article, and play an important role as summaries of the articles, and search and screening tools. However, research on abstracts in human biomedicine has shown that abstracts often do not report key methodological features and results. Little research has been done to examine reporting of such features in abstracts from papers detailing pre-harvest food safety trials. Thus, the objective of this study was to assess the quality of reporting of key factors in abstracts detailing trials of pre-harvest food safety interventions. A systematic search algorithm was used to identify all in vivo trials of pre-harvest interventions against foodborne pathogens in PubMed and CAB Direct published from 1999 to October 2009. References were screened for relevance, and 150 were randomly chosen for inclusion in the study. A checklist based on the CONSORT abstract extension and the REFLECT Statement was used to assess the reporting of methodological features and results. All screening and assessment was performed by two independent reviewers with disagreements resolved by consensus. The systematic search returned 3554 unique citations; 356 were found to be relevant and 150 were randomly selected for inclusion. The abstracts were from 51 different journals, and 13 out of 150 were structured. Of the 124 abstracts that reported whether the trial design was deliberate disease challenge or natural exposure, 113 were deliberate challenge and 11 natural exposure. 103 abstracts detailed studies involving poultry, 20 cattle and 15 swine. Most abstracts reported the production stage of the animals (135/150), a hypothesis or objective (123/150), and results for all treatment groups (136/150). However, few abstracts reported on how animals were grouped in housing (25/150), the location of the study (5/150), the primary outcome (2/126), level of treatment allocation (15/150), sample size (63/150) or whether study units were lost to follow up (4/150). Forty-eight (48/150) abstracts reported the name, mode of administration, dose and duration of the intervention(s), while 102 (102/150) reported at least one of these elements. Nine (9/150) abstracts specified that allocation of study units to treatments was randomized, and none of the abstracts reported whether blinding was used (0/150). These results reveal gaps in reporting of methodological features and results. Thus, improving reporting quality in abstracts should be a crucial goal to be pursued by authors, reviewers and journal editors. Copyright © 2011 Elsevier B.V. All rights reserved.

Evaluation of complex community-based childhood obesity prevention interventions.

PubMed

Karacabeyli, D; Allender, S; Pinkney, S; Amed, S

2018-05-16

Multi-setting, multi-component community-based interventions have shown promise in preventing childhood obesity; however, evaluation of these complex interventions remains a challenge. The objective of the study is to systematically review published methodological approaches to outcome evaluation for multi-setting community-based childhood obesity prevention interventions and synthesize a set of pragmatic recommendations. MEDLINE, CINAHL and PsycINFO were searched from inception to 6 July 2017. Papers were included if the intervention targeted children ≤18 years, engaged at least two community sectors and described their outcome evaluation methodology. A single reviewer conducted title and abstract scans, full article review and data abstraction. Directed content analysis was performed by three reviewers to identify prevailing themes. Thirty-three studies were included, and of these, 26 employed a quasi-experimental design; the remaining were randomized control trials. Body mass index was the most commonly measured outcome, followed by health behaviour change and psychosocial outcomes. Six themes emerged, highlighting advantages and disadvantages of active vs. passive consent, quasi-experimental vs. randomized control trials, longitudinal vs. repeat cross-sectional designs and the roles of process evaluation and methodological flexibility in evaluating complex interventions. Selection of study designs and outcome measures compatible with community infrastructure, accompanied by process evaluation, may facilitate successful outcome evaluation. © 2018 World Obesity Federation.

Technologies for Investigating the Physiological Barriers to Efficient Lipid Nanoparticle–siRNA Delivery

PubMed Central

Abrams, Marc

2013-01-01

Small interfering RNA (siRNA) therapeutics have advanced from bench to clinical trials in recent years, along with new tools developed to enable detection of siRNA delivered at the organ, cell, and subcellular levels. Preclinical models of siRNA delivery have benefitted from methodologies such as stem-loop quantitative polymerase chain reaction, histological in situ immunofluorescent staining, endosomal escape assay, and RNA-induced silencing complex loading assay. These technologies have accelerated the detection and optimization of siRNA platforms to overcome the challenges associated with delivering therapeutic oligonucleotides to the cytosol of specific target cells. This review focuses on the methodologies and their application in the biodistribution of siRNA delivered by lipid nanoparticles. PMID:23504369

Mind-body practices: an alternative, drug-free treatment for smoking cessation? A systematic review of the literature.

PubMed

Carim-Todd, Laura; Mitchell, Suzanne H; Oken, Barry S

2013-10-01

The limited success of current smoking cessation therapies encourages research into new treatment strategies. Mind-body practices such as yoga and meditation have the potential to aid smoking cessation and become an alternative drug-free treatment option. The aim of this article is to assess the efficacy of yoga and other meditation-based interventions for smoking cessation, to identify the challenges of clinical trials applying mind-body treatments, and to outline directions for future research on these types of therapies to assist in smoking cessation. A systematic review of the scientific literature. Fourteen clinical trials met the inclusion criteria defined for this review. Each article was reviewed thoroughly, and evaluated for quality, design, and methodology. Although primary outcomes differed between studies, the fourteen articles, most with limitations, reported promising effects supporting further investigation of the use of these practices to improve smoking cessation. The literature supports yoga and meditation-based therapies as candidates to assist smoking cessation. However, the small number of studies available and associated methodological problems require more clinical trials with larger sample sizes and carefully monitored interventions to determine rigorously if yoga and meditation are effective treatments. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Mind-body practices: an alternative, drug-free treatment for smoking cessation? A systematic review of the literature

PubMed Central

Carim-Todd, Laura; Mitchell, Suzanne H.; Oken, Barry S.

2013-01-01

Objective The limited success of current smoking cessation therapies encourages research into new treatment strategies. Mind-body practices such as yoga and meditation have the potential to aid smoking cessation and become an alternative drug-free treatment option. The aim of this article is to assess the efficacy of yoga and other meditation-based interventions for smoking cessation, to identify the challenges of clinical trials applying mind-body treatments, and to outline directions for future research on these types of mind-body therapies to assist in smoking cessation. Method A systematic review of the scientific literature. Results Fourteen clinical trials met the inclusion criteria defined for this review. Each article was reviewed thoroughly, and evaluated for quality, design, and methodology. Although primary outcomes differed between studies, the fourteen articles, most with some limitations, reported promising effects supporting further investigation of the use of these practices to improve smoking cessation. Conclusions The literature supports yoga and meditation-based therapies as candidates to assist smoking cessation. However, the small number of studies available and associated methodological problems require more clinical trials with larger sample sizes and carefully monitored interventions to determine rigorously if yoga and meditation are effective treatments. PMID:23664122

Tailored Communication Within Mobile Apps for Diabetes Self-Management: A Systematic Review.

PubMed

Holmen, Heidi; Wahl, Astrid Klopstad; Cvancarova Småstuen, Milada; Ribu, Lis

2017-06-23

The prevalence of diabetes is increasing and with the requirements for self-management and risk of late complications, it remains a challenge for the individual and society. Patients can benefit from support from health care personnel in their self-management, and the traditional communication between patients and health care personnel is changing. Smartphones and apps offer a unique platform for communication, but apps with integrated health care personnel communication based on patient data are yet to be investigated to provide evidence of possible effects. Our goal was to systematically review studies that aimed to evaluate integrated communication within mobile apps for tailored feedback between patients with diabetes and health care personnel in terms of (1) study characteristics, (2) functions, (3) study outcomes, (4) effects, and (5) methodological quality. A systematic literature search was conducted following our International Prospective Register of Systematic Reviews (PROSPERO) protocol, searching for apps with integrated communication for persons with diabetes tested in a controlled trial in the period 2008 to 2016. We searched the databases PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central, Excerpta Medica database (EMBASE), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform. The search was closed in September 2016. Reference lists of primary articles and review papers were assessed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and we applied the Cochrane risk of bias tool to assess methodological quality. We identified 2822 citations and after duplicate removal, we assessed 1128 citations. A total of 6 papers were included in this systematic review, reporting on data from 431 persons participating in small trials of short duration. The integrated communication features were mostly individualized as written non-real-time feedback. The number of functions varied from 2 to 9, and blood glucose tracking was the most common. HbA 1c was the most common primary outcome, but the remaining reported outcomes were not standardized and comparable. Because of both the heterogeneity of the included trials and the poor methodological quality of the studies, a meta-analysis was not possible. A statistically significant improvement in the primary measure of outcome was found in 3 of the 6 included studies, of which 2 were HbA 1c and 1 was mean daytime ambulatory blood pressure. Participants in the included trials reported positive usability or feasibility postintervention in 5 out of 6 trials. The overall methodological quality of the trials was, however, scored as an uncertain risk of bias. This systematic review highlights the need for more trials of higher methodological quality. Few studies offer an integrated function for communication and feedback from health care personnel, and the research field represents an area of heterogeneity with few studies of highly rigorous methodological quality. This, in combination with a low number of participants and a short follow-up, is making it difficult to provide reliable evidence of effects for stakeholders. ©Heidi Holmen, Astrid Klopstad Wahl, Milada Cvancarova Småstuen, Lis Ribu. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 23.06.2017.

DESIGNING PHASE 0 CANCER CLINICAL TRIALS

PubMed Central

Murgo, Anthony J.; Kummar, Shivaani; Rubinstein, Larry; Gutierrez, Martin; Collins, Jerry; Kinders, Robert; Parchment, Ralph E.; Ji, Jiuping; Steinberg, Seth M.; Yang, Sherry X.; Hollingshead, Melinda; Chen, Alice; Helman, Lee; Wiltrout, Robert; Tomaszewski, Joseph E.; Doroshow, James H.

2008-01-01

Phase 0 trials are designed primarily to evaluate the pharmacodynamic and/or pharmacokinetic properties of selected investigational agents prior to initiating more traditional phase 1 testing. One of the major objectives of phase 0 trials is to interrogate and refine a target or biomarker assay for drug effect in human samples implementing procedures developed and validated in preclinical models. Thus, close collaboration between laboratory scientists and clinical investigators is essential to the design and conduct of phase 0 trials. Given the relatively small number of patients and tissue samples, demonstrating a significant drug effect in phase 0 trials requires precise and reproducible assay procedures and innovative statistical methodology. Furthermore, phase 0 trials involving limited exposure of study agent administered at low doses and/or for a short period allows them to be initiated under the FDA Exploratory IND Guidance with less preclinical toxicity data than usually required for traditional first-in-human studies. Because of the very limited drug exposure, phase 0 trials offer no chance of therapeutic benefit, which can impede patient enrollment, particularly if invasive tumor biopsies are required. However, the challenges to accrual are not insurmountable, and well-designed and executed phase 0 trials are feasible and have great potential for improving the efficiency and success of subsequent trials, particularly those evaluating molecularly targeted agents. PMID:18559582

Linear Combinations of Multiple Outcome Measures to Improve the Power of Efficacy Analysis ---Application to Clinical Trials on Early Stage Alzheimer Disease

PubMed Central

Xiong, Chengjie; Luo, Jingqin; Morris, John C; Bateman, Randall

2018-01-01

Modern clinical trials on Alzheimer disease (AD) focus on the early symptomatic stage or even the preclinical stage. Subtle disease progression at the early stages, however, poses a major challenge in designing such clinical trials. We propose a multivariate mixed model on repeated measures to model the disease progression over time on multiple efficacy outcomes, and derive the optimum weights to combine multiple outcome measures by minimizing the sample sizes to adequately power the clinical trials. A cross-validation simulation study is conducted to assess the accuracy for the estimated weights as well as the improvement in reducing the sample sizes for such trials. The proposed methodology is applied to the multiple cognitive tests from the ongoing observational study of the Dominantly Inherited Alzheimer Network (DIAN) to power future clinical trials in the DIAN with a cognitive endpoint. Our results show that the optimum weights to combine multiple outcome measures can be accurately estimated, and that compared to the individual outcomes, the combined efficacy outcome with these weights significantly reduces the sample size required to adequately power clinical trials. When applied to the clinical trial in the DIAN, the estimated linear combination of six cognitive tests can adequately power the clinical trial. PMID:29546251

Changes in clinical trials methodology over time: a systematic review of six decades of research in psychopharmacology.

PubMed

Brunoni, André R; Tadini, Laura; Fregni, Felipe

2010-03-03

There have been many changes in clinical trials methodology since the introduction of lithium and the beginning of the modern era of psychopharmacology in 1949. The nature and importance of these changes have not been fully addressed to date. As methodological flaws in trials can lead to false-negative or false-positive results, the objective of our study was to evaluate the impact of methodological changes in psychopharmacology clinical research over the past 60 years. We performed a systematic review from 1949 to 2009 on MEDLINE and Web of Science electronic databases, and a hand search of high impact journals on studies of seven major drugs (chlorpromazine, clozapine, risperidone, lithium, fluoxetine and lamotrigine). All controlled studies published 100 months after the first trial were included. Ninety-one studies met our inclusion criteria. We analyzed the major changes in abstract reporting, study design, participants' assessment and enrollment, methodology and statistical analysis. Our results showed that the methodology of psychiatric clinical trials changed substantially, with quality gains in abstract reporting, results reporting, and statistical methodology. Recent trials use more informed consent, periods of washout, intention-to-treat approach and parametric tests. Placebo use remains high and unchanged over time. Clinical trial quality of psychopharmacological studies has changed significantly in most of the aspects we analyzed. There was significant improvement in quality reporting and internal validity. These changes have increased study efficiency; however, there is room for improvement in some aspects such as rating scales, diagnostic criteria and better trial reporting. Therefore, despite the advancements observed, there are still several areas that can be improved in psychopharmacology clinical trials.

Estimating the number needed to treat from continuous outcomes in randomised controlled trials: methodological challenges and worked example using data from the UK Back Pain Exercise and Manipulation (BEAM) trial.

PubMed

Froud, Robert; Eldridge, Sandra; Lall, Ranjit; Underwood, Martin

2009-06-11

Reporting numbers needed to treat (NNT) improves interpretability of trial results. It is unusual that continuous outcomes are converted to numbers of individual responders to treatment (i.e., those who reach a particular threshold of change); and deteriorations prevented are only rarely considered. We consider how numbers needed to treat can be derived from continuous outcomes; illustrated with a worked example showing the methods and challenges. We used data from the UK BEAM trial (n = 1, 334) of physical treatments for back pain; originally reported as showing, at best, small to moderate benefits. Participants were randomised to receive 'best care' in general practice, the comparator treatment, or one of three manual and/or exercise treatments: 'best care' plus manipulation, exercise, or manipulation followed by exercise. We used established consensus thresholds for improvement in Roland-Morris disability questionnaire scores at three and twelve months to derive NNTs for improvements and for benefits (improvements gained+deteriorations prevented). At three months, NNT estimates ranged from 5.1 (95% CI 3.4 to 10.7) to 9.0 (5.0 to 45.5) for exercise, 5.0 (3.4 to 9.8) to 5.4 (3.8 to 9.9) for manipulation, and 3.3 (2.5 to 4.9) to 4.8 (3.5 to 7.8) for manipulation followed by exercise. Corresponding between-group mean differences in the Roland-Morris disability questionnaire were 1.6 (0.8 to 2.3), 1.4 (0.6 to 2.1), and 1.9 (1.2 to 2.6) points. In contrast to small mean differences originally reported, NNTs were small and could be attractive to clinicians, patients, and purchasers. NNTs can aid the interpretation of results of trials using continuous outcomes. Where possible, these should be reported alongside mean differences. Challenges remain in calculating NNTs for some continuous outcomes. UK BEAM trial registration: ISRCTN32683578.

Fundamentals and Catalytic Innovation: The Statistical and Data Management Center of the Antibacterial Resistance Leadership Group

PubMed Central

Huvane, Jacqueline; Komarow, Lauren; Hill, Carol; Tran, Thuy Tien T.; Pereira, Carol; Rosenkranz, Susan L.; Finnemeyer, Matt; Earley, Michelle; Jiang, Hongyu (Jeanne); Wang, Rui; Lok, Judith

2017-01-01

Abstract The Statistical and Data Management Center (SDMC) provides the Antibacterial Resistance Leadership Group (ARLG) with statistical and data management expertise to advance the ARLG research agenda. The SDMC is active at all stages of a study, including design; data collection and monitoring; data analyses and archival; and publication of study results. The SDMC enhances the scientific integrity of ARLG studies through the development and implementation of innovative and practical statistical methodologies and by educating research colleagues regarding the application of clinical trial fundamentals. This article summarizes the challenges and roles, as well as the innovative contributions in the design, monitoring, and analyses of clinical trials and diagnostic studies, of the ARLG SDMC. PMID:28350899

Enhancing the development and approval of acute stroke therapies: Stroke Therapy Academic Industry roundtable.

PubMed

Fisher, Marc; Albers, Gregory W; Donnan, Geoffrey A; Furlan, Anthony J; Grotta, James C; Kidwell, Chelsea S; Sacco, Ralph L; Wechsler, Lawrence R

2005-08-01

Previous Stroke Therapy Academic Industry Roundtable (STAIR) meetings focused on preclinical evidence of drug efficacy and enhancing acute stroke trial design and performance. A fourth (STAIR-IV) was held to discuss relevant issues related to acute stroke drug development and regulatory approval. The STAIR-IV meeting had 3 main focus areas. The first topic was novel approaches to statistical design of acute stroke trials and appropriate outcome measures. The second focus was the need for better cooperation among participants in stroke therapy development that may be addressed through a national consortium of stroke trial centers in the United States and elsewhere. Lastly, regulatory issues related to the approval of novel mono and multiple acute stroke therapies were discussed. The development of additional acute stroke therapies represents a large unmet need with many remaining challenges and also opportunities to incorporate novel approaches to clinical trial design that will lead to regulatory approval. The STAIR-IV meeting explored new concepts of trial methodology and data analysis, initiatives for implementing a US clinical trialist consortium, and pertinent regulatory issues to expedite approval of novel therapies.

Advances towards the design and development of personalized non-small-cell lung cancer drug therapy.

PubMed

Vari, Sabrina; Pilotto, Sara; Maugeri-Saccà, Marcello; Ciuffreda, Ludovica; Cesta Incani, Ursula; Falcone, Italia; Del Curatolo, Anais; Ceribelli, Anna; Gelibter, Alain; De Maria, Ruggero; Tortora, Giampaolo; Cognetti, Francesco; Bria, Emilio; Milella, Michele

2013-11-01

Non-small-cell lung cancer (NSCLC) subtypes are driven by specific genetic aberrations. For reasons such as this, there is a call for treatment personalization. The ability to instigate NSCLC fragmentation poses new methodological problems, and new 'driver' molecular aberrations are being discovered at an unprecedented pace. This article describes the clinical development of epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib for EGFR-mutant and anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Further, the authors briefly describe the emerging molecular targets in NSCLC, in terms of both rationale for therapeutic targeting and strategies, for clinical development. Target identification and validation in NSCLC still requires considerable effort, as not all of the molecular alterations are clear 'drivers' nor can they be efficiently targeted with available drugs. However, 50% of the NSCLC cases are without clear-defined molecular aberrations. Clinical trial methodology will need to develop novel paradigms for targeted drug development, aiming at the validation of an ideal 'biology-to-trial' approach. Despite significant challenges, a truly 'personalized' approach to NSCLC therapy appears to be within our reach.

[Methodological quality and reporting quality evaluation of randomized controlled trials published in China Journal of Chinese Materia Medica].

PubMed

Yu, Dan-Dan; Xie, Yan-Ming; Liao, Xing; Zhi, Ying-Jie; Jiang, Jun-Jie; Chen, Wei

2018-02-01

To evaluate the methodological quality and reporting quality of randomized controlled trials(RCTs) published in China Journal of Chinese Materia Medica, we searched CNKI and China Journal of Chinese Materia webpage to collect RCTs since the establishment of the magazine. The Cochrane risk of bias assessment tool was used to evaluate the methodological quality of RCTs. The CONSORT 2010 list was adopted as reporting quality evaluating tool. Finally, 184 RCTs were included and evaluated methodologically, of which 97 RCTs were evaluated with reporting quality. For the methodological evaluating, 62 trials(33.70%) reported the random sequence generation; 9(4.89%) trials reported the allocation concealment; 25(13.59%) trials adopted the method of blinding; 30(16.30%) trials reported the number of patients withdrawing, dropping out and those lost to follow-up;2 trials （1.09%） reported trial registration and none of the trial reported the trial protocol; only 8(4.35%) trials reported the sample size estimation in details. For reporting quality appraising, 3 reporting items of 25 items were evaluated with high-quality,including: abstract, participants qualified criteria, and statistical methods; 4 reporting items with medium-quality, including purpose, intervention, random sequence method, and data collection of sites and locations; 9 items with low-quality reporting items including title, backgrounds, random sequence types, allocation concealment, blindness, recruitment of subjects, baseline data, harms, and funding;the rest of items were of extremely low quality(the compliance rate of reporting item<10%). On the whole, the methodological and reporting quality of RCTs published in the magazine are generally low. Further improvement in both methodological and reporting quality for RCTs of traditional Chinese medicine are warranted. It is recommended that the international standards and procedures for RCT design should be strictly followed to conduct high-quality trials. At the same time, in order to improve the reporting quality of randomized controlled trials, CONSORT standards should be adopted in the preparation of research reports and submissions. Copyright© by the Chinese Pharmaceutical Association.

[Radiotherapy phase I trials' methodology: Features].

PubMed

Rivoirard, R; Vallard, A; Langrand-Escure, J; Guy, J-B; Ben Mrad, M; Yaoxiong, X; Diao, P; Méry, B; Pigne, G; Rancoule, C; Magné, N

2016-12-01

In clinical research, biostatistical methods allow the rigorous analysis of data collection and should be defined from the trial design to obtain the appropriate experimental approach. Thus, if the main purpose of phase I is to determine the dose to use during phase II, methodology should be finely adjusted to experimental treatment(s). Today, the methodology for chemotherapy and targeted therapy is well known. For radiotherapy and chemoradiotherapy phase I trials, the primary endpoint must reflect both effectiveness and potential treatment toxicities. Methodology should probably be complex to limit failures in the following phases. However, there are very few data about methodology design in the literature. The present study focuses on these particular trials and their characteristics. It should help to raise existing methodological patterns shortcomings in order to propose new and better-suited designs. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

The Development of a Minority Recruitment Plan for Cancer Clinical Trials

PubMed Central

Trevino, Monica; Padalecki, Susan; Karnad, Anand; Parra, Alberto; Weitman, Steve; Nashawati, Melissa; Pollock, Brad H.; Ramirez, Amelie; Thompson, Ian M.

2014-01-01

Background Cancer does not occur in all ethnic and racial groups at similar rates. In addition, responses to treatment also vary in certain ethnic and racial groups. For Hispanics, the overall cancer incidence is generally lower yet for some specific tumor types, the incidence rates are higher compared to other populations. Objectives Although disparities are recognized for treatment outcomes and prevention methodologies for Hispanics and other minority populations, specific recruiting and reporting of minorities remains a challenge. In order to circumvent this problem, the Cancer Therapy and Research Center (CTRC) has developed a new minority recruitment plan for all cancer related clinical trials at this Institute. The overall goal of this initiative is to increase the accrual of minorities in cancer clinical trials by implementing several key interventions. Method The Cancer Therapy & Research Center (CTRC) at the University of Texas Health Science Center at San Antonio established the Clinical Trials Accrual Task Force to develop and monitor interventions designed to increase accrual to cancer clinical trials, specifically the accrual of minorities with a focus on the Hispanic population that makes up 68% of the CTRC's catchment area. Results A Minority Accrual Plan (MAP) was implemented in March 2013 as part of the process for initiating and conducting cancer-related clinical trials at the CTRC. The Minority Accrual Plan focuses on Hispanic enrollment due to the characteristics of the South Texas population served by the CTRC but could be easily adapted to other populations. Conclusions The CTRC has designed a process to prospectively address the challenge of deliberately enrolling minority subjects and accurately accounting for the results by implementing a Minority Accrual Plan for every cancer-related clinical trial at CTRC. PMID:25152846

The Development of a Minority Recruitment Plan for Cancer Clinical Trials.

PubMed

Trevino, Monica; Padalecki, Susan; Karnad, Anand; Parra, Alberto; Weitman, Steve; Nashawati, Melissa; Pollock, Brad H; Ramirez, Amelie; Thompson, Ian M

2013-09-01

Cancer does not occur in all ethnic and racial groups at similar rates. In addition, responses to treatment also vary in certain ethnic and racial groups. For Hispanics, the overall cancer incidence is generally lower yet for some specific tumor types, the incidence rates are higher compared to other populations. Although disparities are recognized for treatment outcomes and prevention methodologies for Hispanics and other minority populations, specific recruiting and reporting of minorities remains a challenge. In order to circumvent this problem, the Cancer Therapy and Research Center (CTRC) has developed a new minority recruitment plan for all cancer related clinical trials at this Institute. The overall goal of this initiative is to increase the accrual of minorities in cancer clinical trials by implementing several key interventions. The Cancer Therapy & Research Center (CTRC) at the University of Texas Health Science Center at San Antonio established the Clinical Trials Accrual Task Force to develop and monitor interventions designed to increase accrual to cancer clinical trials, specifically the accrual of minorities with a focus on the Hispanic population that makes up 68% of the CTRC's catchment area. A Minority Accrual Plan (MAP) was implemented in March 2013 as part of the process for initiating and conducting cancer-related clinical trials at the CTRC. The Minority Accrual Plan focuses on Hispanic enrollment due to the characteristics of the South Texas population served by the CTRC but could be easily adapted to other populations. The CTRC has designed a process to prospectively address the challenge of deliberately enrolling minority subjects and accurately accounting for the results by implementing a Minority Accrual Plan for every cancer-related clinical trial at CTRC.

Challenging the epidemiologic evidence on passive smoking: tactics of tobacco industry expert witnesses.

PubMed

Francis, John A; Shea, Amy K; Samet, Jonathan M

2006-12-01

To analyse the statements given by tobacco industry defence witnesses during trial testimonies and depositions in second-hand smoke cases and in parallel, to review criticisms of epidemiology in industry-funded publications in order to identify strategies for discrediting epidemiologic evidence on passive smoking health effects. A collection of depositions and trial testimony transcripts from tobacco industry-related lawsuits filed in the United States during the 1990s, was compiled and indexed by the Tobacco Deposition and Trial Testimony Archive (DATTA). Statements in DATTA made by expert witnesses representing the tobacco industry relating to the health effects of passive smoking were identified and reviewed. Industry-supported publications within the peer-reviewed literature were also examined for statements on exposure misclassification, meta-analysis, and confounding. The witnesses challenged causation of adverse health effects of passive smoking by citing limitations of epidemiologic research, raising methodological and statistical issues, and disputing biological plausibility. Though not often cited directly by the witnesses, the defence tactics mirrored the strategies used in industry-funded reports in the peer-reviewed literature. The tobacco industry attempted to redirect the focus and dialogue related to the epidemiologic evidence on passive smoking. This approach, used by industry experts in trial testimony and depositions, placed bias as a certain alternative to causation of diseases related to passive smoking and proposed an unachievable standard for establishing the mechanism of disease.

Employing Earned Value Management in Government Research and Design - Lessons Learned from the Trenches

NASA Technical Reports Server (NTRS)

Simon, Tom

2009-01-01

To effectively manage a project, the project manager must have a plan, understand the current conditions, and be able to take action to correct the course when challenges arise. Research and design projects face technical, schedule, and budget challenges that make it difficult to utilize project management tools developed for projects based on previously demonstrated technologies. Projects developing new technologies by their inherent nature are trying something new and thus have little to no data to support estimates for schedule and cost, let alone the technical outcome. Projects with a vision for the outcome but little confidence in the exact tasks to accomplish in order to achieve the vision incur cost and schedule penalties when conceptual solutions require unexpected iterations or even a reinvention of the plan. This presentation will share the project management methodology and tools developed through trial and error for a NASA research and design project combining industry, academia, and NASA inhouse work in which Earned Value Management principles were employed but adapted for the reality of the government financial system and the reality of challenging technology development. The priorities of the presented methodology are flexibility, accountability, and simplicity to give the manager tools to help deliver to the customer while not using up valuable time and resources on extensive planning and analysis. This presentation will share the methodology, tools, and work through failed and successful examples from the three years of process evolution.

The Database for Aggregate Analysis of ClinicalTrials.gov (AACT) and Subsequent Regrouping by Clinical Specialty

PubMed Central

Tasneem, Asba; Aberle, Laura; Ananth, Hari; Chakraborty, Swati; Chiswell, Karen; McCourt, Brian J.; Pietrobon, Ricardo

2012-01-01

Background The ClinicalTrials.gov registry provides information regarding characteristics of past, current, and planned clinical studies to patients, clinicians, and researchers; in addition, registry data are available for bulk download. However, issues related to data structure, nomenclature, and changes in data collection over time present challenges to the aggregate analysis and interpretation of these data in general and to the analysis of trials according to clinical specialty in particular. Improving usability of these data could enhance the utility of ClinicalTrials.gov as a research resource. Methods/Principal Results The purpose of our project was twofold. First, we sought to extend the usability of ClinicalTrials.gov for research purposes by developing a database for aggregate analysis of ClinicalTrials.gov (AACT) that contains data from the 96,346 clinical trials registered as of September 27, 2010. Second, we developed and validated a methodology for annotating studies by clinical specialty, using a custom taxonomy employing Medical Subject Heading (MeSH) terms applied by an NLM algorithm, as well as MeSH terms and other disease condition terms provided by study sponsors. Clinical specialists reviewed and annotated MeSH and non-MeSH disease condition terms, and an algorithm was created to classify studies into clinical specialties based on both MeSH and non-MeSH annotations. False positives and false negatives were evaluated by comparing algorithmic classification with manual classification for three specialties. Conclusions/Significance The resulting AACT database features study design attributes parsed into discrete fields, integrated metadata, and an integrated MeSH thesaurus, and is available for download as Oracle extracts (.dmp file and text format). This publicly-accessible dataset will facilitate analysis of studies and permit detailed characterization and analysis of the U.S. clinical trials enterprise as a whole. In addition, the methodology we present for creating specialty datasets may facilitate other efforts to analyze studies by specialty groups. PMID:22438982

The database for aggregate analysis of ClinicalTrials.gov (AACT) and subsequent regrouping by clinical specialty.

PubMed

Tasneem, Asba; Aberle, Laura; Ananth, Hari; Chakraborty, Swati; Chiswell, Karen; McCourt, Brian J; Pietrobon, Ricardo

2012-01-01

The ClinicalTrials.gov registry provides information regarding characteristics of past, current, and planned clinical studies to patients, clinicians, and researchers; in addition, registry data are available for bulk download. However, issues related to data structure, nomenclature, and changes in data collection over time present challenges to the aggregate analysis and interpretation of these data in general and to the analysis of trials according to clinical specialty in particular. Improving usability of these data could enhance the utility of ClinicalTrials.gov as a research resource. The purpose of our project was twofold. First, we sought to extend the usability of ClinicalTrials.gov for research purposes by developing a database for aggregate analysis of ClinicalTrials.gov (AACT) that contains data from the 96,346 clinical trials registered as of September 27, 2010. Second, we developed and validated a methodology for annotating studies by clinical specialty, using a custom taxonomy employing Medical Subject Heading (MeSH) terms applied by an NLM algorithm, as well as MeSH terms and other disease condition terms provided by study sponsors. Clinical specialists reviewed and annotated MeSH and non-MeSH disease condition terms, and an algorithm was created to classify studies into clinical specialties based on both MeSH and non-MeSH annotations. False positives and false negatives were evaluated by comparing algorithmic classification with manual classification for three specialties. The resulting AACT database features study design attributes parsed into discrete fields, integrated metadata, and an integrated MeSH thesaurus, and is available for download as Oracle extracts (.dmp file and text format). This publicly-accessible dataset will facilitate analysis of studies and permit detailed characterization and analysis of the U.S. clinical trials enterprise as a whole. In addition, the methodology we present for creating specialty datasets may facilitate other efforts to analyze studies by specialty groups.

Global health trials methodological research agenda: results from a priority setting exercise.

PubMed

Rosala-Hallas, Anna; Bhangu, Aneel; Blazeby, Jane; Bowman, Louise; Clarke, Mike; Lang, Trudie; Nasser, Mona; Siegfried, Nandi; Soares-Weiser, Karla; Sydes, Matt R; Wang, Duolao; Zhang, Junhua; Williamson, Paula R

2018-02-05

Methodological research into the design, conduct, analysis and reporting of trials is essential to optimise the process. UK specialists in the field have established a set of top priorities in aid of this research. These priorities, however, may not be reflected in the needs of similar research in low- to middle-income countries (LMICs) with different healthcare provision, resources and research infrastructure. The aim of the study was to identify the top priorities for methodological research in LMICs to inform further research and ultimately to improve clinical trials in these regions. An online, two-round survey was conducted from December 2016 to April 2017 amongst researchers and methodologists working on trials in LMICs. The first round required participants to suggest between three and six topics which they felt were priorities for trial methodological research in LMICs. The second round invited participants to grade the importance of a compulsory list of topics suggested by four or more individuals, and an optional list of the remaining topics. Rounds 1 and 2 were completed by 412 and 314 participants, respectively. A wide spread of years of experience, discipline, current country of residence, origin of trials training and area of involvement in trials was reported. The topics deemed most important for methodological research were: choosing appropriate outcomes to measure and training of research staff. By presenting these top priorities we have the foundations of a global health trials methodological research agenda which we hope will foster future research in specific areas in order to increase and improve trials in LMICs.

Perceptions of Massage Therapists Participating in a Randomized Controlled Trial

PubMed Central

Perlman, Adam; Dreusicke, Mark; Keever, Teresa; Ali, Ather

2015-01-01

Background Clinical practice and randomized trials often have disparate aims, despite involving similar interventions. Attitudes and expectancies of practitioners influence patient outcomes, and there is growing emphasis on optimizing provider–patient relationships. In this study, we evaluated the experiences of licensed massage therapists involved in a randomized controlled clinical trial using qualitative methodology. Methods Seven massage therapists who were interventionists in a randomized controlled trial participated in structured interviews approximately 30 minutes in length. Interviews focused on their experiences and perceptions regarding aspects of the clinical trial, as well as recommendations for future trials. Transcribed interviews were analyzed for emergent topics and themes using standard qualitative methods. Results Six themes emerged. Therapists discussed 1) promoting the profession of massage therapy through research, 2) mixed views on using standardized protocols, 3) challenges of sham interventions, 4) participant response to the sham intervention, 5) views on scheduling and compensation, and 6) unanticipated benefits of participating in research. Conclusions Therapists largely appreciated the opportunity to promote massage through research. They demonstrated insight and understanding of the rationale for a clinical trial adhering to a standardized protocol. Evaluating the experiences and ideas of complementary and alternative medicine practitioners provides valuable insight that is relevant for the implementation and design of randomized trials. PMID:26388961

Clinical trials of homoeopathy.

PubMed Central

Kleijnen, J; Knipschild, P; ter Riet, G

1991-01-01

OBJECTIVE--To establish whether there is evidence of the efficacy of homoeopathy from controlled trials in humans. DESIGN--Criteria based meta-analysis. Assessment of the methodological quality of 107 controlled trials in 96 published reports found after an extensive search. Trials were scored using a list of predefined criteria of good methodology, and the outcome of the trials was interpreted in relation to their quality. SETTING--Controlled trials published world wide. MAIN OUTCOME MEASURES--Results of the trials with the best methodological quality. Trials of classical homoeopathy and several modern varieties were considered separately. RESULTS--In 14 trials some form of classical homoeopathy was tested and in 58 trials the same single homoeopathic treatment was given to patients with comparable conventional diagnosis. Combinations of several homoeopathic treatments were tested in 26 trials; isopathy was tested in nine trials. Most trials seemed to be of very low quality, but there were many exceptions. The results showed a positive trend regardless of the quality of the trial or the variety of homeopathy used. Overall, of the 105 trials with interpretable results, 81 trials indicated positive results whereas in 24 trials no positive effects of homoeopathy were found. The results of the review may be complicated by publication bias, especially in such a controversial subject as homoeopathy. CONCLUSIONS--At the moment the evidence of clinical trials is positive but not sufficient to draw definitive conclusions because most trials are of low methodological quality and because of the unknown role of publication bias. This indicates that there is a legitimate case for further evaluation of homoeopathy, but only by means of well performed trials. PMID:1825800

The ethics of placebo-controlled trials: methodological justifications.

PubMed

Millum, Joseph; Grady, Christine

2013-11-01

The use of placebo controls in clinical trials remains controversial. Ethical analysis and international ethical guidance permit the use of placebo controls in randomized trials when scientifically indicated in four cases: (1) when there is no proven effective treatment for the condition under study; (2) when withholding treatment poses negligible risks to participants; (3) when there are compelling methodological reasons for using placebo, and withholding treatment does not pose a risk of serious harm to participants; and, more controversially, (4) when there are compelling methodological reasons for using placebo, and the research is intended to develop interventions that can be implemented in the population from which trial participants are drawn, and the trial does not require participants to forgo treatment they would otherwise receive. The concept of methodological reasons is essential to assessing the ethics of placebo controls in these controversial last two cases. This article sets out key considerations relevant to considering whether methodological reasons for a placebo control are compelling. © 2013.

Randomized clinical trials in dentistry: Risks of bias, risks of random errors, reporting quality, and methodologic quality over the years 1955–2013

PubMed Central

Armijo-Olivo, Susan; Cummings, Greta G.; Amin, Maryam; Flores-Mir, Carlos

2017-01-01

Objectives To examine the risks of bias, risks of random errors, reporting quality, and methodological quality of randomized clinical trials of oral health interventions and the development of these aspects over time. Methods We included 540 randomized clinical trials from 64 selected systematic reviews. We extracted, in duplicate, details from each of the selected randomized clinical trials with respect to publication and trial characteristics, reporting and methodologic characteristics, and Cochrane risk of bias domains. We analyzed data using logistic regression and Chi-square statistics. Results Sequence generation was assessed to be inadequate (at unclear or high risk of bias) in 68% (n = 367) of the trials, while allocation concealment was inadequate in the majority of trials (n = 464; 85.9%). Blinding of participants and blinding of the outcome assessment were judged to be inadequate in 28.5% (n = 154) and 40.5% (n = 219) of the trials, respectively. A sample size calculation before the initiation of the study was not performed/reported in 79.1% (n = 427) of the trials, while the sample size was assessed as adequate in only 17.6% (n = 95) of the trials. Two thirds of the trials were not described as double blinded (n = 358; 66.3%), while the method of blinding was appropriate in 53% (n = 286) of the trials. We identified a significant decrease over time (1955–2013) in the proportion of trials assessed as having inadequately addressed methodological quality items (P < 0.05) in 30 out of the 40 quality criteria, or as being inadequate (at high or unclear risk of bias) in five domains of the Cochrane risk of bias tool: sequence generation, allocation concealment, incomplete outcome data, other sources of bias, and overall risk of bias. Conclusions The risks of bias, risks of random errors, reporting quality, and methodological quality of randomized clinical trials of oral health interventions have improved over time; however, further efforts that contribute to the development of more stringent methodology and detailed reporting of trials are still needed. PMID:29272315

Randomized clinical trials in dentistry: Risks of bias, risks of random errors, reporting quality, and methodologic quality over the years 1955-2013.

PubMed

Saltaji, Humam; Armijo-Olivo, Susan; Cummings, Greta G; Amin, Maryam; Flores-Mir, Carlos

2017-01-01

To examine the risks of bias, risks of random errors, reporting quality, and methodological quality of randomized clinical trials of oral health interventions and the development of these aspects over time. We included 540 randomized clinical trials from 64 selected systematic reviews. We extracted, in duplicate, details from each of the selected randomized clinical trials with respect to publication and trial characteristics, reporting and methodologic characteristics, and Cochrane risk of bias domains. We analyzed data using logistic regression and Chi-square statistics. Sequence generation was assessed to be inadequate (at unclear or high risk of bias) in 68% (n = 367) of the trials, while allocation concealment was inadequate in the majority of trials (n = 464; 85.9%). Blinding of participants and blinding of the outcome assessment were judged to be inadequate in 28.5% (n = 154) and 40.5% (n = 219) of the trials, respectively. A sample size calculation before the initiation of the study was not performed/reported in 79.1% (n = 427) of the trials, while the sample size was assessed as adequate in only 17.6% (n = 95) of the trials. Two thirds of the trials were not described as double blinded (n = 358; 66.3%), while the method of blinding was appropriate in 53% (n = 286) of the trials. We identified a significant decrease over time (1955-2013) in the proportion of trials assessed as having inadequately addressed methodological quality items (P < 0.05) in 30 out of the 40 quality criteria, or as being inadequate (at high or unclear risk of bias) in five domains of the Cochrane risk of bias tool: sequence generation, allocation concealment, incomplete outcome data, other sources of bias, and overall risk of bias. The risks of bias, risks of random errors, reporting quality, and methodological quality of randomized clinical trials of oral health interventions have improved over time; however, further efforts that contribute to the development of more stringent methodology and detailed reporting of trials are still needed.

Multi-disciplinary rehabilitation for acquired brain injury in adults of working age.

PubMed

Turner-Stokes, Lynne; Pick, Anton; Nair, Ajoy; Disler, Peter B; Wade, Derick T

2015-12-22

Evidence from systematic reviews demonstrates that multi-disciplinary rehabilitation is effective in the stroke population, in which older adults predominate. However, the evidence base for the effectiveness of rehabilitation following acquired brain injury (ABI) in younger adults has not been established, perhaps because this scenario presents different methodological challenges in research. To assess the effects of multi-disciplinary rehabilitation following ABI in adults 16 to 65 years of age. We ran the most recent search on 14 September 2015. We searched the Cochrane Injuries Group Specialised Register, The Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (OvidSP), Web of Science (ISI WOS) databases, clinical trials registers, and we screened reference lists. Randomised controlled trials (RCTs) comparing multi-disciplinary rehabilitation versus routinely available local services or lower levels of intervention; or trials comparing an intervention in different settings, of different intensities or of different timing of onset. Controlled clinical trials were included, provided they met pre-defined methodological criteria. Three review authors independently selected trials and rated their methodological quality. A fourth review author would have arbitrated if consensus could not be reached by discussion, but in fact, this did not occur. As in previous versions of this review, we used the method described by Van Tulder 1997 to rate the quality of trials and to perform a 'best evidence' synthesis by attributing levels of evidence on the basis of methodological quality. Risk of bias assessments were performed in parallel using standard Cochrane methodology. However, the Van Tulder system provided a more discriminative evaluation of rehabilitation trials, so we have continued to use it for our primary synthesis of evidence. We subdivided trials in terms of severity of brain injury, setting and type and timing of rehabilitation offered. We identified a total of 19 studies involving 3480 people. Twelve studies were of good methodological quality and seven were of lower quality, according to the van Tulder scoring system. Within the subgroup of predominantly mild brain injury, 'strong evidence' suggested that most individuals made a good recovery when appropriate information was provided, without the need for additional specific interventions. For moderate to severe injury, 'strong evidence' showed benefit from formal intervention, and 'limited evidence' indicated that commencing rehabilitation early after injury results in better outcomes. For participants with moderate to severe ABI already in rehabilitation, 'strong evidence' revealed that more intensive programmes are associated with earlier functional gains, and 'moderate evidence' suggested that continued outpatient therapy could help to sustain gains made in early post-acute rehabilitation. The context of multi-disciplinary rehabilitation appears to influence outcomes. 'Strong evidence' supports the use of a milieu-oriented model for patients with severe brain injury, in which comprehensive cognitive rehabilitation takes place in a therapeutic environment and involves a peer group of patients. 'Limited evidence' shows that specialist in-patient rehabilitation and specialist multi-disciplinary community rehabilitation may provide additional functional gains, but studies serve to highlight the particular practical and ethical restraints imposed on randomisation of severely affected individuals for whom no realistic alternatives to specialist intervention are available. Problems following ABI vary. Consequently, different interventions and combinations of interventions are required to meet the needs of patients with different problems. Patients who present acutely to hospital with mild brain injury benefit from follow-up and appropriate information and advice. Those with moderate to severe brain injury benefit from routine follow-up so their needs for rehabilitation can be assessed. Intensive intervention appears to lead to earlier gains, and earlier intervention whilst still in emergency and acute care has been supported by limited evidence. The balance between intensity and cost-effectiveness has yet to be determined. Patients discharged from in-patient rehabilitation benefit from access to out-patient or community-based services appropriate to their needs. Group-based rehabilitation in a therapeutic milieu (where patients undergo neuropsychological rehabilitation in a therapeutic environment with a peer group of individuals facing similar challenges) represents an effective approach for patients requiring neuropsychological rehabilitation following severe brain injury. Not all questions in rehabilitation can be addressed by randomised controlled trials or other experimental approaches. For example, trial-based literature does not tell us which treatments work best for which patients over the long term, and which models of service represent value for money in the context of life-long care. In the future, such questions will need to be considered alongside practice-based evidence gathered from large systematic longitudinal cohort studies conducted in the context of routine clinical practice.

Economic evaluation of nurse practitioner and clinical nurse specialist roles: A methodological review.

PubMed

Lopatina, Elena; Donald, Faith; DiCenso, Alba; Martin-Misener, Ruth; Kilpatrick, Kelley; Bryant-Lukosius, Denise; Carter, Nancy; Reid, Kim; Marshall, Deborah A

2017-07-01

Advanced practice nurses (e.g., nurse practitioners and clinical nurse specialists) have been introduced internationally to increase access to high quality care and to tackle increasing health care expenditures. While randomised controlled trials and systematic reviews have demonstrated the effectiveness of nurse practitioner and clinical nurse specialist roles, their cost-effectiveness has been challenged. The poor quality of economic evaluations of these roles to date raises the question of whether current economic evaluation guidelines are adequate when examining their cost-effectiveness. To examine whether current guidelines for economic evaluation are appropriate for economic evaluations of nurse practitioner and clinical nurse specialist roles. Our methodological review was informed by a qualitative synthesis of four sources of information: 1) narrative review of literature reviews and discussion papers on economic evaluation of advanced practice nursing roles; 2) quality assessment of economic evaluations of nurse practitioner and clinical nurse specialist roles alongside randomised controlled trials; 3) review of guidelines for economic evaluation; and, 4) input from an expert panel. The narrative literature review revealed several challenges in economic evaluations of advanced practice nursing roles (e.g., complexity of the roles, variability in models and practice settings where the roles are implemented, and impact on outcomes that are difficult to measure). The quality assessment of economic evaluations of nurse practitioner and clinical nurse specialist roles alongside randomised controlled trials identified methodological limitations of these studies. When we applied the Guidelines for the Economic Evaluation of Health Technologies: Canada to the identified challenges and limitations, discussed those with experts and qualitatively synthesized all findings, we concluded that standard guidelines for economic evaluation are appropriate for economic evaluations of nurse practitioner and clinical nurse specialist roles and should be routinely followed. However, seven out of 15 current guideline sections (describing a decision problem, choosing type of economic evaluation, selecting comparators, determining the study perspective, estimating effectiveness, measuring and valuing health, and assessing resource use and costs) may require additional role-specific considerations to capture costs and effects of these roles. Current guidelines for economic evaluation should form the foundation for economic evaluations of nurse practitioner and clinical nurse specialist roles. The proposed role-specific considerations, which clarify application of standard guidelines sections to economic evaluation of nurse practitioner and clinical nurse specialist roles, may strengthen the quality and comprehensiveness of future economic evaluations of these roles. Copyright © 2017 Elsevier Ltd. All rights reserved.

Creating a database of internet-based clinical trials to support a public-led research programme: A descriptive analysis.

PubMed

Brice, Anne; Price, Amy; Burls, Amanda

2015-01-01

Online trials are rapidly growing in number, offering potential benefits but also methodological, ethical and social challenges. The International Network for Knowledge on Well-being (ThinkWell™) aims to increase public and patient participation in the prioritisation, design and conduct of research through the use of technologies. We aim to provide a baseline understanding of the online trial environment, determining how many trials have used internet-based technologies; how they have been used; and how use has developed over time. We searched a range of bibliographic databases to March 2015, with no date limits, supplemented by citation searching and references provided by experts in the field. Results were screened against inclusion and exclusion criteria, and included studies mapped against a number of key dimensions, with key themes developed iteratively throughout the process. We identified 1992 internet-based trials to March 2015. The number of reported studies increased substantially over the study timeframe. The largest number of trials were conducted in the USA (49.7%), followed by The Netherlands (10.2%); Australia (8.5%); the United Kingdom (5.8%); Sweden (4.6%); Canada (4%); and Germany (2.6%). South Korea (1.5%) has the highest number of reported trials for other continents. There is a predominance of interventions addressing core public health challenges including obesity (8.6%), smoking cessation (5.9%), alcohol abuse (7.7%) and physical activity (10.2%); in mental health issues such as depression (10.9%) and anxiety (5.6%); and conditions where self-management (16.6%) or monitoring (8.1%) is a major feature of care. The results confirm an increase in the use of the internet in trials. Key themes have emerged from the analysis and further research will be undertaken in order to investigate how the data can be used to improve trial design and recruitment, and to build an open access resource to support the public-led research agenda.

Topical, Biological and Clinical Challenges in the Management of Patients with Acne Vulgaris

PubMed Central

Al-Hammadi, Anwar; Al-Ismaily, Abla; Al-Ali, Sameer; Ramadurai, Rajesh; Jain, Rishi; McKinley-Grant, Lynn; Mughal, Tariq I.

2016-01-01

Acne vulgaris is one of the most common chronic inflammatory skin disorders among adolescents and young adults. It is associated with substantial morbidity and, rarely, with mortality. The exact worldwide incidence and prevalence are currently unknown. Current challenges involve improving understanding of the underlying pathophysiology of acne vulgaris and developing a practical treatment consensus. Expert panel discussions were held in 2013 and 2014 among a group of scientists and clinicians from the Omani and United Arab Emirate Dermatology Societies to ascertain the current optimal management of acne vulgaris, identify clinically relevant end-points and construct suitable methodology for future clinical trial designs. This article reviews the discussions of these sessions and recent literature on this topic. PMID:27226905

Control group design: enhancing rigor in research of mind-body therapies for depression.

PubMed

Kinser, Patricia Anne; Robins, Jo Lynne

2013-01-01

Although a growing body of research suggests that mind-body therapies may be appropriate to integrate into the treatment of depression, studies consistently lack methodological sophistication particularly in the area of control groups. In order to better understand the relationship between control group selection and methodological rigor, we provide a brief review of the literature on control group design in yoga and tai chi studies for depression, and we discuss challenges we have faced in the design of control groups for our recent clinical trials of these mind-body complementary therapies for women with depression. To address the multiple challenges of research about mind-body therapies, we suggest that researchers should consider 4 key questions: whether the study design matches the research question; whether the control group addresses performance, expectation, and detection bias; whether the control group is ethical, feasible, and attractive; and whether the control group is designed to adequately control for nonspecific intervention effects. Based on these questions, we provide specific recommendations about control group design with the goal of minimizing bias and maximizing validity in future research.

Control Group Design: Enhancing Rigor in Research of Mind-Body Therapies for Depression

PubMed Central

Kinser, Patricia Anne; Robins, Jo Lynne

2013-01-01

Although a growing body of research suggests that mind-body therapies may be appropriate to integrate into the treatment of depression, studies consistently lack methodological sophistication particularly in the area of control groups. In order to better understand the relationship between control group selection and methodological rigor, we provide a brief review of the literature on control group design in yoga and tai chi studies for depression, and we discuss challenges we have faced in the design of control groups for our recent clinical trials of these mind-body complementary therapies for women with depression. To address the multiple challenges of research about mind-body therapies, we suggest that researchers should consider 4 key questions: whether the study design matches the research question; whether the control group addresses performance, expectation, and detection bias; whether the control group is ethical, feasible, and attractive; and whether the control group is designed to adequately control for nonspecific intervention effects. Based on these questions, we provide specific recommendations about control group design with the goal of minimizing bias and maximizing validity in future research. PMID:23662111

Risk of bias and methodological issues in randomised controlled trials of acupuncture for knee osteoarthritis: a cross-sectional study

PubMed Central

Lee, Andy H; Zhou, Xu; Kang, Deying; Luo, Yanan; Liu, Jiali; Sun, Xin

2018-01-01

Objective To assess risk of bias and to investigate methodological issues concerning the design, conduct and analysis of randomised controlled trials (RCTs) testing acupuncture for knee osteoarthritis (KOA). Methods PubMed, EMBASE, Cochrane Central Register of Controlled Trials and four major Chinese databases were searched for RCTs that investigated the effect of acupuncture for KOA. The Cochrane tool was used to examine the risk of bias of eligible RCTs. Their methodological details were examined using a standardised and pilot-tested questionnaire of 48 items, together with the association between four predefined factors and important methodological quality indicators. Results A total of 248 RCTs were eligible, of which 39 (15.7%) used computer-generated randomisation sequence. Of the 31 (12.5%) trials that stated the allocation concealment, only one used central randomisation. Twenty-five (10.1%) trials mentioned that their acupuncture procedures were standardised, but only 18 (7.3%) specified how the standardisation was achieved. The great majority of trials (n=233, 94%) stated that blinding was in place, but 204 (87.6%) did not clarify who was blinded. Only 27 (10.9%) trials specified the primary outcome, for which 7 used intention-to-treat analysis. Only 17 (6.9%) trials included details on sample size calculation; none preplanned an interim analysis and associated stopping rule. In total, 46 (18.5%) trials explicitly stated that loss to follow-up occurred, but only 6 (2.4%) provided some information to deal with the issue. No trials prespecified, conducted or reported any subgroup or adjusted analysis for the primary outcome. Conclusion The overall risk of bias was high among published RCTs testing acupuncture for KOA. Methodological limitations were present in many important aspects of design, conduct and analyses. These findings inform the development of evidence-based methodological guidance for future trials assessing the effect of acupuncture for KOA. PMID:29511016

An evaluation of the effectiveness of a case-specific approach to challenging behaviour associated with dementia.

PubMed

Bird, Michael; Llewellyn-Jones, Robert H; Korten, Ailsa

2009-01-01

Treatment of challenging behaviour in dementia using standardized psychopharmacological or psychosocial approaches remains problematical. A case-specific approach was trialled in this study, based on extensive evidence that each case is different in aetiology, the effects of the behaviour on others and what interventions are possible given the available resources. Forty-four consecutive referrals for challenging behaviour (two-thirds in residential care) were assessed across multiple causal domains. Both assessment and development of interventions were undertaken in collaboration with family carers and care staff. Measures of behaviour and associated carer distress, as well as medication and service use, were taken pre-intervention and at 2- and 5-month follow-ups. Psychotropic medication was used with a minority of participants but, overall, antipsychotic use was reduced. Psychosocial methods predominated, with 77% of cases judged as mainly or entirely psychosocial by an expert panel. There were significant mean improvements in behaviour and carer distress. Using conservative criteria there was a 65.9% clinical success rate. Results confirm those of other studies which have used multifaceted interventions tailored to the unique needs of each case. They compare favourably with results from trials of standardized psycho-pharmacological or psychosocial approaches. More trials are needed, necessarily involving further development of robust methodologies which reflect the case-specific nature of challenging behaviour associated with dementia.

Analysis of phase II methodologies for single-arm clinical trials with multiple endpoints in rare cancers: An example in Ewing's sarcoma.

PubMed

Dutton, P; Love, S B; Billingham, L; Hassan, A B

2018-05-01

Trials run in either rare diseases, such as rare cancers, or rare sub-populations of common diseases are challenging in terms of identifying, recruiting and treating sufficient patients in a sensible period. Treatments for rare diseases are often designed for other disease areas and then later proposed as possible treatments for the rare disease after initial phase I testing is complete. To ensure the trial is in the best interests of the patient participants, frequent interim analyses are needed to force the trial to stop promptly if the treatment is futile or toxic. These non-definitive phase II trials should also be stopped for efficacy to accelerate research progress if the treatment proves to be particularly promising. In this paper, we review frequentist and Bayesian methods that have been adapted to incorporate two binary endpoints and frequent interim analyses. The Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma (LINES) is used as a motivating example and provides a suitable platform to compare these approaches. The Bayesian approach provides greater design flexibility, but does not provide additional value over the frequentist approaches in a single trial setting when the prior is non-informative. However, Bayesian designs are able to borrow from any previous experience, using prior information to improve efficiency.

Effectiveness and implementation of an obesity prevention intervention: the HeLP-her Rural cluster randomised controlled trial.

PubMed

Lombard, Catherine B; Harrison, Cheryce L; Kozica, Samantha L; Zoungas, Sophia; Keating, Catherine; Teede, Helena J

2014-06-16

To impact on the obesity epidemic, interventions that prevent weight gain across populations are urgently needed. However, even the most efficacious interventions will have little impact on obesity prevention unless they are successfully implemented in diverse populations and settings. Implementation research takes isolated efficacy studies into practice and policy and is particularly important in obesity prevention where there is an urgent need to accelerate the evidence to practice cycle. Despite the recognised need, few obesity prevention interventions have been implemented in real life settings and to our knowledge rarely target rural communities. Here we describe the rationale, design and implementation of a Healthy Lifestyle Program for women living in small rural communities (HeLP-her Rural). The primary goal of HeLP-her Rural is to prevent weight gain using a low intensity, self-management intervention. Six hundred women from 42 small rural communities in Australia will be randomised as clusters (n-21 control towns and n = 21 intervention towns). A pragmatic randomised controlled trial methodology will test efficacy and a comprehensive mixed methods community evaluation and cost analysis will inform effectiveness and implementation of this novel prevention program. Implementing population interventions to prevent obesity is complex, costly and challenging. To address these barriers, evidence based interventions need to move beyond isolated efficacy trials and report outcomes related to effectiveness and implementation. Large pragmatic trials provide an opportunity to inform both effectiveness and implementation leading to potential for greater impact at the population level. Pragmatic trials should incorporate both effectiveness and implementation outcomes and a multidimensional methodology to inform scale-up to population level. The learnings from this trial will impact on the design and implementation of population obesity prevention strategies nationally and internationally. ANZ clinical trial registry ACTRN12612000115831. Date of registration 24/01/2012.

Considerations for preparing a randomized population health intervention trial: lessons from a South African–Canadian partnership to improve the health of health workers

PubMed Central

Yassi, Annalee; O’Hara, Lyndsay Michelle; Engelbrecht, Michelle C.; Uebel, Kerry; Nophale, Letshego Elizabeth; Bryce, Elizabeth Ann; Buxton, Jane A; Siegel, Jacob; Spiegel, Jerry Malcolm

2014-01-01

Background Community-based cluster-randomized controlled trials (RCTs) are increasingly being conducted to address pressing global health concerns. Preparations for clinical trials are well-described, as are the steps for multi-component health service trials. However, guidance is lacking for addressing the ethical and logistic challenges in (cluster) RCTs of population health interventions in low- and middle-income countries. Objective We aimed to identify the factors that population health researchers must explicitly consider when planning RCTs within North–South partnerships. Design We reviewed our experiences and identified key ethical and logistic issues encountered during the pre-trial phase of a recently implemented RCT. This trial aimed to improve tuberculosis (TB) and Human Immunodeficiency Virus (HIV) prevention and care for health workers by enhancing workplace assessment capability, addressing concerns about confidentiality and stigma, and providing onsite counseling, testing, and treatment. An iterative framework was used to synthesize this analysis with lessons taken from other studies. Results The checklist of critical factors was grouped into eight categories: 1) Building trust and shared ownership; 2) Conducting feasibility studies throughout the process; 3) Building capacity; 4) Creating an appropriate information system; 5) Conducting pilot studies; 6) Securing stakeholder support, with a view to scale-up; 7) Continuously refining methodological rigor; and 8) Explicitly addressing all ethical issues both at the start and continuously as they arise. Conclusion Researchers should allow for the significant investment of time and resources required for successful implementation of population health RCTs within North–South collaborations, recognize the iterative nature of the process, and be prepared to revise protocols as challenges emerge. PMID:24802561

Death, bereavement and randomised controlled trials (BRACELET): a methodological study of policy and practice in neonatal and paediatric intensive care trials.

PubMed

Snowdon, Claire; Brocklehurst, Peter; Tasker, Robert; Ward Platt, Martin; Harvey, Sheila; Elbourne, Diana

2014-07-01

Researchers have seldom included bereaved parents in studies of participants' views of randomised controlled trials (RCTs); hence our understanding of the impact of trials is based on skewed and incomplete samples. Little is known about parental experiences of the death of a child subsequent to their enrolment in a trial or of provision made for this experience by clinicians and trial teams. The Bereavement and RAndomised ControlLEd Trials (BRACELET) study was funded to consider bereavement in the context of paediatric intensive care (PIC) and neonatal intensive care (NIC) trials. The study comprised three interlinked components: a quantitative survey of RCT activity in UK paediatric intensive care units (PICUs) and neonatal intensive care units (NICUs), UK RCT recruitment and mortality rates, and provision for bereavement during 2002-6; a qualitative interview study involving 51 bereaved parents and 59 clinicians and trial team members associated with five neonatal trials; and a methodological study to inform future research. Fifty RCTs were identified as having enrolled babies or children from 2002 to 2006. Approximately 50% of UK NICUs and PICUs (54 NICUs, six PICUs) participated in at least one of these trials. Collectively they enrolled over 3000 children. Most enrolled small numbers, the majority of participants being enrolled by a small group of academic medical units. The proportion of deaths following trial enrolment was 17% in NIC trials and 6% in PIC trials. The qualitative study showed that trial-related decisions were made in a range of circumstances, some after extremely preterm births, others after complicated term deliveries, often under time pressures and in escalating crises. Parents' interest in trials appeared to recede initially but could re-emerge over time. They often valued opportunities to engage with a trial and were interested in more contact and information than they actually received. Clinicians often saw NICU bereavement policies as meeting parental needs, and trial participation as being of relatively minor significance in bereavement. This view may result from the positioning of clinicians' encounters with parents only in the initial stages of grief when trials were not a priority. Trial teams used a range of bereavement strategies, from no further contact to a pioneering multipart follow-up package. Communication with bereaved parents was complicated by limited contact opportunities. Trial teams were obliged to work without knowing whether their communications were appreciated, were problematic, or even whether they were received by parents. The methodological component highlighted strategies for recruitment and data collection in this sensitive setting. Recruitment by unsupported postal contact generally failed and a more personal approach via clinicians was more effective, supplemented by publicity material distributed via trusted organisations. A co-ordinated response to bereavement is as much a part of the running of trials as recruitment, and needs to be considered at trial inception. BRACELET has demonstrated the value and feasibility of research with bereaved parents involved in NIC trials. In order to respond to bereavement in a fair and sensitive way, as well as to better inform the design of RCTs, it is crucial that we listen to bereaved parents and evaluate new methods for so doing. More research is therefore needed into the experiences of bereavement subsequent to trial enrolment, with study of bereavement strategies in NIC trials as they are introduced. In addition, future studies should determine whether parents and triallists in PIC trials (and trials in adults) face the same issues as in NIC trials. Careful studies are necessary to explore how feedback of trial results are received and understood by bereaved and non-bereaved parents, and how individual trial teams manage this situation. An additional research area for exploring experiences of parenting twins and higher-order births in trials arose from BRACELET. Developmental research should continue to explore means of involving a wider range of parents in future research, including via publicity and specialist websites. Finally, methodological research is needed to ensure that we have the tools to explore, with parents and other relatives, as partners in research, a range of trial-related topics, which might be challenging, as the information is complex or the focus is sensitive. Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.

Methodology of phase II clinical trials in metastatic elderly breast cancer: a literature review.

PubMed

Cabarrou, B; Mourey, L; Dalenc, F; Balardy, L; Kanoun, D; Roché, H; Boher, J M; Rougé-Bugat, M E; Filleron, Thomas

2017-08-01

As the incidence of invasive breast cancer will increase with age, the number of elderly patients with a diagnosis metastatic breast cancer will also rise. But the use of cytotoxic drugs in elderly metastatic breast cancer patients is not systematic and is dreaded by medical oncologists. The need for prospective oncologic data from this population seems increasingly obvious. The main objective of this review is to investigate design and characteristics of phase II trials that assess activity and feasibility of chemotherapies in elderly advanced/metastatic breast cancer patients. An electronic search in PUBMED allowed us to retrieve articles published in English language on phase II trials in elderly metastatic breast cancer between January 2002 and May 2016. Sixteen publications were finally included in this review. The primary endpoint was a simple, a composite, and a co-primary endpoints in 11, three, and two studies, respectively. Efficacy was the primary objective in 15 studies: simple (n = 10), composite (n = 3), co-primary endpoints (n = 2). Composite or co-primary endpoints combined efficacy and toxicity. Thirteen studies used multistage designs. Only five studies evaluated the feasibility, i.e., to jointly assess efficacy and tolerance to treatment (toxicity, quality of life, etc) as primary endpoint. Development of elderly specific phase III clinical trials might be challenging, it therefore seems essential to conduct phase II clinical trials evaluating jointly efficacy and toxicity in a well-defined geriatric population. Use of multistage designs that take into account heterogeneity would allow to identify a subpopulation at interim analysis and to reduce the number of patients exposed to an inefficient or a toxic treatment regimen. It is crucial to evaluate new therapies (targeted therapies, immunotherapies) using adequate methodologies (Study design, endpoint).

A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials

PubMed Central

de Sola, Susana; de la Torre, Rafael; Sánchez-Benavides, Gonzalo; Benejam, Bessy; Cuenca-Royo, Aida; del Hoyo, Laura; Rodríguez, Joan; Catuara-Solarz, Silvina; Sanchez-Gutierrez, Judit; Dueñas-Espin, Ivan; Hernandez, Gimena; Peña-Casanova, Jordi; Langohr, Klaus; Videla, Sebastia; Blehaut, Henry; Farre, Magi; Dierssen, Mara; Cuenca-Royo, Aida

2015-01-01

The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of DS. PMID:26089807

Participatory Research Challenges in Drug Abuse Studies Among Transnational Mexican Migrants

PubMed Central

Garcia, Victor; Gonzalez, Laura

2011-01-01

Participatory research is essential in public health studies, but using this methodology to examine sensitive public health problems among vulnerable populations is a challenge. We share some of our trials and tribulations in attempting to use participatory research in our substance abuse studies among transnational Mexican migrants in southeastern Pennsylvania. Major challenges did not permit partnerships across the community in all phases of research, including the dissemination of findings. Especially difficult was including transnational migrants and nearby relatives as partners in the research, similar to partnerships created with others in the community. The sensitive nature of our research and associated human subject concerns did not permit a more participatory methodology. Another problem involved partnerships with members of the larger community, given the apathy and ambivalence towards drug use by transnational migrants. Finally, collaborating with community stakeholders to develop and implement research-based recommendations was also problematic. As we learned, there are more to generating substance abuse recommendations in partnership with stakeholders than simply working together on recommendations, which also require an effective implementation strategy. Based on these experiences, we elaborate useful suggestions in development and application of local-level programs aimed at curtailing substance abuse among transnational migrant workers while they are at their work sites in Pennsylvania. PMID:22003376

What are the roles and valued attributes of a Trial Steering Committee? Ethnographic study of eight clinical trials facing challenges.

PubMed

Daykin, Anne; Selman, Lucy E; Cramer, Helen; McCann, Sharon; Shorter, Gillian W; Sydes, Matthew R; Gamble, Carrol; Macefield, Rhiannon; Lane, J Athene; Shaw, Alison

2016-07-01

Clinical trials oversight by a Trial Steering Committee (TSC) is mandated by Good Clinical Practice. This study used qualitative methods to explore the role and valued attributes of the TSC to inform planned updates of Medical Research Council guidance and TSC terms of reference. An ethnographic study was conducted during 2013-2014. TSC and Trial Management Group meetings from eight trials were observed and audio-recorded, and semi-structured interviews conducted with purposively sampled key informants: independent and non-independent TSC members, trial sponsor representatives, funder representatives and chief investigators. The selected trials were currently recruiting and dealing with challenging scenarios. Data were analysed thematically and findings triangulated and integrated to give a multi-perspective account of the role and valued attributes of a TSC. Eight TSC meetings and six Trial Management Group meetings were observed. Sixty-five interviews were conducted with 51 informants. The two main roles played by the TSC were quality assurance and patient advocacy. Quality assurance involved being a 'critical friend' or a provider of 'tough love'. Factors influencing the ability of the TSC to fulfil this role included the TSC Chair, other independent TSC members and the model of the TSC and its fit with the trial subject. The role of the TSC as an advocate for patient well-being was perceived as paramount. Two attributes of TSC members emerged as critical: experience (of running a trial, trial oversight or in a clinical/methodological area) and independence. While independence was valued for giving impartiality, the lack of consensus about its definition and strict requirements of some funders made it difficult to operationalise. We found tensions and ambiguities in the roles expected of TSCs and the attributes valued of TSC members. In particular, the requirements of independence and experience could conflict, impacting the TSCs' quality assurance role. Concerns were raised regarding whose interests are served by funders' criteria of independence; in particular, funders' selection of TSC members was thought to potentially inhibit TSCs' ability to fulfil their patient advocacy role. These findings should be incorporated in revising guidance and terms of reference for TSCs.

Did we describe what you meant? Findings and methodological discussion of an empirical validation study for a systematic review of reasons.

PubMed

Mertz, Marcel; Sofaer, Neema; Strech, Daniel

2014-09-27

The systematic review of reasons is a new way to obtain comprehensive information about specific ethical topics. One such review was carried out for the question of why post-trial access to trial drugs should or need not be provided. The objective of this study was to empirically validate this review using an author check method. The article also reports on methodological challenges faced by our study. We emailed a questionnaire to the 64 corresponding authors of those papers that were assessed in the review of reasons on post-trial access. The questionnaire consisted of all quotations ("reason mentions") that were identified by the review to represent a reason in a given author's publication, together with a set of codings for the quotations. The authors were asked to rate the correctness of the codings. We received 19 responses, from which only 13 were completed questionnaires. In total, 98 quotations and their related codes in the 13 questionnaires were checked by the addressees. For 77 quotations (79%), all codings were deemed correct, for 21 quotations (21%), some codings were deemed to need correction. Most corrections were minor and did not imply a complete misunderstanding of the citation. This first attempt to validate a review of reasons leads to four crucial methodological questions relevant to the future conduct of such validation studies: 1) How can a description of a reason be deemed incorrect? 2) Do the limited findings of this author check study enable us to determine whether the core results of the analysed SRR are valid? 3) Why did the majority of surveyed authors refrain from commenting on our understanding of their reasoning? 4) How can the method for validating reviews of reasons be improved?

Identifying trial recruitment uncertainties using a James Lind Alliance Priority Setting Partnership - the PRioRiTy (Prioritising Recruitment in Randomised Trials) study.

PubMed

Healy, Patricia; Galvin, Sandra; Williamson, Paula R; Treweek, Shaun; Whiting, Caroline; Maeso, Beccy; Bray, Christopher; Brocklehurst, Peter; Moloney, Mary Clarke; Douiri, Abdel; Gamble, Carrol; Gardner, Heidi R; Mitchell, Derick; Stewart, Derek; Jordan, Joan; O'Donnell, Martin; Clarke, Mike; Pavitt, Sue H; Guegan, Eleanor Woodford; Blatch-Jones, Amanda; Smith, Valerie; Reay, Hannah; Devane, Declan

2018-03-01

Despite the problem of inadequate recruitment to randomised trials, there is little evidence to guide researchers on decisions about how people are effectively recruited to take part in trials. The PRioRiTy study aimed to identify and prioritise important unanswered trial recruitment questions for research. The PRioRiTy study - Priority Setting Partnership (PSP) included members of the public approached to take part in a randomised trial or who have represented participants on randomised trial steering committees, health professionals and research staff with experience of recruiting to randomised trials, people who have designed, conducted, analysed or reported on randomised trials and people with experience of randomised trials methodology. This partnership was aided by the James Lind Alliance and involved eight stages: (i) identifying a unique, relevant prioritisation area within trial methodology; (ii) establishing a steering group (iii) identifying and engaging with partners and stakeholders; (iv) formulating an initial list of uncertainties; (v) collating the uncertainties into research questions; (vi) confirming that the questions for research are a current recruitment challenge; (vii) shortlisting questions and (viii) final prioritisation through a face-to-face workshop. A total of 790 survey respondents yielded 1693 open-text answers to 6 questions, from which 1880 potential questions for research were identified. After merging duplicates, the number of questions was reduced to 496. Questions were combined further, and those that were submitted by fewer than 15 people and/or fewer than 6 of the 7 stakeholder groups were excluded from the next round of prioritisation resulting in 31 unique questions for research. All 31 questions were confirmed as being unanswered after checking relevant, up-to-date research evidence. The 10 highest priority questions were ranked at a face-to-face workshop. The number 1 ranked question was "How can randomised trials become part of routine care and best utilise current clinical care pathways?" The top 10 research questions can be viewed at www.priorityresearch.ie . The prioritised questions call for a collective focus on normalising trials as part of clinical care, enhancing communication, addressing barriers, enablers and motivators around participation and exploring greater public involvement in the research process.

Methodological reporting of randomized trials in five leading Chinese nursing journals.

PubMed

Shi, Chunhu; Tian, Jinhui; Ren, Dan; Wei, Hongli; Zhang, Lihuan; Wang, Quan; Yang, Kehu

2014-01-01

Randomized controlled trials (RCTs) are not always well reported, especially in terms of their methodological descriptions. This study aimed to investigate the adherence of methodological reporting complying with CONSORT and explore associated trial level variables in the Chinese nursing care field. In June 2012, we identified RCTs published in five leading Chinese nursing journals and included trials with details of randomized methods. The quality of methodological reporting was measured through the methods section of the CONSORT checklist and the overall CONSORT methodological items score was calculated and expressed as a percentage. Meanwhile, we hypothesized that some general and methodological characteristics were associated with reporting quality and conducted a regression with these data to explore the correlation. The descriptive and regression statistics were calculated via SPSS 13.0. In total, 680 RCTs were included. The overall CONSORT methodological items score was 6.34 ± 0.97 (Mean ± SD). No RCT reported descriptions and changes in "trial design," changes in "outcomes" and "implementation," or descriptions of the similarity of interventions for "blinding." Poor reporting was found in detailing the "settings of participants" (13.1%), "type of randomization sequence generation" (1.8%), calculation methods of "sample size" (0.4%), explanation of any interim analyses and stopping guidelines for "sample size" (0.3%), "allocation concealment mechanism" (0.3%), additional analyses in "statistical methods" (2.1%), and targeted subjects and methods of "blinding" (5.9%). More than 50% of trials described randomization sequence generation, the eligibility criteria of "participants," "interventions," and definitions of the "outcomes" and "statistical methods." The regression analysis found that publication year and ITT analysis were weakly associated with CONSORT score. The completeness of methodological reporting of RCTs in the Chinese nursing care field is poor, especially with regard to the reporting of trial design, changes in outcomes, sample size calculation, allocation concealment, blinding, and statistical methods.

Core outcome sets in dermatology: report from the second meeting of the International Cochrane Skin Group Core Outcome Set Initiative.

PubMed

Kottner, J; Jacobi, L; Hahnel, E; Alam, M; Balzer, K; Beeckman, D; Busard, C; Chalmers, J; Deckert, S; Eleftheriadou, V; Furlan, K; Horbach, S E R; Kirkham, J; Nast, A; Spuls, P; Thiboutot, D; Thorlacius, L; Weller, K; Williams, H C; Schmitt, J

2018-04-01

Results of clinical trials are the most important information source for generating external clinical evidence. The use of different outcomes across trials, which investigate similar interventions for similar patient groups, significantly limits the interpretation, comparability and clinical application of trial results. Core outcome sets (COSs) aim to overcome this limitation. A COS is an agreed standardized collection of outcomes that should be measured and reported in all clinical trials for a specific clinical condition. The Core Outcome Set Initiative within the Cochrane Skin Group (CSG-COUSIN) supports the development of core outcomes in dermatology. In the second CSG-COUSIN meeting held in 2017, 11 COS development groups working on skin diseases presented their current work. The presentations and discussions identified the following overarching methodological challenges for COS development in dermatology: it is not always easy to define the disease focus of a COS; the optimal method for outcome domain identification and level of detail needed to specify such domains is challenging to many; decision rules within Delphi surveys need to be improved; appropriate ways of patient involvement are not always clear. In addition, there appear to be outcome domains that may be relevant as potential core outcome domains for the majority of skin diseases. The close collaboration between methodologists in the Core Outcome Set Initiative and the international Cochrane Skin Group has major advantages for trialists, systematic reviewers and COS developers. © 2018 British Association of Dermatologists.

Choice of design and outcomes in trials among children with moderate acute malnutrition.

PubMed

Friis, Henrik; Michaelsen, Kim F; Wells, Jonathan C

2015-03-01

There is a need for trials on the effects of food aid products for children with moderate acute malnutrition, to identify how best to restore body tissues and function. The choice of control intervention is a major challenge, with both ethical and scientific implications. While randomized trials are needed, special designs, such as cluster-randomized, stepped-wedged or factorial designs may offer advantages. Anthropometry is widely used as the primary outcome in such trials, but anthropometric traits do not refer directly to specific organs, tissues, or functions. Thus, it is difficult to understand what components of health might be impacted by public health programs, or the underlying mechanisms whereby improved nutritional status might benefit short- and long-term health. Measurement of body composition, specific growth markers and functional outcomes may provide greater insight into the nature and implications of growth failure and recovery. There are now several methodologies suitable for application in infants and young children, e.g., measuring body composition with deuterium dilution, physical activity with accelerometers and linear growth with knemometers. To evaluate the generalizability of the findings from nutrition trials, it is important to collect data on baseline nutritional status.

A new proposal for randomized start design to investigate disease-modifying therapies for Alzheimer disease.

PubMed

Zhang, Richard Y; Leon, Andrew C; Chuang-Stein, Christy; Romano, Steven J

2011-02-01

The increasing prevalence of Alzheimer disease (AD) and lack of effective agents to attenuate progression have accelerated research and development of disease modifying (DM) therapies. The traditional parallel group design and single time point analysis used in the support of past AD drug approvals address symptomatic benefit over relatively short treatment durations. More recent trials investigating disease modification are by necessity longer in duration and require larger sample sizes. Nevertheless, trial design and analysis remain mostly unchanged and may not be adequate to meet the objective of demonstrating disease modification. Randomized start design (RSD) has been proposed as an option to study DM effects, but its application in AD trials may have been hampered by certain methodological challenges. To address the methodological issues that have impeded more extensive use of RSD in AD trial and to encourage other researchers to develop novel design and analysis methodologies to better ascertain DM effects for the next generation of AD therapies, we propose a stepwise testing procedure to evaluate potential DM effects of novel AD therapies. Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) is used for illustration. We propose to test three hypotheses in a stepwise sequence. The three tests pertain to treatment difference at two separate time points and a difference in the rate of change. Estimation is facilitated by the Mixed-effects Model for Repeated Measures approach. The required sample size is estimated using Monte Carlo simulations and by modeling ADAS-cog data from prior longitudinal AD studies. The greatest advantage of the RSD proposed in this article is its ability to critically address the question on a DM effect. The AD trial using the new approach would be longer (12-month placebo period plus 12-month delay-start period; total 24-month duration) and require more subjects (about 1000 subjects per arm for the non-inferiority margin chosen in the illustration). It would also require additional evaluations to estimate the rate of ADAS-cog change toward the end of the trial. A regulatory claim of disease modification for any compound will likely require additional verification of a drug's effect on a validated biomarker of Alzheimer's pathology. Incorporation of the RSD in AD trials is feasible. With proper trial setup and statistical procedures, this design could support the detection of a disease-modifying effect. In our opinion, a two-phase RSD with a stepwise hypothesis testing procedure could be a reasonable option for future studies.

Clinical trials in palliative care: a systematic review of their methodological characteristics and of the quality of their reporting.

PubMed

Bouça-Machado, Raquel; Rosário, Madalena; Alarcão, Joana; Correia-Guedes, Leonor; Abreu, Daisy; Ferreira, Joaquim J

2017-01-25

Over the past decades there has been a significant increase in the number of published clinical trials in palliative care. However, empirical evidence suggests that there are methodological problems in the design and conduct of studies, which raises questions about the validity and generalisability of the results and of the strength of the available evidence. We sought to evaluate the methodological characteristics and assess the quality of reporting of clinical trials in palliative care. We performed a systematic review of published clinical trials assessing therapeutic interventions in palliative care. Trials were identified using MEDLINE (from its inception to February 2015). We assessed methodological characteristics and describe the quality of reporting using the Cochrane Risk of Bias tool. We retrieved 107 studies. The most common medical field studied was oncology, and 43.9% of trials evaluated pharmacological interventions. Symptom control and physical dimensions (e.g. intervention on pain, breathlessness, nausea) were the palliative care-specific issues most studied. We found under-reporting of key information in particular on random sequence generation, allocation concealment, and blinding. While the number of clinical trials in palliative care has increased over time, methodological quality remains suboptimal. This compromises the quality of studies. Therefore, a greater effort is needed to enable the appropriate performance of future studies and increase the robustness of evidence-based medicine in this important field.

Canadian-led capacity-building in biostatistics and methodology in cardiovascular and diabetes trials: the CANNeCTIN Biostatistics and Methodological Innovation Working Group

PubMed Central

2011-01-01

The Biostatistics and Methodological Innovation Working (BMIW) Group is one of several working groups within the CANadian Network and Centre for Trials INternationally (CANNeCTIN). This programme received funding from the Canadian Institutes of Health Research and the Canada Foundation for Innovation beginning in 2008, to enhance the infrastructure and build capacity for large Canadian-led clinical trials in cardiovascular diseases (CVD) and diabetes mellitus (DM). The overall aims of the BMIW Group's programme within CANNeCTIN, are to advance biostatistical and methodological research, and to build biostatistical capacity in CVD and DM. Our program of research and training includes: monthly videoconferences on topical biostatistical and methodological issues in CVD/DM clinical studies; providing presentations on methods issues at the annual CANNeCTIN meetings; collaborating with clinician investigators on their studies; training young statisticians in biostatistics and methods in CVD/DM trials and organizing annual symposiums on topical methodological issues. We are focused on the development of new biostatistical methods and the recruitment and training of highly qualified personnel - who will become leaders in the design and analysis of CVD/DM trials. The ultimate goal is to enhance global health by contributing to efforts to reduce the burden of CVD and DM. PMID:21332987

The role of qualitative research in adding value to a randomised controlled trial: lessons from a pilot study of a guided e-learning intervention for managers to improve employee wellbeing and reduce sickness absence.

PubMed

Russell, Jill; Berney, Lee; Stansfeld, Stephen; Lanz, Doris; Kerry, Sally; Chandola, Tarani; Bhui, Kamaldeep

2016-08-09

Despite the growing popularity of mixed-methods studies and considerable emphasis on the potential value of qualitative research to the trial endeavour, there remains a dearth of published studies reporting on actual contribution. This paper presents a critically reflective account of our experience of the actual value of undertaking qualitative research alongside a pilot cluster randomised controlled trial of a guided e-learning intervention for managers in an NHS Mental Health Trust to improve employee wellbeing and reduce sickness absence. For the qualitative study we undertook 36 in-depth interviews with key informants, managers and employees. We observed and took in-depth field notes of 10 meetings involving managers and employees at the Trust, and the two qualitative researchers acted as participant observers at steering committee and monthly research team meetings. We adopted a narrative methodological orientation alongside a thematic approach to data analysis, eliciting a rich account of the complexities of managing stress at work. We identified two key overarching roles played by the qualitative research: 'problematising' and 'contextualising'. Specifically, the qualitative data revealed and challenged assumptions embedded in the trial about the nature of the learning process, and exposed the slippery and contested nature of abstracted variables, on which a trial depends. The qualitative data challenged the trial's logic model, and provided a rich understanding of the context within which the trial and intervention took place. While acknowledging the ever-present tension in mixed-methods research between the requirements of quantitative research to represent the social world as abstracted variables, and the goal of qualitative research to explore and document the complexity of social phenomena, we adopted a pragmatic position that enabled us to engage with this tension in a productive and partially integrative way. Our critically reflective account of the praxis of integration illuminated opportunities and challenges for maximising the value of qualitative research to a trial. This paper sets out tangible illustrative lessons for other mixed-methods researchers endeavouring to get the most from qualitative research. This study is registered as ISRCTN58661009 . Registration was submitted on 22 April 2013 and completed on 17 June 2013.

Interventions to modify sexual risk behaviours for preventing HIV in homeless youth.

PubMed

Naranbhai, Vivek; Abdool Karim, Quarraisha; Meyer-Weitz, Anna

2011-01-19

Homeless youth are at high risk for HIV infection as a consequence of risky sexual behaviour. Interventions for homeless youth are challenging. Assessment of the effectiveness of interventions to modify sexual risk behaviours for preventing HIV in homeless youth is needed. To evaluate and summarize the effectiveness of interventions for modifying sexual risk behaviours and preventing transmission of HIV among homeless youth. We searched electronic databases (CENTRAL, MEDLINE, EMBASE, AIDSearch, Gateway, PsycInfo, LILACS), reference lists of eligible articles, international health agency publication lists, and clinical trial registries. The search was updated January 2010. We contacted authors of published reports and other key role players. Randomised studies of interventions to modify sexual risk behaviour (biological, self-reporting of sexual-risk behaviour or health-seeking behaviour) in homeless youth (12-24 years). Data from eligible studies were extracted by two reviewers. We assessed risk of bias per the Cochrane Collaborations tool. None of the eligible studies reported any primary biological outcomes for this review. Reports of self-reporting sexual risk behaviour outcomes varied across studies precluding calculation of summary measures of effect; we present the outcomes descriptively for each study. We contacted authors for missing or ambiguous data. We identified three eligible studies after screening a total of 255 unique records. All three were performed in the United States of America and recruited substance-abusing male and female adolescents (total N=615) through homeless shelters into randomised controlled trials of independent and non-overlapping behavioural interventions. The three trials differed in theoretical background, delivery method, dosage (number of sessions,) content and outcome assessments. Overall, the variability in delivery and outcomes precluded estimation of summary of effect measures. We assessed the risk of bias to be high for each of the studies. Whilst some effect of the interventions on outcome measures were reported, heterogeneity and lack of robustness in these studies necessitate caution in interpreting the effectiveness of these interventions.  The body of evidence does not permit conclusions on the impact of interventions to modify sexual risk behaviour in homeless youth; more research is required. While the psychosocial and contextual factors that fuel sexual risk behaviours among homeless youth challenge stringent methodologies of RCT's, novel ways for program delivery and trial retention are in need of development. Future trials should comply with rigorous methodology in design, delivery, outcome measurement and reporting.

Risk of bias and methodological issues in randomised controlled trials of acupuncture for knee osteoarthritis: a cross-sectional study.

PubMed

Jia, Pengli; Tang, Li; Yu, Jiajie; Lee, Andy H; Zhou, Xu; Kang, Deying; Luo, Yanan; Liu, Jiali; Sun, Xin

2018-03-06

To assess risk of bias and to investigate methodological issues concerning the design, conduct and analysis of randomised controlled trials (RCTs) testing acupuncture for knee osteoarthritis (KOA). PubMed, EMBASE, Cochrane Central Register of Controlled Trials and four major Chinese databases were searched for RCTs that investigated the effect of acupuncture for KOA. The Cochrane tool was used to examine the risk of bias of eligible RCTs. Their methodological details were examined using a standardised and pilot-tested questionnaire of 48 items, together with the association between four predefined factors and important methodological quality indicators. A total of 248 RCTs were eligible, of which 39 (15.7%) used computer-generated randomisation sequence. Of the 31 (12.5%) trials that stated the allocation concealment, only one used central randomisation. Twenty-five (10.1%) trials mentioned that their acupuncture procedures were standardised, but only 18 (7.3%) specified how the standardisation was achieved. The great majority of trials (n=233, 94%) stated that blinding was in place, but 204 (87.6%) did not clarify who was blinded. Only 27 (10.9%) trials specified the primary outcome, for which 7 used intention-to-treat analysis. Only 17 (6.9%) trials included details on sample size calculation; none preplanned an interim analysis and associated stopping rule. In total, 46 (18.5%) trials explicitly stated that loss to follow-up occurred, but only 6 (2.4%) provided some information to deal with the issue. No trials prespecified, conducted or reported any subgroup or adjusted analysis for the primary outcome. The overall risk of bias was high among published RCTs testing acupuncture for KOA. Methodological limitations were present in many important aspects of design, conduct and analyses. These findings inform the development of evidence-based methodological guidance for future trials assessing the effect of acupuncture for KOA. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Methodological aspects of clinical trials in tinnitus: A proposal for an international standard

PubMed Central

Landgrebe, Michael; Azevedo, Andréia; Baguley, David; Bauer, Carol; Cacace, Anthony; Coelho, Claudia; Dornhoffer, John; Figueiredo, Ricardo; Flor, Herta; Hajak, Goeran; van de Heyning, Paul; Hiller, Wolfgang; Khedr, Eman; Kleinjung, Tobias; Koller, Michael; Lainez, Jose Miguel; Londero, Alain; Martin, William H.; Mennemeier, Mark; Piccirillo, Jay; De Ridder, Dirk; Rupprecht, Rainer; Searchfield, Grant; Vanneste, Sven; Zeman, Florian; Langguth, Berthold

2013-01-01

Chronic tinnitus is a common condition with a high burden of disease. While many different treatments are used in clinical practice, the evidence for the efficacy of these treatments is low and the variance of treatment response between individuals is high. This is most likely due to the great heterogeneity of tinnitus with respect to clinical features as well as underlying pathophysiological mechanisms. There is a clear need to find effective treatment options in tinnitus, however, clinical trials differ substantially with respect to methodological quality and design. Consequently, the conclusions that can be derived from these studies are limited and jeopardize comparison between studies. Here, we discuss our view of the most important aspects of trial design in clinical studies in tinnitus and make suggestions for an international methodological standard in tinnitus trials. We hope that the proposed methodological standard will stimulate scientific discussion and will help to improve the quality of trials in tinnitus. PMID:22789414

Implementing the PAIN RelieveIt Randomized Controlled Trial in Hospice Care: Mechanisms for Success and Meeting PCORI Methodology Standards.

PubMed

Ezenwa, Miriam O; Suarez, Marie L; Carrasco, Jesus D; Hipp, Theresa; Gill, Anayza; Miller, Jacob; Shea, Robert; Shuey, David; Zhao, Zhongsheng; Angulo, Veronica; McCurry, Timothy; Martin, Joanna; Yao, Yingwei; Molokie, Robert E; Wang, Zaijie Jim; Wilkie, Diana J

2017-07-01

This purpose of this article is to describe how we adhere to the Patient-Centered Outcomes Research Institute's (PCORI) methodology standards relevant to the design and implementation of our PCORI-funded study, the PAIN RelieveIt Trial. We present details of the PAIN RelieveIt Trial organized by the PCORI methodology standards and components that are relevant to our study. The PAIN RelieveIt Trial adheres to four PCORI standards and 21 subsumed components. The four standards include standards for formulating research questions, standards associated with patient centeredness, standards for data integrity and rigorous analyses, and standards for preventing and handling missing data. In the past 24 months, we screened 2,837 cancer patients and their caregivers; 874 dyads were eligible; 223.5 dyads consented and provided baseline data. Only 55 patients were lost to follow-up-a 25% attrition rate. The design and implementation of the PAIN RelieveIt Trial adhered to PCORI's methodology standards for research rigor.

Using GRADE methodology for the development of public health guidelines for the prevention and treatment of HIV and other STIs among men who have sex with men and transgender people

PubMed Central

2012-01-01

Background The World Health Organization (WHO) Department of HIV/AIDS led the development of public health guidelines for delivering an evidence-based, essential package of interventions for the prevention and treatment of HIV and other sexually transmitted infections (STIs) among men who have sex with men (MSM) and transgender people in the health sector in low- and middle-income countries. The objective of this paper is to review the methodological challenges faced and solutions applied during the development of the guidelines. Methods The development of the guidelines followed the WHO guideline development process, which utilizes the GRADE approach. We identified, categorized and labeled the challenges identified in the guidelines development process and described the solutions through an interactive process of in-person and electronic communication. Results We describe how we dealt with the following challenges: (1) heterogeneous and complex interventions; (2) paucity of trial data; (3) selecting outcomes of interest; (4) using indirect evidence; (5) integrating values and preferences; (6) considering resource use; (7) addressing social and legal barriers; (8) wording of recommendations; and (9) developing global guidelines. Conclusion We were able to successfully apply the GRADE approach for developing recommendations for public health interventions. Applying the general principles of the approach while carefully considering specific challenges can enhance both the process and the outcome of guideline development. PMID:22640260

Differing antidepressant maintenance methodologies.

PubMed

Safer, Daniel J

2017-10-01

The principle evidence that antidepressant medication (ADM) is an effective maintenance treatment for adults with major depressive disorder (MDD) is from placebo substitution trials. These trials enter responders from ADM efficacy trials into randomized, double-blind placebo-controlled (RDBPC) effectiveness trials to measure the rate of MDD relapse over time. However, other randomized maintenance trial methodologies merit consideration and comparison. A systematic review of ADM randomized maintenance trials included research reports from multiple databases. Relapse rate was the main effectiveness outcome assessed. Five ADM randomized maintenance methodologies for MDD responders are described and compared for outcome. These effectiveness trials include: placebo-substitution, ADM/placebo extension, ADM extension, ADM vs. psychotherapy, and treatment as usual. The placebo-substitution trials for those abruptly switched to placebo resulted in unusually high (46%) rates of relapse over 6-12months, twice the continuing ADM rate. These trials were characterized by selective screening, high attrition, an anxious anticipation of a switch to placebo, and a risk of drug withdrawal symptoms. Selectively screened ADM efficacy responders who entered into 4-12month extension trials experienced relapse rates averaging ~10% with a low attrition rate. Non-industry sponsored randomized trials of adults with multiple prior MDD episodes who were treated with ADM maintenance for 1-2years experienced relapse rates averaging 40%. Placebo substitution trial methodology represents only one approach to assess ADM maintenance. Antidepressant maintenance research for adults with MDD should be evaluated for industry sponsorship, attrition, the impact of the switch to placebo, and major relapse differences in MDD subpopulations. Copyright © 2017. Published by Elsevier Inc.

Changing cluster composition in cluster randomised controlled trials: design and analysis considerations

PubMed Central

2014-01-01

Background There are many methodological challenges in the conduct and analysis of cluster randomised controlled trials, but one that has received little attention is that of post-randomisation changes to cluster composition. To illustrate this, we focus on the issue of cluster merging, considering the impact on the design, analysis and interpretation of trial outcomes. Methods We explored the effects of merging clusters on study power using standard methods of power calculation. We assessed the potential impacts on study findings of both homogeneous cluster merges (involving clusters randomised to the same arm of a trial) and heterogeneous merges (involving clusters randomised to different arms of a trial) by simulation. To determine the impact on bias and precision of treatment effect estimates, we applied standard methods of analysis to different populations under analysis. Results Cluster merging produced a systematic reduction in study power. This effect depended on the number of merges and was most pronounced when variability in cluster size was at its greatest. Simulations demonstrate that the impact on analysis was minimal when cluster merges were homogeneous, with impact on study power being balanced by a change in observed intracluster correlation coefficient (ICC). We found a decrease in study power when cluster merges were heterogeneous, and the estimate of treatment effect was attenuated. Conclusions Examples of cluster merges found in previously published reports of cluster randomised trials were typically homogeneous rather than heterogeneous. Simulations demonstrated that trial findings in such cases would be unbiased. However, simulations also showed that any heterogeneous cluster merges would introduce bias that would be hard to quantify, as well as having negative impacts on the precision of estimates obtained. Further methodological development is warranted to better determine how to analyse such trials appropriately. Interim recommendations include avoidance of cluster merges where possible, discontinuation of clusters following heterogeneous merges, allowance for potential loss of clusters and additional variability in cluster size in the original sample size calculation, and use of appropriate ICC estimates that reflect cluster size. PMID:24884591

Methodological reporting of randomized controlled trials in major hepato-gastroenterology journals in 2008 and 1998: a comparative study

PubMed Central

2011-01-01

Background It was still unclear whether the methodological reporting quality of randomized controlled trials (RCTs) in major hepato-gastroenterology journals improved after the Consolidated Standards of Reporting Trials (CONSORT) Statement was revised in 2001. Methods RCTs in five major hepato-gastroenterology journals published in 1998 or 2008 were retrieved from MEDLINE using a high sensitivity search method and their reporting quality of methodological details were evaluated based on the CONSORT Statement and Cochrane Handbook for Systematic Reviews of interventions. Changes of the methodological reporting quality between 2008 and 1998 were calculated by risk ratios with 95% confidence intervals. Results A total of 107 RCTs published in 2008 and 99 RCTs published in 1998 were found. Compared to those in 1998, the proportion of RCTs that reported sequence generation (RR, 5.70; 95%CI 3.11-10.42), allocation concealment (RR, 4.08; 95%CI 2.25-7.39), sample size calculation (RR, 3.83; 95%CI 2.10-6.98), incomplete outecome data addressed (RR, 1.81; 95%CI, 1.03-3.17), intention-to-treat analyses (RR, 3.04; 95%CI 1.72-5.39) increased in 2008. Blinding and intent-to-treat analysis were reported better in multi-center trials than in single-center trials. The reporting of allocation concealment and blinding were better in industry-sponsored trials than in public-funded trials. Compared with historical studies, the methodological reporting quality improved with time. Conclusion Although the reporting of several important methodological aspects improved in 2008 compared with those published in 1998, which may indicate the researchers had increased awareness of and compliance with the revised CONSORT statement, some items were still reported badly. There is much room for future improvement. PMID:21801429

Inconsistency prevents the valuable synergism of explanatory and pragmatic trails.

PubMed

Correia, Luis C L; Correia, Vitor C A; Souza, Thiago M B; Cerqueira, Antonio Maurício S; Alexandre, Felipe K B; Garcia, Guilherme; Ferreira, Felipe R M; Lopes, Fernanda O A

2018-05-01

To assess review articles on pragmatic trials in order to describe how authors define the aim of this type of study, how comprehensive methodological topics are covered, and which topics are most valued by authors. Review articles were selected from Medline Database, based on the expression "pragmatic trial" in the titles. Five trained medical students evaluated the articles, based on a list of 15 self-explanatory methodological topics. Each article was evaluated regarding topics covered. Baseline statements on the aim of pragmatic trials were derived. Among 22 articles identified, there was general agreement that the aim of a pragmatic trial is to evaluate if the intervention works under real-world conditions. The mean number of methodological topics addressed by each article was 7.6 ± 3.1. Only one article covered all 15 topics, three articles (14%) responded to at least 75% of topics and 13 articles (59%) mentioned at least 50% of the topics. The relative frequency each of the 15 topics was cited by articles had a mean of 50% ± 25%. No topic was addressed by all articles, only three (20%) were addressed by more than 75% of articles. There is agreement on the different aims of explanatory and pragmatic trials. But there is a large variation on methodological topics used to define a pragmatic trial, which led to inconsistency in defining the typical methodology of a pragmatic trial. © 2018 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.

Controlled Trials in Children: Quantity, Methodological Quality and Descriptive Characteristics of Pediatric Controlled Trials Published 1948-2006

PubMed Central

Thomson, Denise; Hartling, Lisa; Cohen, Eyal; Vandermeer, Ben; Tjosvold, Lisa; Klassen, Terry P.

2010-01-01

Background The objective of this study was to describe randomized controlled trials (RCTs) and controlled clinical trials (CCTs) in child health published between 1948 and 2006, in terms of quantity, methodological quality, and publication and trial characteristics. We used the Trials Register of the Cochrane Child Health Field for overall trends and a sample from this to explore trial characteristics in more detail. Methodology/Principal Findings We extracted descriptive data on a random sample of 578 trials. Ninety-six percent of the trials were published in English; the percentage of child-only trials was 90.5%. The most frequent diagnostic categories were infectious diseases (13.2%), behavioural and psychiatric disorders (11.6%), neonatal critical care (11.4%), respiratory disorders (8.9%), non-critical neonatology (7.9%), and anaesthesia (6.5%). There were significantly fewer child-only studies (i.e., more mixed child and adult studies) over time (P = 0.0460). The proportion of RCTs to CCTs increased significantly over time (P<0.0001), as did the proportion of multicentre trials (P = 0.002). Significant increases over time were found in methodological quality (Jadad score) (P<0.0001), the proportion of double-blind studies (P<0.0001), and studies with adequate allocation concealment (P<0.0001). Additionally, we found an improvement in reporting over time: adequate description of withdrawals and losses to follow-up (P<0.0001), sample size calculations (P<0.0001), and intention-to-treat analysis (P<0.0001). However, many trials still do not describe their level of blinding, and allocation concealment was inadequately reported in the majority of studies across the entire time period. The proportion of studies with industry funding decreased slightly over time (P = 0.003), and these studies were more likely to report positive conclusions (P = 0.028). Conclusions/Significance The quantity and quality of pediatric controlled trials has increased over time; however, much work remains to be done, particularly in improving methodological issues around conduct and reporting of trials. PMID:20927344

Lessons learned from IDeAl - 33 recommendations from the IDeAl-net about design and analysis of small population clinical trials.

PubMed

Hilgers, Ralf-Dieter; Bogdan, Malgorzata; Burman, Carl-Fredrik; Dette, Holger; Karlsson, Mats; König, Franz; Male, Christoph; Mentré, France; Molenberghs, Geert; Senn, Stephen

2018-05-11

IDeAl (Integrated designs and analysis of small population clinical trials) is an EU funded project developing new statistical design and analysis methodologies for clinical trials in small population groups. Here we provide an overview of IDeAl findings and give recommendations to applied researchers. The description of the findings is broken down by the nine scientific IDeAl work packages and summarizes results from the project's more than 60 publications to date in peer reviewed journals. In addition, we applied text mining to evaluate the publications and the IDeAl work packages' output in relation to the design and analysis terms derived from in the IRDiRC task force report on small population clinical trials. The results are summarized, describing the developments from an applied viewpoint. The main result presented here are 33 practical recommendations drawn from the work, giving researchers a comprehensive guidance to the improved methodology. In particular, the findings will help design and analyse efficient clinical trials in rare diseases with limited number of patients available. We developed a network representation relating the hot topics developed by the IRDiRC task force on small population clinical trials to IDeAl's work as well as relating important methodologies by IDeAl's definition necessary to consider in design and analysis of small-population clinical trials. These network representation establish a new perspective on design and analysis of small-population clinical trials. IDeAl has provided a huge number of options to refine the statistical methodology for small-population clinical trials from various perspectives. A total of 33 recommendations developed and related to the work packages help the researcher to design small population clinical trial. The route to improvements is displayed in IDeAl-network representing important statistical methodological skills necessary to design and analysis of small-population clinical trials. The methods are ready for use.

Risk of bias in overviews of reviews: a scoping review of methodological guidance and four-item checklist.

PubMed

Ballard, Madeleine; Montgomery, Paul

2017-03-01

To assess the conditions under which employing an overview of systematic reviews is likely to lead to a high risk of bias. To synthesise existing guidance concerning overview practice, a scoping review was conducted. Four electronic databases were searched with a pre-specified strategy (PROSPERO 2015:CRD42015027592) ending October 2015. Included studies needed to describe or develop overview methodology. Data were narratively synthesised to delineate areas highlighted as outstanding challenges or where methodological recommendations conflict. Twenty-four papers met the inclusion criteria. There is emerging debate regarding overlapping systematic reviews; systematic review scope; quality of included research; updating; and synthesizing and reporting results. While three functions for overviews have been proposed-identify gaps, explore heterogeneity, summarize evidence-overviews cannot perform the first; are unlikely to achieve the second and third simultaneously; and can only perform the third under specific circumstances. Namely, when identified systematic reviews meet the following four conditions: (1) include primary trials that do not substantially overlap, (2) match overview scope, (3) are of high methodological quality, and (4) are up-to-date. Considering the intended function of proposed overviews with the corresponding methodological conditions may improve the quality of this burgeoning publication type. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

A methodology for successfully producing global translations of patient reported outcome measures for use in multiple countries.

PubMed

Two, Rebecca; Verjee-Lorenz, Aneesa; Clayson, Darren; Dalal, Mehul; Grotzinger, Kelly; Younossi, Zobair M

2010-01-01

The production of accurate and culturally relevant translations of patient reported outcome (PRO) measures is essential for the success of international clinical trials. Although there are many reports in publication regarding the translation of PRO measures, the techniques used to produce single translations for use in multiple countries (global translations) are not well documented. This article addresses this apparent lack of documentation and presents the methodology used to create global translations of the Chronic Liver Disease Questionnaire-Hepatitis C Virus (CLDQ-HCV). The challenges of creating a translation for use in multiple countries are discussed, and the criteria for a global translation project explained. Based on a thorough translation and linguistic validation methodology including a concept elaboration, multiple forward translations, two back translations, reviews by in-country clinicians and the instrument developer, pilot testing in each target country and multiple sets of proofreading, the key concept of the global translation methodology is consistent international harmonization, achieved through the involvement of linguists from each target country at every stage of the process. This methodology enabled the successful resolution of the translation issues encountered, and resulted in consistent translations of the CLDQ-HCV that were linguistically and culturally appropriate for all target countries.

Analysis of phase II methodologies for single-arm clinical trials with multiple endpoints in rare cancers: An example in Ewing’s sarcoma

PubMed Central

Dutton, P; Love, SB; Billingham, L; Hassan, AB

2016-01-01

Trials run in either rare diseases, such as rare cancers, or rare sub-populations of common diseases are challenging in terms of identifying, recruiting and treating sufficient patients in a sensible period. Treatments for rare diseases are often designed for other disease areas and then later proposed as possible treatments for the rare disease after initial phase I testing is complete. To ensure the trial is in the best interests of the patient participants, frequent interim analyses are needed to force the trial to stop promptly if the treatment is futile or toxic. These non-definitive phase II trials should also be stopped for efficacy to accelerate research progress if the treatment proves to be particularly promising. In this paper, we review frequentist and Bayesian methods that have been adapted to incorporate two binary endpoints and frequent interim analyses. The Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma (LINES) is used as a motivating example and provides a suitable platform to compare these approaches. The Bayesian approach provides greater design flexibility, but does not provide additional value over the frequentist approaches in a single trial setting when the prior is non-informative. However, Bayesian designs are able to borrow from any previous experience, using prior information to improve efficiency. PMID:27587590

A Monte Carlo analysis of breast screening randomized trials.

PubMed

Zamora, Luis I; Forastero, Cristina; Guirado, Damián; Lallena, Antonio M

2016-12-01

To analyze breast screening randomized trials with a Monte Carlo simulation tool. A simulation tool previously developed to simulate breast screening programmes was adapted for that purpose. The history of women participating in the trials was simulated, including a model for survival after local treatment of invasive cancers. Distributions of time gained due to screening detection against symptomatic detection and the overall screening sensitivity were used as inputs. Several randomized controlled trials were simulated. Except for the age range of women involved, all simulations used the same population characteristics and this permitted to analyze their external validity. The relative risks obtained were compared to those quoted for the trials, whose internal validity was addressed by further investigating the reasons of the disagreements observed. The Monte Carlo simulations produce results that are in good agreement with most of the randomized trials analyzed, thus indicating their methodological quality and external validity. A reduction of the breast cancer mortality around 20% appears to be a reasonable value according to the results of the trials that are methodologically correct. Discrepancies observed with Canada I and II trials may be attributed to a low mammography quality and some methodological problems. Kopparberg trial appears to show a low methodological quality. Monte Carlo simulations are a powerful tool to investigate breast screening controlled randomized trials, helping to establish those whose results are reliable enough to be extrapolated to other populations and to design the trial strategies and, eventually, adapting them during their development. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Funding source and the quality of reports of chronic wounds trials: 2004 to 2011

PubMed Central

2014-01-01

Background Critical commentaries suggest that wound care randomised controlled trials (RCTs) are often poorly reported with many methodological flaws. Furthermore, interventions in chronic wounds, rather than being drugs, are often medical devices for which there are no requirements for RCTs to bring products to market. RCTs in wounds trials therefore potentially represent a form of marketing. This study presents a methodological overview of chronic wound trials published between 2004 and 2011 and investigates the influence of industry funding on methodological quality. Methods A systematic search for RCTs for the treatment of chronic wounds published in the English language between 2004 and 2011 (inclusive) in the Cochrane Wounds Group Specialised Register of Trials was carried out. Data were extracted on aspects of trial design, conduct and quality including sample size, duration of follow-up, specification of a primary outcome, use of surrogate outcomes, and risks of bias. In addition, the prevalence of industry funding was assessed and its influence on the above aspects of trial design, conduct and quality was assessed. Results A total of 167 RCTs met our inclusion criteria. We found chronic wound trials often have short durations of follow-up (median 12 weeks), small sample sizes (median 63), fail to define a primary outcome in 41% of cases, and those that do define a primary outcome, use surrogate measures of healing in 40% of cases. Only 40% of trials used appropriate methods of randomisation, 25% concealed allocation and 34% blinded outcome assessors. Of the included trials, 41% were wholly or partially funded by industry, 33% declared non-commercial funding and 26% did not report a funding source. Industry funding was not statistically significantly associated with any measure of methodological quality, though this analysis was probably underpowered. Conclusions This overview confirms concerns raised about the methodological quality of RCTs in wound care and illustrates that greater efforts must be made to follow international standards for conducting and reporting RCTs. There is currently minimal evidence of an influence of industry funding on methodological quality although analyses had limited power and funding source was not reported for a quarter of studies. PMID:24422753

Funding source and the quality of reports of chronic wounds trials: 2004 to 2011.

PubMed

Hodgson, Robert; Allen, Richard; Broderick, Ellen; Bland, J Martin; Dumville, Jo C; Ashby, Rebecca; Bell-Syer, Sally; Foxlee, Ruth; Hall, Jill; Lamb, Karen; Madden, Mary; O'Meara, Susan; Stubbs, Nikki; Cullum, Nicky

2014-01-14

Critical commentaries suggest that wound care randomised controlled trials (RCTs) are often poorly reported with many methodological flaws. Furthermore, interventions in chronic wounds, rather than being drugs, are often medical devices for which there are no requirements for RCTs to bring products to market. RCTs in wounds trials therefore potentially represent a form of marketing. This study presents a methodological overview of chronic wound trials published between 2004 and 2011 and investigates the influence of industry funding on methodological quality. A systematic search for RCTs for the treatment of chronic wounds published in the English language between 2004 and 2011 (inclusive) in the Cochrane Wounds Group Specialised Register of Trials was carried out.Data were extracted on aspects of trial design, conduct and quality including sample size, duration of follow-up, specification of a primary outcome, use of surrogate outcomes, and risks of bias. In addition, the prevalence of industry funding was assessed and its influence on the above aspects of trial design, conduct and quality was assessed. A total of 167 RCTs met our inclusion criteria. We found chronic wound trials often have short durations of follow-up (median 12 weeks), small sample sizes (median 63), fail to define a primary outcome in 41% of cases, and those that do define a primary outcome, use surrogate measures of healing in 40% of cases. Only 40% of trials used appropriate methods of randomisation, 25% concealed allocation and 34% blinded outcome assessors. Of the included trials, 41% were wholly or partially funded by industry, 33% declared non-commercial funding and 26% did not report a funding source. Industry funding was not statistically significantly associated with any measure of methodological quality, though this analysis was probably underpowered. This overview confirms concerns raised about the methodological quality of RCTs in wound care and illustrates that greater efforts must be made to follow international standards for conducting and reporting RCTs. There is currently minimal evidence of an influence of industry funding on methodological quality although analyses had limited power and funding source was not reported for a quarter of studies.

Voice quality outcomes of idiopathic Parkinson's disease medical treatment: A systematic review.

PubMed

Lechien, J R; Blecic, S; Huet, K; Delvaux, V; Piccaluga, M; Roland, V; Harmegnies, B; Saussez, S

2018-06-01

To investigate voice quality (VQ) impairments in idiopathic Parkinson's disease (IPD) and to explore the impact of medical treatments and L-Dopa challenge testing on voice. Relevant studies published between January 1980 and June 2017 describing VQ evaluations in IPD were retrieved using PubMed, Scopus, Biological Abstracts, BioMed Central and Cochrane databases. Issues of clinical relevance, including IPD treatment efficiency and voice quality outcomes, were evaluated for each study. The grade of recommendation for each publication was determined according to the Oxford Centre for Evidence-Based Medicine evidence levels. The database research yielded 106 relevant publications, of which 33 studies met the inclusion criteria, for a total of 964 patients with IPD. Data were extracted by 3 independent physicians who identified 21, 11 and 1 trials with IIIb, IIb and IIa evidence levels, respectively. The main VQ assessment tools used were acoustic testing (N = 27), aerodynamic testing (N = 10), subjective measurements (N = 8) and videolaryngostroboscopy (N = 3). The majority of trials (N = 32/33) identified subjective or objective VQ improvements after medical treatment (N = 10) or better VQ evaluations in healthy subjects compared to patients with IPD (N = 22). Especially, our analysis supports that VQ overall improves during the L-Dopa challenge testing, making the VQ evaluation an additional tool for the IPD diagnosis. The methodology used to assess subjective and objective VQ substantially varied from 1 study to another. All of the included studies took into consideration the patient's clinical profile in the VQ analysis. The majority of studies supported that VQ assessments remain useful as outcome measures of the effectiveness of medical treatment and could be helpful for the IPD diagnosis based on L-Dopa challenge testing. Further controlled studies using standardised and transparent methodology for measuring acoustic parameters are necessary to confirm the place of each tool in both IPD diagnosis and treatment evaluation. © 2018 John Wiley & Sons Ltd.

Methodological Reporting of Randomized Trials in Five Leading Chinese Nursing Journals

PubMed Central

Shi, Chunhu; Tian, Jinhui; Ren, Dan; Wei, Hongli; Zhang, Lihuan; Wang, Quan; Yang, Kehu

2014-01-01

Background Randomized controlled trials (RCTs) are not always well reported, especially in terms of their methodological descriptions. This study aimed to investigate the adherence of methodological reporting complying with CONSORT and explore associated trial level variables in the Chinese nursing care field. Methods In June 2012, we identified RCTs published in five leading Chinese nursing journals and included trials with details of randomized methods. The quality of methodological reporting was measured through the methods section of the CONSORT checklist and the overall CONSORT methodological items score was calculated and expressed as a percentage. Meanwhile, we hypothesized that some general and methodological characteristics were associated with reporting quality and conducted a regression with these data to explore the correlation. The descriptive and regression statistics were calculated via SPSS 13.0. Results In total, 680 RCTs were included. The overall CONSORT methodological items score was 6.34±0.97 (Mean ± SD). No RCT reported descriptions and changes in “trial design,” changes in “outcomes” and “implementation,” or descriptions of the similarity of interventions for “blinding.” Poor reporting was found in detailing the “settings of participants” (13.1%), “type of randomization sequence generation” (1.8%), calculation methods of “sample size” (0.4%), explanation of any interim analyses and stopping guidelines for “sample size” (0.3%), “allocation concealment mechanism” (0.3%), additional analyses in “statistical methods” (2.1%), and targeted subjects and methods of “blinding” (5.9%). More than 50% of trials described randomization sequence generation, the eligibility criteria of “participants,” “interventions,” and definitions of the “outcomes” and “statistical methods.” The regression analysis found that publication year and ITT analysis were weakly associated with CONSORT score. Conclusions The completeness of methodological reporting of RCTs in the Chinese nursing care field is poor, especially with regard to the reporting of trial design, changes in outcomes, sample size calculation, allocation concealment, blinding, and statistical methods. PMID:25415382

Published methodological quality of randomized controlled trials does not reflect the actual quality assessed in protocols

PubMed Central

Mhaskar, Rahul; Djulbegovic, Benjamin; Magazin, Anja; Soares, Heloisa P.; Kumar, Ambuj

2011-01-01

Objectives To assess whether reported methodological quality of randomized controlled trials (RCTs) reflect the actual methodological quality, and to evaluate the association of effect size (ES) and sample size with methodological quality. Study design Systematic review Setting Retrospective analysis of all consecutive phase III RCTs published by 8 National Cancer Institute Cooperative Groups until year 2006. Data were extracted from protocols (actual quality) and publications (reported quality) for each study. Results 429 RCTs met the inclusion criteria. Overall reporting of methodological quality was poor and did not reflect the actual high methodological quality of RCTs. The results showed no association between sample size and actual methodological quality of a trial. Poor reporting of allocation concealment and blinding exaggerated the ES by 6% (ratio of hazard ratio [RHR]: 0.94, 95%CI: 0.88, 0.99) and 24% (RHR: 1.24, 95%CI: 1.05, 1.43), respectively. However, actual quality assessment showed no association between ES and methodological quality. Conclusion The largest study to-date shows poor quality of reporting does not reflect the actual high methodological quality. Assessment of the impact of quality on the ES based on reported quality can produce misleading results. PMID:22424985

Fidelity considerations in translational research: Eating As Treatment - a stepped wedge, randomised controlled trial of a dietitian delivered behaviour change counselling intervention for head and neck cancer patients undergoing radiotherapy.

PubMed

Beck, Alison Kate; Baker, Amanda; Britton, Ben; Wratten, Chris; Bauer, Judith; Wolfenden, Luke; Carter, Gregory

2015-10-15

The confidence with which researchers can comment on intervention efficacy relies on evaluation and consideration of intervention fidelity. Accordingly, there have been calls to increase the transparency with which fidelity methodology is reported. Despite this, consideration and/or reporting of fidelity methods remains poor. We seek to address this gap by describing the methodology for promoting and facilitating the evaluation of intervention fidelity in The EAT (Eating As Treatment) project: a multi-site stepped wedge randomised controlled trial of a dietitian delivered behaviour change counselling intervention to improve nutrition (primary outcome) in head and neck cancer patients undergoing radiotherapy. In accordance with recommendations from the National Institutes of Health Behaviour Change Consortium Treatment Fidelity Workgroup, we sought to maximise fidelity in this stepped wedge randomised controlled trial via strategies implemented from study design through to provider training, intervention delivery and receipt. As the EAT intervention is designed to be incorporated into standard dietetic consultations, we also address unique challenges for translational research. We offer a strong model for improving the quality of translational findings via real world application of National Institutes of Health Behaviour Change Consortium recommendations. Greater transparency in the reporting of behaviour change research is an important step in improving the progress and quality of behaviour change research. ACTRN12613000320752 (Date of registration 21 March 2013).

Safety of disease-modifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance.

PubMed

Lu, Ellen; Wang, Bing Wei; Guimond, Colleen; Synnes, Anne; Sadovnick, A Dessa; Dahlgren, Leanne; Traboulsee, Anthony; Tremlett, Helen

2013-03-01

When contemplating a pregnancy, women treated for multiple sclerosis (MS) with a disease-modifying drug must decide to discontinue their medication before conception or risk exposing their unborn child to potential drug toxicity. Few studies exist as reference for patients and physicians, and of those available, the majority are less than ideal due to real-world constraints, ethical issues and methodological shortcomings. The authors provide a brief summary of existing animal and human data with current recommendations regarding the safety of IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod and teriflunomide during pregnancy and lactation in women with MS. We also assess the quality, strengths and limitations of the existing studies including challenges with study design. The investigation of outcomes such as spontaneous abortion and congenital anomalies are highlighted with potential methodological improvements for future studies on drug safety in pregnancy suggested. The authors explore the pharmacokinetics and pharmacodynamics of the MS disease-modifying drugs for their possible mechanistic role in fetal harm and discuss the potential role of clinical trials. Future pharmacovigilance studies should continue to pursue multicenter collaboration with an emphasis on appropriate study design.

Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial): study protocol for a randomised controlled trial.

PubMed

Hartman, Linda; Rasch, Linda A; Klausch, Thomas; Bijlsma, Hans W J; Christensen, Robin; Smulders, Yvo M; Ralston, Stuart H; Buttgereit, Frank; Cutolo, Maurizio; Da Silva, Jose A P; Opris, Daniela; Rovenský, Jozef; Szamosi, Szilvia; Middelink, Leonie M; Lems, Willem F; Boers, Maarten

2018-01-25

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called "JAK/STAT inhibitors") have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA. The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions. Pragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA. ClinicalTrials.gov, NCT02585258 . Registered on 20 October 2015.

Challenges in the research ethics review of cluster randomized trials: international survey of investigators.

PubMed

Chaudhry, Shazia H; Brehaut, Jamie C; Grimshaw, Jeremy M; Weijer, Charles; Boruch, Robert; Donner, Allan; Eccles, Martin P; McRae, Andrew D; Saginur, Raphael; Skea, Zoë C; Zwarenstein, Merrick; Taljaard, Monica

2013-04-01

Cluster randomized trials (CRTs) complicate the interpretation of standard research ethics guidelines for several reasons. For one, the units of allocation, intervention, and observation often may differ within a single trial. In the absence of tailored and internationally accepted ethics guidelines for CRTs, researchers and research ethics committees have no common standard by which to judge ethically appropriate practices in CRTs. Moreover, lack of familiarity with and consideration of the unique features of the CRT design by research ethics committees may cause difficulties in the research ethics review process, and amplify problems such as variability in the requirements and decisions reached by different research ethics committees. We aimed to characterize research ethics review of CRTs, examine investigator experiences with the ethics review process, and assess the need for ethics guidelines for CRTs. An electronic search strategy implemented in MEDLINE was used to identify and randomly sample 300 CRTs published in English language journals from 2000 to 2008. A web-based survey with closed- and open-ended questions was administered to corresponding authors in a series of six contacts. The survey response rate was 64%. Among 182 of 285 eligible respondents, 91% indicated that they had sought research ethics approval for the identified CRT, although only 70% respondents reported research ethics approval in the published article. Nearly one-third (31%) indicated that they have had to meet with ethics committees to explain aspects of their trials, nearly half (46%) experienced variability in the ethics review process in multijurisdictional trials, and 38% experienced negative impacts of the ethics review process on their trials, including delays in trial initiation (28%), increased costs (10%), compromised ability to recruit participants (16%), and compromised methodological quality (9%). Most respondents (74%; 95% confidence interval (CI): 67%-80%) agreed or strongly agreed that there is a need to develop ethics guidelines for CRTs, and (70%; 95% CI: 63%-77%) that ethics committees could be better informed about distinct ethical issues surrounding CRTs. Thirty-six percent of authors did not respond to the survey. Due to the absence of comparable results from a representative sample of authors of individually randomized trials, it is unclear to what extent the reported challenges result from the CRT design. CRT investigators are experiencing challenges in the research ethics review of their trials, including excessive delays, variability in process and outcome, and imposed requirements that can have negative consequences for study conduct. Investigators identified a clear need for ethics guidelines for CRTs and education of research ethics committees about distinct ethical issues in CRTs.

Pragmatic clinical trials embedded in healthcare systems: generalizable lessons from the NIH Collaboratory.

PubMed

Weinfurt, Kevin P; Hernandez, Adrian F; Coronado, Gloria D; DeBar, Lynn L; Dember, Laura M; Green, Beverly B; Heagerty, Patrick J; Huang, Susan S; James, Kathryn T; Jarvik, Jeffrey G; Larson, Eric B; Mor, Vincent; Platt, Richard; Rosenthal, Gary E; Septimus, Edward J; Simon, Gregory E; Staman, Karen L; Sugarman, Jeremy; Vazquez, Miguel; Zatzick, Douglas; Curtis, Lesley H

2017-09-18

The clinical research enterprise is not producing the evidence decision makers arguably need in a timely and cost effective manner; research currently involves the use of labor-intensive parallel systems that are separate from clinical care. The emergence of pragmatic clinical trials (PCTs) poses a possible solution: these large-scale trials are embedded within routine clinical care and often involve cluster randomization of hospitals, clinics, primary care providers, etc. Interventions can be implemented by health system personnel through usual communication channels and quality improvement infrastructure, and data collected as part of routine clinical care. However, experience with these trials is nascent and best practices regarding design operational, analytic, and reporting methodologies are undeveloped. To strengthen the national capacity to implement cost-effective, large-scale PCTs, the Common Fund of the National Institutes of Health created the Health Care Systems Research Collaboratory (Collaboratory) to support the design, execution, and dissemination of a series of demonstration projects using a pragmatic research design. In this article, we will describe the Collaboratory, highlight some of the challenges encountered and solutions developed thus far, and discuss remaining barriers and opportunities for large-scale evidence generation using PCTs. A planning phase is critical, and even with careful planning, new challenges arise during execution; comparisons between arms can be complicated by unanticipated changes. Early and ongoing engagement with both health care system leaders and front-line clinicians is critical for success. There is also marked uncertainty when applying existing ethical and regulatory frameworks to PCTS, and using existing electronic health records for data capture adds complexity.

Progress in Treatment Development for Neuropsychiatric Symptoms in Alzheimer’s Disease: Focus on Agitation and Aggression. A Report from the EU/US/CTAD Task Force

PubMed Central

Soto, M.; Abushakra, S.; Cummings, J.; Siffert, J.; Robert, P.; Vellas, B.; Lyketsos, C.G.

2015-01-01

BACKGROUND The management of neuropsychiatric symptoms (NPS) such as agitation and aggression is a major priority in caring for people with Alzheimer’s disease (AD). Agitation and aggression (A/A) are among the most disruptive symptoms, and given their impact, they are increasingly an important target for development of effective treatments. Considerable progress has been made in the last years with a growing number of randomized controlled trials (RCTs) of drugs for NPS. The limited benefits reported in some RCTs may be accounted for by the absence of a biological link of the tested molecule to NPS and also by key methodological issues. In recent RCTs of A/A, a great heterogeneity design was found. Designing trials for dementia populations with NPS presents many challenges, including identification of appropriate participants for such trials, engagement and compliance of patients and caregivers in the trials and the choice of optimal outcome measures to demonstrate treatment effectiveness. The EU/US -CTAD Task Force, an international collaboration of investigators from academia, industry, non-profit foundations, and regulatory agencies met in Philadelphia on November 19, 2014 to address some of these challenges. Despite potential heterogeneity in clinical manifestations and neurobiology, agitation and aggression seems to be accepted as an entity for drug development. The field appears to be reaching a consensus in using both agitation and aggression (or other NPS)-specific quantitative measures plus a global rating of change for agitation outcomes based on clinician judgment as the main outcomes. PMID:26413494

A taxonomy of multinational ethical and methodological standards for clinical trials of therapeutic interventions.

PubMed

Ashton, Carol M; Wray, Nelda P; Jarman, Anna F; Kolman, Jacob M; Wenner, Danielle M; Brody, Baruch A

2011-06-01

If trials of therapeutic interventions are to serve society's interests, they must be of high methodological quality and must satisfy moral commitments to human subjects. The authors set out to develop a clinical-trials compendium in which standards for the ethical treatment of human subjects are integrated with standards for research methods. The authors rank-ordered the world's nations and chose the 31 with >700 active trials as of 24 July 2008. Governmental and other authoritative entities of the 31 countries were searched, and 1004 English-language documents containing ethical and/or methodological standards for clinical trials were identified. The authors extracted standards from 144 of those: 50 designated as 'core', 39 addressing trials of invasive procedures and a 5% sample (N=55) of the remainder. As the integrating framework for the standards we developed a coherent taxonomy encompassing all elements of a trial's stages. Review of the 144 documents yielded nearly 15 000 discrete standards. After duplicates were removed, 5903 substantive standards remained, distributed in the taxonomy as follows: initiation, 1401 standards, 8 divisions; design, 1869 standards, 16 divisions; conduct, 1473 standards, 8 divisions; analysing and reporting results, 997 standards, four divisions; and post-trial standards, 168 standards, 5 divisions. The overwhelming number of source documents and standards uncovered in this study was not anticipated beforehand and confirms the extraordinary complexity of the clinical trials enterprise. This taxonomy of multinational ethical and methodological standards may help trialists and overseers improve the quality of clinical trials, particularly given the globalisation of clinical research.

Growth Hormone Research Society Workshop Summary: Consensus Guidelines for Recombinant Human Growth Hormone Therapy in Prader-Willi Syndrome

PubMed Central

Tony, Michèle; Höybye, Charlotte; Allen, David B.; Tauber, Maïthé; Christiansen, Jens Sandahl; Ambler, Geoffrey R.; Battista, Renaldo; Beauloye, Véronique; Berall, Glenn; Biller, Beverly M. K.; Butler, Merlin G.; Cassidy, Suzanne B.; Chihara, Kazuo; Cohen, Pinchas; Craig, Maria; Farholt, Stense; Goetghebeur, Mireille; Goldstone, Anthony P.; Greggi, Tiziana; Grugni, Graziano; Hokken-Koelega, Anita C.; Johannsson, Gudmundur; Johnson, Keegan; Kemper, Alex; Kopchick, John J.; Malozowski, Saul; Miller, Jennifer; Mogul, Harriette R.; Muscatelli, Françoise; Nergårdh, Ricard; Nicholls, Robert D.; Radovick, Sally; Rosenthal, M. Sara; Sipilä, Ilkka; Tarride, Jean-Eric; Vogels, Annick; Waters, Michael J.

2013-01-01

Context: Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events. Objective: The aim of the study was to formulate recommendations for the use of rhGH in children and adult patients with PWS. Evidence: We performed a systematic review of the clinical evidence in the pediatric population, including randomized controlled trials, comparative observational studies, and long-term studies (>3.5 y). Adult studies included randomized controlled trials of rhGH treatment for ≥ 6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials, and pharmaceutical registries. Methodology: Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (http://bit.ly.PWGHIN). Conclusions: Following a multidisciplinary evaluation, preferably by experts, rhGH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental, and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer, or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental, and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks. PMID:23543664

Quality of reporting of outcomes in phase III studies of pulmonary tuberculosis: a systematic review.

PubMed

Bonnett, Laura Jayne; Ken-Dror, Gie; Davies, Geraint Rhys

2018-02-21

Despite more than 60 years of clinical trials, tuberculosis (TB) still causes a high global burden of mortality and morbidity. Treatment currently requires multiple drugs in combination, taken over a prolonged period. New drugs are needed to shorten treatment duration, prevent resistance and reduce adverse events. However, to improve on current methodology in drug development, a more complete understanding of the existing clinical evidence base is required. A systematic review was undertaken to summarise outcomes reported in phase III trials of patients with newly diagnosed pulmonary TB. A systematic search of databases (PubMed, MEDLINE, EMBASE, CENTRAL and LILACs) was conducted on 30 November 2017 to retrieve relevant peer-reviewed articles. Reference lists of included studies were also searched. This systematic review considered all reported outcomes. Of 248 included studies, 229 considered "on-treatment" outcomes whilst 148 reported "off-treatment" outcomes. There was wide variation and ambiguity in the definition of reported outcomes, including their relationship to treatment and in the time points evaluated. Additional challenges were observed regarding the analysis approach taken (per protocol versus intention to treat) and the varying durations of "intensive" and "continuation" phases of treatment. Bacteriological outcomes were most frequently reported but radiological and clinical data were often included as an implicit or explicit component of the overall definition of outcome. Terminology used to define long-term outcomes in phase III trials is inconsistent, reflecting evolving differences in protocols and practices. For successful future cumulative meta-analysis, the findings of this review suggest that greater availability of individual patient data and the development of a core outcome set would be desirable. In the meantime, we propose a simple and logical approach which should facilitate combination of key evidence and inform improvements in the methodology of TB drug development and clinical trials.

The Efficacy of Eye Movement Desensitization and Reprocessing in Children and Adults Who Have Experienced Complex Childhood Trauma: A Systematic Review of Randomized Controlled Trials.

PubMed

Chen, Runsen; Gillespie, Amy; Zhao, Yanhui; Xi, Yingjun; Ren, Yanping; McLean, Loyola

2018-01-01

Background: Survivors of complex childhood trauma (CT) such as sexual abuse show poorer outcomes compared to single event trauma survivors. A growing number of studies investigate Eye Movement Desensitization and Reprocessing (EMDR) treatment for posttraumatic stress disorder (PTSD), but no systematic reviews have focused on EMDR treatment for CT as an intervention for both adults and children. This study therefore systematically reviewed all randomized controlled trials (RCTs) evaluating the effect of EMDR on PTSD symptoms in adults and children exposed to CT. Methods: Databases including PubMed, Web of Science, and PsycINFO were searched in October 2017. Randomized controlled trials which recruited adult and children with experience of CT, which compared EMDR to alternative treatments or control conditions, and which measured PTSD symptoms were included. Study methodology quality was evaluated with Platinum Standard scale. Results: Six eligible RCTs of 251 participants were included in this systematic review. The results indicated that EMDR was associated with reductions in PTSD symptoms, depression and/or anxiety both post-treatment and at follow-up compared with all other alternative therapies (cognitive behavior therapy, individual/group therapy and fluoxetine) and control treatment (pill placebo, active listening, EMDR delayed treatment, and treatment as usual). However, studies suffered from significant heterogeneity in study populations, length of EMDR treatment, length of follow-up, comparison groups, and outcome measures. One study had a high risk of bias. Discussion: This systematic review suggests that there is growing evidence to support the clinical efficacy of EMDR in treating CT in both children and adults. However, conclusions are limited by the small number of heterogenous trials. Further RCTs with standardized methodologies, as well as studies addressing real world challenges in treating CT are required.

The Efficacy of Eye Movement Desensitization and Reprocessing in Children and Adults Who Have Experienced Complex Childhood Trauma: A Systematic Review of Randomized Controlled Trials

PubMed Central

Chen, Runsen; Gillespie, Amy; Zhao, Yanhui; Xi, Yingjun; Ren, Yanping; McLean, Loyola

2018-01-01

Background: Survivors of complex childhood trauma (CT) such as sexual abuse show poorer outcomes compared to single event trauma survivors. A growing number of studies investigate Eye Movement Desensitization and Reprocessing (EMDR) treatment for posttraumatic stress disorder (PTSD), but no systematic reviews have focused on EMDR treatment for CT as an intervention for both adults and children. This study therefore systematically reviewed all randomized controlled trials (RCTs) evaluating the effect of EMDR on PTSD symptoms in adults and children exposed to CT. Methods: Databases including PubMed, Web of Science, and PsycINFO were searched in October 2017. Randomized controlled trials which recruited adult and children with experience of CT, which compared EMDR to alternative treatments or control conditions, and which measured PTSD symptoms were included. Study methodology quality was evaluated with Platinum Standard scale. Results: Six eligible RCTs of 251 participants were included in this systematic review. The results indicated that EMDR was associated with reductions in PTSD symptoms, depression and/or anxiety both post-treatment and at follow-up compared with all other alternative therapies (cognitive behavior therapy, individual/group therapy and fluoxetine) and control treatment (pill placebo, active listening, EMDR delayed treatment, and treatment as usual). However, studies suffered from significant heterogeneity in study populations, length of EMDR treatment, length of follow-up, comparison groups, and outcome measures. One study had a high risk of bias. Discussion: This systematic review suggests that there is growing evidence to support the clinical efficacy of EMDR in treating CT in both children and adults. However, conclusions are limited by the small number of heterogenous trials. Further RCTs with standardized methodologies, as well as studies addressing real world challenges in treating CT are required. PMID:29695993

Methodological quality of randomized controlled trials of spinal manipulation and mobilization in tension-type headache, migraine, and cervicogenic headache.

PubMed

Fernández-de-las-Peñas, César; Alonso-Blanco, Cristina; San-Roman, Jesús; Miangolarra-Page, Juan C

2006-03-01

Literature review of quality of clinical trials. To determine the methodological quality of published randomized controlled trials that used spinal manipulation and/or mobilization to treat patients with tension-type headache (TTH), cervicogenic headache (CeH), and migraine (M) in the last decade. TTH, CeH, and M are the most prevalent types of headaches seen in adults. Individuals who have headaches frequently use physical therapy, manual therapy, or chiropractic care. Randomized controlled trials are considered an optimal method with which to assess the efficacy of any intervention. Computerized literature searches were performed in MEDLINE, EMBASE, COCHRANE, AMED, MANTIS, CINHAL, and PEDro databases. Randomized controlled trials in which spinal manipulation and/or mobilization had been used for TTH, CeH, and M published in a peer-reviewed journal as full text, and with at least 1 clinically relevant outcome measure (ie, headache intensity, duration, or frequency) were reviewed. The methodological quality of the studies was assessed independently by 2 reviewers using a set of predefined criteria. Only 8 studies met all the inclusion criteria. One clinical trial evaluated spinal manipulation and mobilization together, and the remaining 7 assessed spinal manipulative therapy. No controlled trials analyzing exclusively the effects of spinal mobilization were found. Methodological scores ranged from 35 to 56 points out of a theoretical maximum of 100 points, indicating an overall poor methodology of the studies. Only 2 studies obtained a high-quality score (greater than 50 points). No significant differences in quality scores were found based on the type of headache investigated. Methodological quality was not associated with the year of publication (before 2000, or later) nor with the results (positive, neutral, negative) reported in the studies. The most common flaws were a small sample size, the absence of a placebo control group, lack of blinded patients, and no description of the manipulative procedure. There are few published randomized controlled trials analyzing the effectiveness of spinal manipulation and/or mobilization for TTH, CeH, and M in the last decade. In addition, the methodological quality of these papers is typically low. Clearly, there is a need for high-quality randomized controlled trials assessing the effectiveness of these interventions in these headache disorders.

Graphical tools for network meta-analysis in STATA.

PubMed

Chaimani, Anna; Higgins, Julian P T; Mavridis, Dimitris; Spyridonos, Panagiota; Salanti, Georgia

2013-01-01

Network meta-analysis synthesizes direct and indirect evidence in a network of trials that compare multiple interventions and has the potential to rank the competing treatments according to the studied outcome. Despite its usefulness network meta-analysis is often criticized for its complexity and for being accessible only to researchers with strong statistical and computational skills. The evaluation of the underlying model assumptions, the statistical technicalities and presentation of the results in a concise and understandable way are all challenging aspects in the network meta-analysis methodology. In this paper we aim to make the methodology accessible to non-statisticians by presenting and explaining a series of graphical tools via worked examples. To this end, we provide a set of STATA routines that can be easily employed to present the evidence base, evaluate the assumptions, fit the network meta-analysis model and interpret its results.

Graphical Tools for Network Meta-Analysis in STATA

PubMed Central

Chaimani, Anna; Higgins, Julian P. T.; Mavridis, Dimitris; Spyridonos, Panagiota; Salanti, Georgia

2013-01-01

Network meta-analysis synthesizes direct and indirect evidence in a network of trials that compare multiple interventions and has the potential to rank the competing treatments according to the studied outcome. Despite its usefulness network meta-analysis is often criticized for its complexity and for being accessible only to researchers with strong statistical and computational skills. The evaluation of the underlying model assumptions, the statistical technicalities and presentation of the results in a concise and understandable way are all challenging aspects in the network meta-analysis methodology. In this paper we aim to make the methodology accessible to non-statisticians by presenting and explaining a series of graphical tools via worked examples. To this end, we provide a set of STATA routines that can be easily employed to present the evidence base, evaluate the assumptions, fit the network meta-analysis model and interpret its results. PMID:24098547

Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations.

PubMed

Dworkin, Robert H; Turk, Dennis C; Peirce-Sandner, Sarah; Baron, Ralf; Bellamy, Nicholas; Burke, Laurie B; Chappell, Amy; Chartier, Kevin; Cleeland, Charles S; Costello, Ann; Cowan, Penney; Dimitrova, Rozalina; Ellenberg, Susan; Farrar, John T; French, Jacqueline A; Gilron, Ian; Hertz, Sharon; Jadad, Alejandro R; Jay, Gary W; Kalliomäki, Jarkko; Katz, Nathaniel P; Kerns, Robert D; Manning, Donald C; McDermott, Michael P; McGrath, Patrick J; Narayana, Arvind; Porter, Linda; Quessy, Steve; Rappaport, Bob A; Rauschkolb, Christine; Reeve, Bryce B; Rhodes, Thomas; Sampaio, Cristina; Simpson, David M; Stauffer, Joseph W; Stucki, Gerold; Tobias, Jeffrey; White, Richard E; Witter, James

2010-05-01

There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain. Copyright 2010 International Association for the Study of Pain. All rights reserved.

Sources of Safety Data and Statistical Strategies for Design and Analysis: Clinical Trials.

PubMed

Zink, Richard C; Marchenko, Olga; Sanchez-Kam, Matilde; Ma, Haijun; Jiang, Qi

2018-03-01

There has been an increased emphasis on the proactive and comprehensive evaluation of safety endpoints to ensure patient well-being throughout the medical product life cycle. In fact, depending on the severity of the underlying disease, it is important to plan for a comprehensive safety evaluation at the start of any development program. Statisticians should be intimately involved in this process and contribute their expertise to study design, safety data collection, analysis, reporting (including data visualization), and interpretation. In this manuscript, we review the challenges associated with the analysis of safety endpoints and describe the safety data that are available to influence the design and analysis of premarket clinical trials. We share our recommendations for the statistical and graphical methodologies necessary to appropriately analyze, report, and interpret safety outcomes, and we discuss the advantages and disadvantages of safety data obtained from clinical trials compared to other sources. Clinical trials are an important source of safety data that contribute to the totality of safety information available to generate evidence for regulators, sponsors, payers, physicians, and patients. This work is a result of the efforts of the American Statistical Association Biopharmaceutical Section Safety Working Group.

Exploring the Benefits of Respite Services to Family Caregivers: Methodological Issues and Current Findings

PubMed Central

Zarit, Steven H.; Liu, Yin; Bangerter, Lauren R.; Rovine, Michael J.

2017-01-01

Objectives There is growing emphasis on empirical validation of the efficacy of community-based services for older people and their families, but research on services such as respite care faces methodological challenges that have limited the growth of outcome studies. We identify problems associated with the usual research approaches for studying respite care, with the goal of stimulating use of novel and more appropriate research designs that can lead to improved studies of community-based services. Method Using the concept of research validity, we evaluate the methodological approaches in the current literature on respite services, including adult day services, in-home respite and overnight respite. Results Although randomized control trials (RCTs) are possible in community settings, validity is compromised by practical limitations of randomization and other problems. Quasi-experimental and interrupted time series designs offer comparable validity to RCTs and can be implemented effectively in community settings. Conclusion An emphasis on RCTs by funders and researchers is not supported by scientific evidence. Alternative designs can lead to development of a valid body of research on community services such as respite. PMID:26729467

Exploring the benefits of respite services to family caregivers: methodological issues and current findings.

PubMed

Zarit, Steven H; Bangerter, Lauren R; Liu, Yin; Rovine, Michael J

2017-03-01

There is growing emphasis on empirical validation of the efficacy of community-based services for older people and their families, but research on services such as respite care faces methodological challenges that have limited the growth of outcome studies. We identify problems associated with the usual research approaches for studying respite care, with the goal of stimulating use of novel and more appropriate research designs that can lead to improved studies of community-based services. Using the concept of research validity, we evaluate the methodological approaches in the current literature on respite services, including adult day services, in-home respite and overnight respite. Although randomized control trials (RCTs) are possible in community settings, validity is compromised by practical limitations of randomization and other problems. Quasi-experimental and interrupted time series designs offer comparable validity to RCTs and can be implemented effectively in community settings. An emphasis on RCTs by funders and researchers is not supported by scientific evidence. Alternative designs can lead to development of a valid body of research on community services such as respite.

Measuring the costs of outreach motivational interviewing for smoking cessation and relapse prevention among low-income pregnant women

PubMed Central

Ruger, Jennifer Prah; Emmons, Karen M; Kearney, Margaret H; Weinstein, Milton C

2009-01-01

Background Economic theory provides the philosophical foundation for valuing costs in judging medical and public health interventions. When evaluating smoking cessation interventions, accurate data on costs are essential for understanding resource consumption. Smoking cessation interventions, for which prior data on resource costs are typically not available, present special challenges. We develop a micro-costing methodology for estimating the real resource costs of outreach motivational interviewing (MI) for smoking cessation and relapse prevention among low-income pregnant women and report results from a randomized controlled trial (RCT) employing the methodology. Methodological standards in cost analysis are necessary for comparison and uniformity in analysis across interventions. Estimating the costs of outreach programs is critical for understanding the economics of reaching underserved and hard-to-reach populations. Methods Randomized controlled trial (1997-2000) collecting primary cost data for intervention. A sample of 302 low-income pregnant women was recruited from multiple obstetrical sites in the Boston metropolitan area. MI delivered by outreach health nurses vs. usual care (UC), with economic costs as the main outcome measures. Results The total cost of the MI intervention for 156 participants was $48,672 or $312 per participant. The total cost of $311.8 per participant for the MI intervention compared with a cost of $4.82 per participant for usual care, a difference of $307 ([CI], $289.2 to $322.8). The total fixed costs of the MI were $3,930 and the total variable costs of the MI were $44,710. The total expected program costs for delivering MI to 500 participants would be 147,430, assuming no economies of scale in program delivery. The main cost components of outreach MI were intervention delivery, travel time, scheduling, and training. Conclusion Grounded in economic theory, this methodology systematically identifies and measures resource utilization, using a process tracking system and calculates both component-specific and total costs of outreach MI. The methodology could help improve collection of accurate data on costs and estimates of the real resource costs of interventions alongside clinical trials and improve the validity and reliability of estimates of resource costs for interventions targeted at underserved and hard-to-reach populations. PMID:19775455

The 20-year effort to reduce access to mammography screening: historical facts dispute a commentary in Cancer.

PubMed

Kopans, Daniel B; Webb, Matthew L; Cady, Blake

2014-09-15

Mammography screening fulfills all requirements for an effective screening test. It detects many cancers earlier when they are at a smaller size and earlier stage, and it has been demonstrated that this reduces breast cancer deaths in randomized controlled trials. When screening is introduced into the population, the death rate from breast cancer declines. Nevertheless, scientifically unsupported arguments that appear in the medical literature are passed on to the public and continue to confuse women and physicians regarding the value of screening. Methodologically flawed challenges to mammography have been almost continuous since the 1990s. And, as each challenge has been invalidated, a new, specious challenge has been raised. The authors of this report address the long history of misinformation that has developed in the effort to reduce access to screening, and they address the issues raised by commentators concerning their recent publication in this journal. © 2014 American Cancer Society.

Bayesian probability of success for clinical trials using historical data

PubMed Central

Ibrahim, Joseph G.; Chen, Ming-Hui; Lakshminarayanan, Mani; Liu, Guanghan F.; Heyse, Joseph F.

2015-01-01

Developing sophisticated statistical methods for go/no-go decisions is crucial for clinical trials, as planning phase III or phase IV trials is costly and time consuming. In this paper, we develop a novel Bayesian methodology for determining the probability of success of a treatment regimen on the basis of the current data of a given trial. We introduce a new criterion for calculating the probability of success that allows for inclusion of covariates as well as allowing for historical data based on the treatment regimen, and patient characteristics. A new class of prior distributions and covariate distributions is developed to achieve this goal. The methodology is quite general and can be used with univariate or multivariate continuous or discrete data, and it generalizes Chuang-Stein’s work. This methodology will be invaluable for informing the scientist on the likelihood of success of the compound, while including the information of covariates for patient characteristics in the trial population for planning future pre-market or post-market trials. PMID:25339499

Bayesian probability of success for clinical trials using historical data.

PubMed

Ibrahim, Joseph G; Chen, Ming-Hui; Lakshminarayanan, Mani; Liu, Guanghan F; Heyse, Joseph F

2015-01-30

Developing sophisticated statistical methods for go/no-go decisions is crucial for clinical trials, as planning phase III or phase IV trials is costly and time consuming. In this paper, we develop a novel Bayesian methodology for determining the probability of success of a treatment regimen on the basis of the current data of a given trial. We introduce a new criterion for calculating the probability of success that allows for inclusion of covariates as well as allowing for historical data based on the treatment regimen, and patient characteristics. A new class of prior distributions and covariate distributions is developed to achieve this goal. The methodology is quite general and can be used with univariate or multivariate continuous or discrete data, and it generalizes Chuang-Stein's work. This methodology will be invaluable for informing the scientist on the likelihood of success of the compound, while including the information of covariates for patient characteristics in the trial population for planning future pre-market or post-market trials. Copyright © 2014 John Wiley & Sons, Ltd.

Controlled trials in children: quantity, methodological quality and descriptive characteristics of pediatric controlled trials published 1948-2006.

PubMed

Thomson, Denise; Hartling, Lisa; Cohen, Eyal; Vandermeer, Ben; Tjosvold, Lisa; Klassen, Terry P

2010-09-30

The objective of this study was to describe randomized controlled trials (RCTs) and controlled clinical trials (CCTs) in child health published between 1948 and 2006, in terms of quantity, methodological quality, and publication and trial characteristics. We used the Trials Register of the Cochrane Child Health Field for overall trends and a sample from this to explore trial characteristics in more detail. We extracted descriptive data on a random sample of 578 trials. Ninety-six percent of the trials were published in English; the percentage of child-only trials was 90.5%. The most frequent diagnostic categories were infectious diseases (13.2%), behavioural and psychiatric disorders (11.6%), neonatal critical care (11.4%), respiratory disorders (8.9%), non-critical neonatology (7.9%), and anaesthesia (6.5%). There were significantly fewer child-only studies (i.e., more mixed child and adult studies) over time (P = 0.0460). The proportion of RCTs to CCTs increased significantly over time (P<0.0001), as did the proportion of multicentre trials (P = 0.002). Significant increases over time were found in methodological quality (Jadad score) (P<0.0001), the proportion of double-blind studies (P<0.0001), and studies with adequate allocation concealment (P<0.0001). Additionally, we found an improvement in reporting over time: adequate description of withdrawals and losses to follow-up (P<0.0001), sample size calculations (P<0.0001), and intention-to-treat analysis (P<0.0001). However, many trials still do not describe their level of blinding, and allocation concealment was inadequately reported in the majority of studies across the entire time period. The proportion of studies with industry funding decreased slightly over time (P = 0.003), and these studies were more likely to report positive conclusions (P = 0.028). The quantity and quality of pediatric controlled trials has increased over time; however, much work remains to be done, particularly in improving methodological issues around conduct and reporting of trials.

Fundamentals and Catalytic Innovation: The Statistical and Data Management Center of the Antibacterial Resistance Leadership Group.

PubMed

Huvane, Jacqueline; Komarow, Lauren; Hill, Carol; Tran, Thuy Tien T; Pereira, Carol; Rosenkranz, Susan L; Finnemeyer, Matt; Earley, Michelle; Jiang, Hongyu Jeanne; Wang, Rui; Lok, Judith; Evans, Scott R

2017-03-15

The Statistical and Data Management Center (SDMC) provides the Antibacterial Resistance Leadership Group (ARLG) with statistical and data management expertise to advance the ARLG research agenda. The SDMC is active at all stages of a study, including design; data collection and monitoring; data analyses and archival; and publication of study results. The SDMC enhances the scientific integrity of ARLG studies through the development and implementation of innovative and practical statistical methodologies and by educating research colleagues regarding the application of clinical trial fundamentals. This article summarizes the challenges and roles, as well as the innovative contributions in the design, monitoring, and analyses of clinical trials and diagnostic studies, of the ARLG SDMC. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

How to design and write a clinical research protocol in Cosmetic Dermatology*

PubMed Central

Bagatin, Ediléia; Miot, Helio A.

2013-01-01

Cosmetic Dermatology is a growing subspecialty. High-quality basic science studies have been published; however, few double-blind, randomized controlled clinical trials, which are the major instrument for evidence-based medicine, have been conducted in this area. Clinical research is essential for the discovery of new knowledge, improvement of scientific basis, resolution of challenges, and good clinical practice. Some basic principles for a successful researcher include interest, availability, persistence, and honesty. It is essential to learn how to write a protocol research and to know the international and national regulatory rules. A complete clinical trial protocol should include question, background, objectives, methodology (design, variable description, sample size, randomization, inclusion and exclusion criteria, intervention, efficacy and safety measures, and statistical analysis), consent form, clinical research form, and references. Institutional ethical review board approval and financial support disclosure are necessary. Publication of positive or negative results should be an authors' commitment. PMID:23539006

Facing Challenges in Differential Classical Conditioning Research: Benefits of a Hybrid Design for Simultaneous Electrodermal and Electroencephalographic Recording.

PubMed

Pastor, M Carmen; Rehbein, Maimu Alissa; Junghöfer, Markus; Poy, Rosario; López, Raul; Moltó, Javier

2015-01-01

Several challenges make it difficult to simultaneously investigate central and autonomous nervous system correlates of conditioned stimulus (CS) processing in classical conditioning paradigms. Such challenges include, for example, the discrepant requirements of electroencephalography (EEG) and electrodermal activity (EDA) recordings with regard to multiple repetitions of conditions and sufficient trial duration. Here, we propose a MultiCS conditioning set-up, in which we increased the number of CSs, decreased the number of learning trials, and used trials of short and long durations for meeting requirements of simultaneous EEG-EDA recording in a differential aversive conditioning task. Forty-eight participants underwent MultiCS conditioning, in which four neutral faces (CS+) were paired four times each with aversive electric stimulation (unconditioned stimulus) during acquisition, while four different neutral faces (CS-) remained unpaired. When comparing after relative to before learning measurements, EEG revealed an enhanced centro-posterior positivity to CS+ vs. CS- during 368-600 ms, and subjective ratings indicated CS+ to be less pleasant and more arousing than CS-. Furthermore, changes in CS valence and arousal were strong enough to bias subjective ratings when faces of CS+/CS- identity were displayed with different emotional expression (happy, angry) in a post-experimental behavioral task. In contrast to a persistent neural and evaluative CS+/CS- differentiation that sustained multiple unreinforced CS presentations, electrodermal differentiation was rapidly extinguished. Current results suggest that MultiCS conditioning provides a promising paradigm for investigating pre-post-learning changes under minimal influences of extinction and overlearning of simple stimulus features. Our data also revealed methodological pitfalls, such as the possibility of occurring artifacts when combining different acquisition systems for central and peripheral psychophysiological measures.

Facing Challenges in Differential Classical Conditioning Research: Benefits of a Hybrid Design for Simultaneous Electrodermal and Electroencephalographic Recording

PubMed Central

Pastor, M. Carmen; Rehbein, Maimu Alissa; Junghöfer, Markus; Poy, Rosario; López, Raul; Moltó, Javier

2015-01-01

Several challenges make it difficult to simultaneously investigate central and autonomous nervous system correlates of conditioned stimulus (CS) processing in classical conditioning paradigms. Such challenges include, for example, the discrepant requirements of electroencephalography (EEG) and electrodermal activity (EDA) recordings with regard to multiple repetitions of conditions and sufficient trial duration. Here, we propose a MultiCS conditioning set-up, in which we increased the number of CSs, decreased the number of learning trials, and used trials of short and long durations for meeting requirements of simultaneous EEG–EDA recording in a differential aversive conditioning task. Forty-eight participants underwent MultiCS conditioning, in which four neutral faces (CS+) were paired four times each with aversive electric stimulation (unconditioned stimulus) during acquisition, while four different neutral faces (CS−) remained unpaired. When comparing after relative to before learning measurements, EEG revealed an enhanced centro-posterior positivity to CS+ vs. CS− during 368–600 ms, and subjective ratings indicated CS+ to be less pleasant and more arousing than CS−. Furthermore, changes in CS valence and arousal were strong enough to bias subjective ratings when faces of CS+/CS− identity were displayed with different emotional expression (happy, angry) in a post-experimental behavioral task. In contrast to a persistent neural and evaluative CS+/CS− differentiation that sustained multiple unreinforced CS presentations, electrodermal differentiation was rapidly extinguished. Current results suggest that MultiCS conditioning provides a promising paradigm for investigating pre–post-learning changes under minimal influences of extinction and overlearning of simple stimulus features. Our data also revealed methodological pitfalls, such as the possibility of occurring artifacts when combining different acquisition systems for central and peripheral psychophysiological measures. PMID:26106318

A taxonomy of multinational ethical and methodological standards for clinical trials of therapeutic interventions

PubMed Central

Ashton, Carol M; Wray, Nelda P; Jarman, Anna F; Kolman, Jacob M; Wenner, Danielle M; Brody, Baruch A

2013-01-01

Background If trials of therapeutic interventions are to serve society’s interests, they must be of high methodological quality and must satisfy moral commitments to human subjects. The authors set out to develop a clinical-trials compendium in which standards for the ethical treatment of human subjects are integrated with standards for research methods. Methods The authors rank-ordered the world’s nations and chose the 31 with >700 active trials as of 24 July 2008. Governmental and other authoritative entities of the 31 countries were searched, and 1004 English-language documents containing ethical and/or methodological standards for clinical trials were identified. The authors extracted standards from 144 of those: 50 designated as ‘core’, 39 addressing trials of invasive procedures and a 5% sample (N=55) of the remainder. As the integrating framework for the standards we developed a coherent taxonomy encompassing all elements of a trial’s stages. Findings Review of the 144 documents yielded nearly 15 000 discrete standards. After duplicates were removed, 5903 substantive standards remained, distributed in the taxonomy as follows: initiation, 1401 standards, 8 divisions; design, 1869 standards, 16 divisions; conduct, 1473 standards, 8 divisions; analysing and reporting results, 997 standards, four divisions; and post-trial standards, 168 standards, 5 divisions. Conclusions The overwhelming number of source documents and standards uncovered in this study was not anticipated beforehand and confirms the extraordinary complexity of the clinical trials enterprise. This taxonomy of multinational ethical and methodological standards may help trialists and overseers improve the quality of clinical trials, particularly given the globalisation of clinical research. PMID:21429960

Methods to improve recruitment to randomised controlled trials: Cochrane systematic review and meta-analysis

PubMed Central

Treweek, Shaun; Lockhart, Pauline; Pitkethly, Marie; Cook, Jonathan A; Kjeldstrøm, Monica; Johansen, Marit; Taskila, Taina K; Sullivan, Frank M; Wilson, Sue; Jackson, Catherine; Jones, Ritu; Mitchell, Elizabeth D

2013-01-01

This review is an abridged version of a Cochrane Review previously published in the Cochrane Database of Systematic Reviews 2010, Issue 4, Art. No.: MR000013 DOI: 10.1002/14651858.MR000013.pub5 (see www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and Cochrane Database of Systematic Reviews should be consulted for the most recent version of the review. Objective To identify interventions designed to improve recruitment to randomised controlled trials, and to quantify their effect on trial participation. Design Systematic review. Data sources The Cochrane Methodology Review Group Specialised Register in the Cochrane Library, MEDLINE, EMBASE, ERIC, Science Citation Index, Social Sciences Citation Index, C2-SPECTR, the National Research Register and PubMed. Most searches were undertaken up to 2010; no language restrictions were applied. Study selection Randomised and quasi-randomised controlled trials, including those recruiting to hypothetical studies. Studies on retention strategies, examining ways to increase questionnaire response or evaluating the use of incentives for clinicians were excluded. The study population included any potential trial participant (eg, patient, clinician and member of the public), or individual or group of individuals responsible for trial recruitment (eg, clinicians, researchers and recruitment sites). Two authors independently screened identified studies for eligibility. Results 45 trials with over 43 000 participants were included. Some interventions were effective in increasing recruitment: telephone reminders to non-respondents (risk ratio (RR) 1.66, 95% CI 1.03 to 2.46; two studies, 1058 participants), use of opt-out rather than opt-in procedures for contacting potential participants (RR 1.39, 95% CI 1.06 to 1.84; one study, 152 participants) and open designs where participants know which treatment they are receiving in the trial (RR 1.22, 95% CI 1.09 to 1.36; two studies, 4833 participants). However, the effect of many other strategies is less clear, including the use of video to provide trial information and interventions aimed at recruiters. Conclusions There are promising strategies for increasing recruitment to trials, but some methods, such as open-trial designs and opt-out strategies, must be considered carefully as their use may also present methodological or ethical challenges. Questions remain as to the applicability of results originating from hypothetical trials, including those relating to the use of monetary incentives, and there is a clear knowledge gap with regard to effective strategies aimed at recruiters. PMID:23396504

Challenges in Antibody Development against Tn and Sialyl-Tn Antigens

PubMed Central

Loureiro, Liliana R.; Carrascal, Mylène A.; Barbas, Ana; Ramalho, José S.; Novo, Carlos; Delannoy, Philippe; Videira, Paula A.

2015-01-01

The carbohydrate antigens Tn and sialyl-Tn (STn) are expressed in most carcinomas and usually absent in healthy tissues. These antigens have been correlated with cancer progression and poor prognosis, and associated with immunosuppressive microenvironment. Presently they are used in clinical trials as therapeutic vaccination, but with limited success due to their low immunogenicity. Alternatively, anti-Tn and/or STn antibodies may be used to harness the immune system against tumor cells. Whilst the development of antibodies against these antigens had a boost two decades ago for diagnostic use, so far no such antibody entered into clinical trials. Possible limitations are the low specificity and efficiency of existing antibodies and that novel antibodies are still necessary. The vast array of methodologies available today will allow rapid antibody development and novel formats. Following the advent of hybridoma technology, the immortalization of human B cells became a methodology to obtain human monoclonal antibodies with better specificity. Advances in molecular biology including phage display technology for high throughput screening, transgenic mice and more recently molecularly engineered antibodies enhanced the field of antibody production. The development of novel antibodies against Tn and STn taking advantage of innovative technologies and engineering techniques may result in innovative therapeutic antibodies for cancer treatment. PMID:26270678

Methodological Issues in Trials of Complementary and Alternative Medicine Interventions

PubMed Central

Sikorskii, Alla; Wyatt, Gwen; Victorson, David; Faulkner, Gwen; Rahbar, Mohammad Hossein

2010-01-01

Background Complementary and alternative medicine (CAM) use is widespread among cancer patients. Information on safety and efficacy of CAM therapies is needed for both patients and health care providers. Well-designed randomized clinical trials (RCTs) of CAM therapy interventions can inform both clinical research and practice. Objectives To review important issues that affect the design of RCTs for CAM interventions. Methods Using the methods component of the Consolidated Standards for Reporting Trials (CONSORT) as a guiding framework, and a National Cancer Institute-funded reflexology study as an exemplar, methodological issues related to participants, intervention, objectives, outcomes, sample size, randomization, blinding, and statistical methods were reviewed. Discussion Trials of CAM interventions designed and implemented according to appropriate methodological standards will facilitate the needed scientific rigor in CAM research. Interventions in CAM can be tested using proposed methodology, and the results of testing will inform nursing practice in providing safe and effective supportive care and improving the well-being of patients. PMID:19918155

Published methodological quality of randomized controlled trials does not reflect the actual quality assessed in protocols.

PubMed

Mhaskar, Rahul; Djulbegovic, Benjamin; Magazin, Anja; Soares, Heloisa P; Kumar, Ambuj

2012-06-01

To assess whether the reported methodological quality of randomized controlled trials (RCTs) reflects the actual methodological quality and to evaluate the association of effect size (ES) and sample size with methodological quality. Systematic review. This is a retrospective analysis of all consecutive phase III RCTs published by eight National Cancer Institute Cooperative Groups up to 2006. Data were extracted from protocols (actual quality) and publications (reported quality) for each study. Four hundred twenty-nine RCTs met the inclusion criteria. Overall reporting of methodological quality was poor and did not reflect the actual high methodological quality of RCTs. The results showed no association between sample size and actual methodological quality of a trial. Poor reporting of allocation concealment and blinding exaggerated the ES by 6% (ratio of hazard ratio [RHR]: 0.94; 95% confidence interval [CI]: 0.88, 0.99) and 24% (RHR: 1.24; 95% CI: 1.05, 1.43), respectively. However, actual quality assessment showed no association between ES and methodological quality. The largest study to date shows that poor quality of reporting does not reflect the actual high methodological quality. Assessment of the impact of quality on the ES based on reported quality can produce misleading results. Copyright © 2012 Elsevier Inc. All rights reserved.

Design of Economic Evaluations of Mindfulness-Based Interventions: Ten Methodological Questions of Which to Be Mindful.

PubMed

Edwards, Rhiannon Tudor; Bryning, Lucy; Crane, Rebecca

Mindfulness-based interventions (MBIs) are being increasingly applied in a variety of settings. A growing body of evidence to support the effectiveness of these interventions exists and there are a few published cost-effectiveness studies. With limited resources available within public sectors (health care, social care, and education), it is necessary to build in concurrent economic evaluations alongside trials in order to inform service commissioning and policy. If future research studies are well-designed, they have strong potential to investigate the economic impact of MBIs. The particular challenge to the health economist is how best to capture the ways that MBIs help people adjust to or build resilience to difficult life circumstances, and to disseminate effectively to enable policy makers to judge the value of the contribution that MBIs can make within the context of the limited resourcing of public services. In anticipation of more research worldwide evaluating MBIs in various settings, this article suggests ten health economics methodological design questions that researchers may want to consider prior to conducting MBI research. These questions draw on both published standards of good methodological practice in economic evaluation of medical interventions, and on the authors' knowledge and experience of mindfulness-based practice. We argue that it is helpful to view MBIs as both complex interventions and as public health prevention initiatives. Our suggestions for well-designed economic evaluations of MBIs in health and other settings, mirror current thinking on the challenges and opportunities of public health economics.

Developments in clinical trials: a Pharma Matters report.

PubMed

Arjona, A; Nuskey, B; Rabasseda, X; Arias, E

2014-08-01

As the pharmaceutical industry strives to meet the ever-increasing complexity of drug development, new technology in clinical trials has become a beacon of hope. With big data comes the promise of accelerated patient recruitment, real-time monitoring of clinical trials, bioinformatics empowerment of quicker phase progression, and the overwhelming benefits of precision medicine for select trials. Risk-based monitoring stands to benefit as well. With a strengthening focus on centralized data by the FDA and industry's transformative initiative, TransCelerate, a new era in trial risk mitigation has begun. The traditional method of intensive on-site monitoring is becoming a thing of the past as statistical, real-time analysis of site and trial-wide data provides the means to monitor with greater efficiency and effectiveness from afar. However, when it comes to big data, there are challenges that lie ahead. Patient privacy, commercial investment protection, technology woes and data variability are all limitations to be met with considerable thought. At the Annual Meeting of the American Academy of Dermatology this year, clinical trials on psoriasis, atopic dermatitis and other skin diseases were discussed in detail. This review of clinical research reports on novel therapies for psoriasis and atopic dermatitis reveals the impact of these diseases and the drug candidates that have been successful in phase II and III studies. Data-focused highlights of novel dermatological trials, as well as real-life big data approaches and an insight on the new methodology of risk-based monitoring, are all discussed in this edition of Developments in Clinical Trials. Copyright 2014 Prous Science, S.A.U. or its licensors. All rights reserved.

Reporting and Methodological Quality of Randomised Controlled Trials in Vascular and Endovascular Surgery.

PubMed

Hajibandeh, S; Hajibandeh, S; Antoniou, G A; Green, P A; Maden, M; Torella, F

2015-11-01

Randomised controlled trials (RCTs) are subject to bias if they lack methodological quality. Moreover, optimal and transparent reporting of RCT findings aids their critical appraisal and interpretation. The aim of this study was to ascertain whether the methodological and reporting quality of RCTs in vascular and endovascular surgery is improving. The most recent 75 and oldest 75 RCTs published in leading journals over a 10-year period (2003-2012) were identified. The reporting quality and methodological quality data of the old and new RCTs were extracted and compared. The former was analysed using the Consolidated Standards of Reporting Trials (CONSORT) statement, the latter with the Scottish Intercollegiate Guidelines Network (SIGN) checklist. Reporting quality measured by CONSORT was better in the new studies than in the old studies (0.68 [95% CI, 0.66-0.7] vs. 0.60 [95% CI, 0.58-0.62], p < .001); however, both new and old studies had similar methodological quality measured by SIGN (0.9 [IQR 0.1] vs. .09 [IQR: 0.2], p = .787). Unlike clinical items, the methodological items of the CONSORT statement were not well reported in old and new RCTs. More trials in the new group were endovascular related (33.33% vs. 17.33%, p = .038) and industry sponsored (28% vs. 6.67%, p = .001). Despite some progress, there remains room for improvement in the reporting quality of RCTs in vascular and endovascular surgery. The methodological quality of recent RCTs is similar to that of trials performed >10 years ago. Copyright © 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Randomized controlled drug trials on very elderly subjects: descriptive and methodological analysis of trials published between 1990 and 2002 and comparison with trials on adults.

PubMed

Le Quintrec, Jean-Laurent; Bussy, Caroline; Golmard, Jean-Louis; Hervé, Christian; Baulon, Alain; Piette, François

2005-03-01

Very elderly subjects (VES; aged 80 years or older) constitute a special population as they frequently present multiple diseases (polypathology). Results from trials on general adult populations therefore cannot be extrapolated to VES. We performed a census of randomized controlled trials (RCT) on VES published between 1990 and 2002, and carried out a descriptive and methodological analysis of these RCT/VES, comparing them with matched RCT on general adult populations (control RCT, RCT/C). We searched for RCT/VES in two international databases (EMBASE and MEDLINE) and then manually. RCT/C were matched to RCT/VES for disease area and year of publication. The methodological quality of each RCT was assessed with Chalmers' scale. We identified 84 RCT/VES, 63 of which were conclusive and 21, inconclusive. Subjects were institutionalized in 48 RCT, and community dwelling in 11 RCT (unspecified in 25 RCT). Efficacy was the main criterion in 75 RCT; tolerance in 9 RCT. Twenty-six RCT were published by geriatrics journals, and 58 by general medical journals. The RCT/VES covered most of the disease areas of geriatrics. The 84 RCT/VES had a mean methodological quality score of 0.578 +/- 0.157. The matched 84 RCT/C had a mean methodological quality score of 0.592 +/- 0.116 (p = .466). The methodological quality score of RCT/VES increased with the number of included subjects (p = .004) and the year of publication (p = .001). The methodological quality of RCT/VES is equivalent to that of RCT in general adult populations. Nevertheless, RCT/VES remain very scarce, and neglect certain diseases. RCT/VES and the inclusion of very elderly subjects in RCT on adults should be strongly encouraged.

Pramipexole in the treatment of REM sleep behaviour disorder: A critical review.

PubMed

Tan, Shian Ming; Wan, Yi Min

2016-09-30

While widely accepted as a first-line treatment for rapid eye movement sleep (REM) behaviour disorder, clonazepam (CNZP) has side effects that limit its applicability. Pramipexole is a possible alternative, but limited literature on its effectiveness exists. This review aims to summarize the available data on the use of pramipexole in REM sleep behaviour disorder. A systematic search of major databases was conducted to look for published and on-going trials. This search yielded a total of five articles, all of which are observational in nature. Factors associated with effectiveness include low doses (less than 1.5mg/day) and idiopathic rapid eye movement sleep behaviour disorder/absence of neurodegenerative disease. Overall, the evidence is inconclusive. This is due to the lack of randomised controlled trials and the challenges in interpreting polysomgraphy findings in rapid eye movement sleep behaviour disorder. Suggestions are given on how future trials evaluating pramipexole treatment in rapid eye movement sleep behaviour disorder could overcome current methodological issues in extant literature. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Methodological Choices in Muscle Synergy Analysis Impact Differentiation of Physiological Characteristics Following Stroke

PubMed Central

Banks, Caitlin L.; Pai, Mihir M.; McGuirk, Theresa E.; Fregly, Benjamin J.; Patten, Carolynn

2017-01-01

Muscle synergy analysis (MSA) is a mathematical technique that reduces the dimensionality of electromyographic (EMG) data. Used increasingly in biomechanics research, MSA requires methodological choices at each stage of the analysis. Differences in methodological steps affect the overall outcome, making it difficult to compare results across studies. We applied MSA to EMG data collected from individuals post-stroke identified as either responders (RES) or non-responders (nRES) on the basis of a critical post-treatment increase in walking speed. Importantly, no clinical or functional indicators identified differences between the cohort of RES and nRES at baseline. For this exploratory study, we selected the five highest RES and five lowest nRES available from a larger sample. Our goal was to assess how the methodological choices made before, during, and after MSA affect the ability to differentiate two groups with intrinsic physiologic differences based on MSA results. We investigated 30 variations in MSA methodology to determine which choices allowed differentiation of RES from nRES at baseline. Trial-to-trial variability in time-independent synergy vectors (SVs) and time-varying neural commands (NCs) were measured as a function of: (1) number of synergies computed; (2) EMG normalization method before MSA; (3) whether SVs were held constant across trials or allowed to vary during MSA; and (4) synergy analysis output normalization method after MSA. MSA methodology had a strong effect on our ability to differentiate RES from nRES at baseline. Across all 10 individuals and MSA variations, two synergies were needed to reach an average of 90% variance accounted for (VAF). Based on effect sizes, differences in SV and NC variability between groups were greatest using two synergies with SVs that varied from trial-to-trial. Differences in SV variability were clearest using unit magnitude per trial EMG normalization, while NC variability was less sensitive to EMG normalization method. No outcomes were greatly impacted by output normalization method. MSA variability for some, but not all, methods successfully differentiated intrinsic physiological differences inaccessible to traditional clinical or biomechanical assessments. Our results were sensitive to methodological choices, highlighting the need for disclosure of all aspects of MSA methodology in future studies. PMID:28912707

Methodological Choices in Muscle Synergy Analysis Impact Differentiation of Physiological Characteristics Following Stroke.

PubMed

Banks, Caitlin L; Pai, Mihir M; McGuirk, Theresa E; Fregly, Benjamin J; Patten, Carolynn

2017-01-01

Muscle synergy analysis (MSA) is a mathematical technique that reduces the dimensionality of electromyographic (EMG) data. Used increasingly in biomechanics research, MSA requires methodological choices at each stage of the analysis. Differences in methodological steps affect the overall outcome, making it difficult to compare results across studies. We applied MSA to EMG data collected from individuals post-stroke identified as either responders (RES) or non-responders (nRES) on the basis of a critical post-treatment increase in walking speed. Importantly, no clinical or functional indicators identified differences between the cohort of RES and nRES at baseline. For this exploratory study, we selected the five highest RES and five lowest nRES available from a larger sample. Our goal was to assess how the methodological choices made before, during, and after MSA affect the ability to differentiate two groups with intrinsic physiologic differences based on MSA results. We investigated 30 variations in MSA methodology to determine which choices allowed differentiation of RES from nRES at baseline. Trial-to-trial variability in time-independent synergy vectors (SVs) and time-varying neural commands (NCs) were measured as a function of: (1) number of synergies computed; (2) EMG normalization method before MSA; (3) whether SVs were held constant across trials or allowed to vary during MSA; and (4) synergy analysis output normalization method after MSA. MSA methodology had a strong effect on our ability to differentiate RES from nRES at baseline. Across all 10 individuals and MSA variations, two synergies were needed to reach an average of 90% variance accounted for (VAF). Based on effect sizes, differences in SV and NC variability between groups were greatest using two synergies with SVs that varied from trial-to-trial. Differences in SV variability were clearest using unit magnitude per trial EMG normalization, while NC variability was less sensitive to EMG normalization method. No outcomes were greatly impacted by output normalization method. MSA variability for some, but not all, methods successfully differentiated intrinsic physiological differences inaccessible to traditional clinical or biomechanical assessments. Our results were sensitive to methodological choices, highlighting the need for disclosure of all aspects of MSA methodology in future studies.

Challenges and Innovations in a Community-Based Participatory Randomized Controlled Trial.

PubMed

Goodkind, Jessica R; Amer, Suha; Christian, Charlisa; Hess, Julia Meredith; Bybee, Deborah; Isakson, Brian L; Baca, Brandon; Ndayisenga, Martin; Greene, R Neil; Shantzek, Cece

2017-02-01

Randomized controlled trials (RCTs) are a long-standing and important design for conducting rigorous tests of the effectiveness of health interventions. However, many questions have been raised about the external validity of RCTs, their utility in explicating mechanisms of intervention and participants' intervention experiences, and their feasibility and acceptability. In the current mixed-methods study, academic and community partners developed and implemented an RCT to test the effectiveness of a collaboratively developed community-based advocacy, learning, and social support intervention. The goals of the intervention were to address social determinants of health and build trust and connections with other mental health services in order to reduce mental health disparities among Afghan, Great Lakes Region African, and Iraqi refugee adults and to engage and retain refugees in trauma-focused treatment, if needed. Two cohorts completed the intervention between 2013 and 2015. Ninety-three adult refugees were randomly assigned to intervention or control group and completed four research interviews (pre-, mid-, and postintervention, and follow-up). Several challenges to conducting a community-based RCT emerged, including issues related to interviewer intervention to assist participants in the control group, diffusion of intervention resources throughout the small refugee communities, and staff and community concerns about the RCT design and what evidence is meaningful to demonstrate intervention effectiveness. These findings highlight important epistemological, methodological, and ethical challenges that should be considered when conducting community-based RCTs and interpreting results from them. In addition, several innovations were developed to address these challenges, which may be useful for other community-academic partnerships engaged in RCTs.

CHALLENGES AND INNOVATIONS IN A COMMUNITY-BASED PARTICIPATORY RANDOMIZED CONTROLLED TRIAL

PubMed Central

Goodkind, Jessica R.; Amer, Suha; Christian, Charlisa; Hess, Julia Meredith; Bybee, Deborah; Isakson, Brian; Baca, Brandon; Ndaysenga, Martin; Greene, R. Neil; Shantzek, Cece

2016-01-01

Randomized controlled trials (RCTs) are a long-standing and important design for conducting rigorous tests of the effectiveness of health interventions. However, many questions have been raised about the external validity of RCTs, their utility in explicating mechanisms of intervention and participants’ intervention experiences, and their feasibility and acceptability. In the current mixed methods study, academic and community partners developed and implemented an RCT to test the effectiveness of a collaboratively developed community-based advocacy, learning, and social support intervention. The goals of the intervention were to address social determinants of health and build trust and connections with other mental health services in order to reduce mental health disparities among Afghan, Great Lakes Region African and Iraqi refugee adults and engage and retain refugees in trauma-focused treatment, if needed. Two cohorts completed the intervention between 2013-2015. Ninety-three adult refugees were randomly assigned to intervention or control group and completed four research interviews (pre-, mid-, post-intervention, and follow-up). Several challenges to conducting a community-based RCT emerged, including issues related to interviewer intervention to assist participants in the control group, diffusion of intervention resources throughout the small refugee communities, and staff and community concerns about the RCT design and what evidence is meaningful to demonstrate intervention effectiveness. These findings highlight important epistemological, methodological, and ethical challenges that should be considered when conducting community-based RCTs and interpreting results from them. In addition, several innovations were developed to address these challenges, which may be useful for other community-academic partnerships engaged in RCTs. PMID:27179291

Did we describe what you meant? Findings and methodological discussion of an empirical validation study for a systematic review of reasons

PubMed Central

2014-01-01

Background The systematic review of reasons is a new way to obtain comprehensive information about specific ethical topics. One such review was carried out for the question of why post-trial access to trial drugs should or need not be provided. The objective of this study was to empirically validate this review using an author check method. The article also reports on methodological challenges faced by our study. Methods We emailed a questionnaire to the 64 corresponding authors of those papers that were assessed in the review of reasons on post-trial access. The questionnaire consisted of all quotations (“reason mentions”) that were identified by the review to represent a reason in a given author’s publication, together with a set of codings for the quotations. The authors were asked to rate the correctness of the codings. Results We received 19 responses, from which only 13 were completed questionnaires. In total, 98 quotations and their related codes in the 13 questionnaires were checked by the addressees. For 77 quotations (79%), all codings were deemed correct, for 21 quotations (21%), some codings were deemed to need correction. Most corrections were minor and did not imply a complete misunderstanding of the citation. Conclusions This first attempt to validate a review of reasons leads to four crucial methodological questions relevant to the future conduct of such validation studies: 1) How can a description of a reason be deemed incorrect? 2) Do the limited findings of this author check study enable us to determine whether the core results of the analysed SRR are valid? 3) Why did the majority of surveyed authors refrain from commenting on our understanding of their reasoning? 4) How can the method for validating reviews of reasons be improved? PMID:25262532

Interventions to modify sexual risk behaviours for preventing HIV in homeless youth

PubMed Central

Naranbhai, Vivek; Karim, Quarraisha Abdool; Meyer-Weitz, Anna

2013-01-01

Background Homeless youth are at high risk for HIV infection as a consequence of risky sexual behavior. Interventions in homeless youth are challenging. Assessment of the effectiveness of interventions to modify sexual risk behaviours for preventing HIV in homeless youth is needed. Objectives To evaluate and summarize the effectiveness of interventions for modifying sexual risk behaviours and preventing transmission of HIV among homeless youth. Search methods We searched electronic databases (CENTRAL, Medline, EMBASE, AIDSearch, Gateway, PsycInfo, LILACS), reference lists of eligible articles, international health agency publication lists, and clinical trial registries. The search was updated January 2010. We contacted authors of published reports and other key role players. Selection criteria Randomized studies of interventions to modify sexual risk behavior (biological, self-report sexual-risk behavior or health seeking behavior) in homeless youth (12–24 years). Data collection and analysis Data from eligible studies were extracted by two reviewers. We assessed risk of bias per the Cochrane Collaborations tool. None of the eligible studies reported any primary biological outcomes for this review and the reporting of self-report sexual risk behavior outcomes was highly variable across studies precluding calculation of summary measures of effect; we present the outcomes descriptively for each study. We contacted authors for missing or ambiguous data. Results We identified three eligible studies after screening a total of 255 unique records. All three were performed in the United States of America and recruited substance-abusing male and female adolescents (total N=615) through homeless shelters into randomised controlled trials of independent and non-overlapping behavioural interventions. The three trials differed in theoretical background, delivery method, dosage (number of sessions,) content and outcome assessments. Overall, the variability in delivery and outcomes precluded estimation of summary of effect measures. We assessed the risk of bias to be high for each of the studies. Whilst some effect of the interventions on outcome measures were reported, heterogeneity and lack of robustness in these studies necessitate caution in interpreting the effectiveness of these interventions. Authors’ conclusions The body of evidence does not permit conclusions on the impact of interventions to modify sexual risk behaviour in homeless youth. More research is required. While the psychosocial and contextual factors that fuel sexual risk behaviours among homeless youth challenge stringent methodologies of RCT’s, novel ways for program delivery and trial retention are in need of development. Future trials should endeavour to comply with rigorous methodology in design, delivery, outcome measurement and reporting. PMID:21249691

A regulator's view of comparative effectiveness research.

PubMed

Temple, Robert

2012-02-01

'Comparative effectiveness' is the current enthusiasm, and for good reason. After knowing a treatment works, the most critical question is how it compares with alternatives. Comparative studies are not commonly conducted by drug companies and they represent a significant methodological challenge. Comparative data could include evidence of overall superiority to an alternative or advantages in identifiable subsets, for example, people who do not respond to or tolerate alternatives, or members of a genetic subset and could also include convincing evidence that there is little difference between two treatments. To describe regulations, guidance, and Food and Drug Administration experience related to studies of comparative effectiveness, including approaches to showing superiority and problems encountered in showing similarity. Review of Food and Drug Administration regulations and guidance and experience with showing superiority and similarity, particularly related to randomized trials and epidemiologic studies. Methods exist, and they have been successful for showing overall superiority of one drug over another, advantages in specific population subsets. Efforts to show true equivalence face problems of definition and very large sample sizes needed to rule out small differences. There is need for further discussion of what is meant by similarity or equivalence of two treatments. Comparative studies are challenging because differences between effective therapies are likely to be small and can be detected reliably only in randomized trials, often large ones. Despite the difficulties, comparative trials have been successful and we clearly would like to see more of them.

Preserving cognition, quality of life, physical health and functional ability in Alzheimer's disease: the effect of physical exercise (ADEX trial): rationale and design.

PubMed

Hoffmann, Kristine; Frederiksen, Kristian S; Sobol, Nanna Aue; Beyer, Nina; Vogel, Asmus; Simonsen, Anja Hviid; Johannsen, Peter; Lolk, Annette; Terkelsen, Ole; Cotman, Carl W; Hasselbalch, Steen G; Waldemar, Gunhild

2013-01-01

Exercise is hypothesized to improve cognition, physical performance, functional ability and quality of life, but evidence is scarce. Previous studies were of short duration, often underpowered and involving home-based light exercise programs in patients with undefined dementia. The aim of the ADEX ('Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: the Effect of Physical Exercise') trial is to establish whether aerobic exercise is effective in improving cognition as well as in reducing the prevalence of psychiatric symptoms among patients with Alzheimer's disease (AD). The ADEX study is a multicenter, single-blind, randomized trial with two arms: an intervention group attending 16 weeks of continuously supervised moderate-to-high intensity aerobic exercise and a control group receiving usual care. We plan to recruit 192 patients with mild AD. The primary outcome measure is change from baseline in cognitive performance at 16 weeks (as measured by the Symbol Digit Modalities test). To our knowledge this is the first large-scale controlled study to investigate the effects of supervised moderate aerobic exercise on cognition in patients with AD. Recruitment began in January 2012 and results are expected to be available in 2014. We summarize the methodological challenges we and other studies have faced in this type of complex multicenter intervention with unique challenges to study design. © 2013 S. Karger AG, Basel.

Chinese herbal medicine for cancer-related fatigue: a systematic review of randomized clinical trials.

PubMed

Su, Chun-Xiang; Wang, Li-Qiong; Grant, Suzanne J; Liu, Jian-Ping

2014-06-01

To assess the effectiveness and safety of Chinese herbal medicine for the treatment of cancer-related fatigue. We systematically searched seven electronic databases and two trial registries for randomized clinical trials of Chinese herbal medicine for cancer-related fatigue. Two authors independently extracted data and assessed the methodological quality of the included trials using the Cochrane risk of bias tool. Data were synthesized using RevMan 5.2 software. A total of 10 trials involving 751 participants with cancer-related fatigue were identified and the methodological quality of the included trials was generally poor. Chinese herbal medicine used alone or in combination with chemotherapy or supportive care showed significant relief in cancer-related fatigue compared to placebo, chemotherapy or supportive care based on single trials. Chinese herbal medicine plus chemotherapy or supportive care was superior to chemotherapy or supportive care in improving quality of life. Data from one trial demonstrated Chinese herbal medicine exerted a greater beneficial effect on relieving anxiety but no difference in alleviating depression. Seven trials reported adverse events and no severe adverse effects were found in Chinese herbal medicine groups. The findings from limited number of trials suggest that Chinese herbal medicine seems to be effective and safe in the treatment of cancer-related fatigue. However, the current evidence is insufficient to draw a confirmative conclusion due to the poor methodological quality of included trials. Thus, conducting rigorously designed trials on potential Chinese herbal medicine is warranted. Copyright © 2014 Elsevier Ltd. All rights reserved.

Methodological issues with adaptation of clinical trial design.

PubMed

Hung, H M James; Wang, Sue-Jane; O'Neill, Robert T

2006-01-01

Adaptation of clinical trial design generates many issues that have not been resolved for practical applications, though statistical methodology has advanced greatly. This paper focuses on some methodological issues. In one type of adaptation such as sample size re-estimation, only the postulated value of a parameter for planning the trial size may be altered. In another type, the originally intended hypothesis for testing may be modified using the internal data accumulated at an interim time of the trial, such as changing the primary endpoint and dropping a treatment arm. For sample size re-estimation, we make a contrast between an adaptive test weighting the two-stage test statistics with the statistical information given by the original design and the original sample mean test with a properly corrected critical value. We point out the difficulty in planning a confirmatory trial based on the crude information generated by exploratory trials. In regards to selecting a primary endpoint, we argue that the selection process that allows switching from one endpoint to the other with the internal data of the trial is not very likely to gain a power advantage over the simple process of selecting one from the two endpoints by testing them with an equal split of alpha (Bonferroni adjustment). For dropping a treatment arm, distributing the remaining sample size of the discontinued arm to other treatment arms can substantially improve the statistical power of identifying a superior treatment arm in the design. A common difficult methodological issue is that of how to select an adaptation rule in the trial planning stage. Pre-specification of the adaptation rule is important for the practicality consideration. Changing the originally intended hypothesis for testing with the internal data generates great concerns to clinical trial researchers.

The trials methodological research agenda: results from a priority setting exercise.

PubMed

Tudur Smith, Catrin; Hickey, Helen; Clarke, Mike; Blazeby, Jane; Williamson, Paula

2014-01-23

Research into the methods used in the design, conduct, analysis, and reporting of clinical trials is essential to ensure that effective methods are available and that clinical decisions made using results from trials are based on the best available evidence, which is reliable and robust. An on-line Delphi survey of 48 UK Clinical Research Collaboration registered Clinical Trials Units (CTUs) was undertaken. During round one, CTU Directors were asked to identify important topics that require methodological research. During round two, their opinion about the level of importance of each topic was recorded, and during round three, they were asked to review the group's average opinion and revise their previous opinion if appropriate. Direct reminders were sent to maximise the number of responses at each round. Results are summarised using descriptive methods. Forty one (85%) CTU Directors responded to at least one round of the Delphi process: 25 (52%) responded in round one, 32 (67%) responded in round two, 24 (50%) responded in round three. There were only 12 (25%) who responded to all three rounds and 18 (38%) who responded to both rounds two and three. Consensus was achieved amongst CTU Directors that the top three priorities for trials methodological research were 'Research into methods to boost recruitment in trials' (considered the highest priority), 'Methods to minimise attrition' and 'Choosing appropriate outcomes to measure'. Fifty other topics were included in the list of priorities and consensus was reached that two topics, 'Radiotherapy study designs' and 'Low carbon trials', were not priorities. This priority setting exercise has identified the research topics felt to be most important to the key stakeholder group of Directors of UKCRC registered CTUs. The use of robust methodology to identify these priorities will help ensure that this work informs the trials methodological research agenda, with a focus on topics that will have most impact and relevance.

Priorities for clinical research in intracerebral hemorrhage: report from a National Institute of Neurological Disorders and Stroke workshop.

PubMed

2005-03-01

Spontaneous intracerebral hemorrhage (ICH) is one of the most lethal stroke types. In December 2003, a National Institute of Neurological Disorders and Stroke (NINDS) workshop was convened to develop a consensus for ICH research priorities. The focus was clinical research aimed at acute ICH in patients. Workshop participants were divided into 6 groups: (1) current state of ICH research; (2) basic science; and (3) imaging, (4) medical, (5) surgical, and (6) clinical methodology. Each group formulated research priorities before the workshop. At the workshop, these were discussed and refined. Recent progress in management of hemorrhage growth, intraventricular hemorrhage, and limitations in the benefit of open craniotomy were noted. The workshop identified the importance of developing animal models to reflect human ICH, as well as the phenomena of rebleeding. More human ICH pathology is needed. Real-time, high-field magnets and 3-dimensional imaging, as well as high-resolution tissue probes, are ICH imaging priorities. Trials of acute blood pressure-lowering in ICH and coagulopathy reversal are medical priorities. The exact role of edema in human ICH pathology and its treatment requires intensive study. Trials of minimally invasive surgical techniques including mechanical and chemical surgical adjuncts are critically important. The methodologic challenges include establishing research networks and a multi-specialty approach. Waiver of consent issues and standardizing care in trials are important issues. Encouragement of young investigators from varied backgrounds to enter the ICH research field is critical. Increasing ICH research is crucial. A collaborative approach is likely to yield therapies for this devastating form of brain injury.

Informing efficient randomised controlled trials: exploration of challenges in developing progression criteria for internal pilot studies.

PubMed

Avery, Kerry N L; Williamson, Paula R; Gamble, Carrol; O'Connell Francischetto, Elaine; Metcalfe, Chris; Davidson, Peter; Williams, Hywel; Blazeby, Jane M

2017-02-17

Designing studies with an internal pilot phase may optimise the use of pilot work to inform more efficient randomised controlled trials (RCTs). Careful selection of preagreed decision or 'progression' criteria at the juncture between the internal pilot and main trial phases provides a valuable opportunity to evaluate the likely success of the main trial and optimise its design or, if necessary, to make the decision not to proceed with the main trial. Guidance on the appropriate selection and application of progression criteria is, however, lacking. This paper outlines the key issues to consider in the optimal development and review of operational progression criteria for RCTs with an internal pilot phase. A structured literature review and exploration of stakeholders' opinions at a Medical Research Council (MRC) Hubs for Trials Methodology Research workshop. Key stakeholders included triallists, methodologists, statisticians and funders. There is considerable variation in the use of progression criteria for RCTs with an internal pilot phase, although 3 common issues predominate: trial recruitment, protocol adherence and outcome data. Detailed and systematic reporting around the decision-making process for stopping, amending or proceeding to a main trial is uncommon, which may hamper understanding in the research community about the appropriate and optimal use of RCTs with an internal pilot phase. 10 top tips for the development, use and reporting of progression criteria for internal pilot studies are presented. Systematic and transparent reporting of the design, results and evaluation of internal pilot trials in the literature should be encouraged in order to facilitate understanding in the research community and to inform future trials. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Informing efficient randomised controlled trials: exploration of challenges in developing progression criteria for internal pilot studies

PubMed Central

Williamson, Paula R; Gamble, Carrol; O'Connell Francischetto, Elaine; Metcalfe, Chris; Davidson, Peter; Williams, Hywel; Blazeby, Jane M

2017-01-01

Objectives Designing studies with an internal pilot phase may optimise the use of pilot work to inform more efficient randomised controlled trials (RCTs). Careful selection of preagreed decision or ‘progression’ criteria at the juncture between the internal pilot and main trial phases provides a valuable opportunity to evaluate the likely success of the main trial and optimise its design or, if necessary, to make the decision not to proceed with the main trial. Guidance on the appropriate selection and application of progression criteria is, however, lacking. This paper outlines the key issues to consider in the optimal development and review of operational progression criteria for RCTs with an internal pilot phase. Design A structured literature review and exploration of stakeholders' opinions at a Medical Research Council (MRC) Hubs for Trials Methodology Research workshop. Key stakeholders included triallists, methodologists, statisticians and funders. Results There is considerable variation in the use of progression criteria for RCTs with an internal pilot phase, although 3 common issues predominate: trial recruitment, protocol adherence and outcome data. Detailed and systematic reporting around the decision-making process for stopping, amending or proceeding to a main trial is uncommon, which may hamper understanding in the research community about the appropriate and optimal use of RCTs with an internal pilot phase. 10 top tips for the development, use and reporting of progression criteria for internal pilot studies are presented. Conclusions Systematic and transparent reporting of the design, results and evaluation of internal pilot trials in the literature should be encouraged in order to facilitate understanding in the research community and to inform future trials. PMID:28213598

Quetiapine versus aripiprazole in children and adolescents with psychosis - protocol for the randomised, blinded clinical Tolerability and Efficacy of Antipsychotics (TEA) trial

PubMed Central

2014-01-01

Background The evidence for choices between antipsychotics for children and adolescents with schizophrenia and other psychotic disorders is limited. The main objective of the Tolerability and Efficacy of Antipsychotics (TEA) trial is to compare the benefits and harms of quetiapine versus aripiprazole in children and adolescents with psychosis in order to inform rational, effective and safe treatment selections. Methods/Design The TEA trial is a Danish investigator-initiated, independently funded, multi-centre, randomised, blinded clinical trial. Based on sample size estimation, 112 patients aged 12-17 years with psychosis, antipsychotic-naïve or treated for a limited period are, 1:1 randomised to a 12- week, double-blind intervention with quetiapine versus aripiprazole. Effects on psychopathology, cognition, health-related quality of life, and adverse events are assessed 2, 4, and 12 weeks after randomisation. The primary outcome is change in the positive symptom score of the Positive and Negative Syndrome Scale. The recruitment period is 2010-2014. Discussion Antipsychotics are currently the only available pharmacologic treatments for psychotic disorders. However, information about head-to-head differences in efficacy and tolerability of antipsychotics are scarce in children and adolescents. The TEA trial aims at expanding the evidence base for the use of antipsychotics in early onset psychosis in order to inform more rational treatment decisions in this vulnerable population. Here, we account for the trial design, address methodological challenges, and discuss the estimation of sample size. Trial registration ClinicalTrials.gov: NCT01119014 PMID:25015535

Coordination and Management of Multisite Complementary and Alternative Medicine (CAM) Therapies: Experience from a Multisite Reflexology Intervention Trial

PubMed Central

Rahbar, Mohammad H.; Wyatt, Gwen; Sikorskii, Alla; Victorson, David; Ardjomand-Hessabi, Manouchehr

2011-01-01

Background Multisite randomized clinical trials allow for increased research collaboration among investigators and expedite data collection efforts. As a result, government funding agencies typically look favorably upon this approach. As the field of complementary and alternative medicine (CAM) continues to evolve, so do increased calls for the use of more rigorous study design and trial methodologies, which can present challenges for investigators. Purpose To describe the processes involved in the coordination and management of a multisite randomized clinical trial of a CAM intervention. Methods Key aspects related to the coordination and management of a multisite CAM randomized clinical trial are presented, including organizational and site selection considerations, recruitment concerns and issues related to data collection and randomization to treatment groups. Management and monitoring of data, as well as quality assurance procedures are described. Finally, a real world perspective is shared from a recently conducted multisite randomized clinical trial of reflexology for women diagnosed with advanced breast cancer. Results The use of multiple sites in the conduct of CAM-based randomized clinical trials can provide an efficient, collaborative and robust approach to study coordination and data collection that maximizes efficiency and ensures the quality of results. Conclusions Multisite randomized clinical trial designs can offer the field of CAM research a more standardized and efficient approach to examine the effectiveness of novel therapies and treatments. Special attention must be given to intervention fidelity, consistent data collection and ensuring data quality. Assessment and reporting of quantitative indicators of data quality should be required. PMID:21664296

Advancing the evidence base in cancer: psychosocial multicenter trials

PubMed Central

2012-01-01

Background The diagnosis and treatment of cancer is associated with significant distress and psychosocial morbidity. Although psychosocial interventions have been developed in an attempt to improve psychosocial outcomes in cancer patients and survivors, there is continued debate about whether there is adequate high-level evidence to establish the effectiveness of these interventions. The evidence base is limited as a result of numerous challenges faced by those attempting to conduct psychosocial intervention trials within the health system. Barriers include insufficient participant recruitment, difficulty generalizing from single-trial studies, difficulty in building and managing research teams with multidisciplinary expertise, lack of research design expertise and a lack of incentives for researchers conducting intervention research. To strengthen the evidence base, more intervention studies employing methodologically rigorous research designs are necessary. Methods In order to advance the evidence base of interventions designed to improve psychosocial outcomes for cancer patients and survivors, we propose the formation of a collaborative trials group that conducts multicenter trials to test the effectiveness of such interventions. Results Establishment of such a group would improve the quality of the evidence base in psychosocial research in cancer patients, by increasing support for conducting intervention research and providing intervention research training opportunities. A multidisciplinary collaborative group conducting multicenter trials would have the capacity to overcome many of the barriers that currently exist. Conclusions A stronger evidence base is necessary to identify effective psychosocial interventions for cancer patients. The proposed formation of a psycho-oncology collaborative trials group that conducts multicenter trials to test the effectiveness of psychosocial interventions would assist in achieving this outcome. PMID:22992443

Rigor and reproducibility in research with transcranial electrical stimulation: An NIMH-sponsored workshop.

PubMed

Bikson, Marom; Brunoni, Andre R; Charvet, Leigh E; Clark, Vincent P; Cohen, Leonardo G; Deng, Zhi-De; Dmochowski, Jacek; Edwards, Dylan J; Frohlich, Flavio; Kappenman, Emily S; Lim, Kelvin O; Loo, Colleen; Mantovani, Antonio; McMullen, David P; Parra, Lucas C; Pearson, Michele; Richardson, Jessica D; Rumsey, Judith M; Sehatpour, Pejman; Sommers, David; Unal, Gozde; Wassermann, Eric M; Woods, Adam J; Lisanby, Sarah H

Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities. This report seeks to promote the science, technology and effective clinical applications of these modalities, identify research challenges, and suggest approaches for addressing these needs in order to achieve rigorous, reproducible findings that can advance clinical treatment. The National Institute of Mental Health (NIMH) convened a workshop in September 2016 that brought together experts in basic and human neuroscience, electrical stimulation biophysics and devices, and clinical trial methods to examine the physiological mechanisms underlying tDCS/tACS, technologies and technical strategies for optimizing stimulation protocols, and the state of the science with respect to therapeutic applications and trial designs. Advances in understanding mechanisms, methodological and technological improvements (e.g., electronics, computational models to facilitate proper dosing), and improved clinical trial designs are poised to advance rigorous, reproducible therapeutic applications of these techniques. A number of challenges were identified and meeting participants made recommendations made to address them. These recommendations align with requirements in NIMH funding opportunity announcements to, among other needs, define dosimetry, demonstrate dose/response relationships, implement rigorous blinded trial designs, employ computational modeling, and demonstrate target engagement when testing stimulation-based interventions for the treatment of mental disorders. Published by Elsevier Inc.

Rigor and reproducibility in research with transcranial electrical stimulation: An NIMH-sponsored workshop

PubMed Central

Bikson, Marom; Brunoni, Andre R.; Charvet, Leigh E.; Clark, Vincent P.; Cohen, Leonardo G.; Deng, Zhi-De; Dmochowski, Jacek; Edwards, Dylan J.; Frohlich, Flavio; Kappenman, Emily S.; Lim, Kelvin O.; Loo, Colleen; Mantovani, Antonio; McMullen, David P.; Parra, Lucas C.; Pearson, Michele; Richardson, Jessica D.; Rumsey, Judith M.; Sehatpour, Pejman; Sommers, David; Unal, Gozde; Wassermann, Eric M.; Woods, Adam J.; Lisanby, Sarah H.

2018-01-01

Background Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities. Objective This report seeks to promote the science, technology and effective clinical applications of these modalities, identify research challenges, and suggest approaches for addressing these needs in order to achieve rigorous, reproducible findings that can advance clinical treatment. Methods The National Institute of Mental Health (NIMH) convened a workshop in September 2016 that brought together experts in basic and human neuroscience, electrical stimulation biophysics and devices, and clinical trial methods to examine the physiological mechanisms underlying tDCS/tACS, technologies and technical strategies for optimizing stimulation protocols, and the state of the science with respect to therapeutic applications and trial designs. Results Advances in understanding mechanisms, methodological and technological improvements (e.g., electronics, computational models to facilitate proper dosing), and improved clinical trial designs are poised to advance rigorous, reproducible therapeutic applications of these techniques. A number of challenges were identified and meeting participants made recommendations made to address them. Conclusions These recommendations align with requirements in NIMH funding opportunity announcements to, among other needs, define dosimetry, demonstrate dose/response relationships, implement rigorous blinded trial designs, employ computational modeling, and demonstrate target engagement when testing stimulation-based interventions for the treatment of mental disorders. PMID:29398575

Active-comparator design and new-user design in observational studies

PubMed Central

Yoshida, Kazuki; Solomon, Daniel H.; Kim, Seoyoung C.

2015-01-01

SUMMARY Over the past decade, an increasing number of observational studies have examined the effectiveness or safety of rheumatoid arthritis treatments. However, unlike randomized controlled trials (RCTs), observational studies of drug effects face methodological challenges including confounding by indication. Two design principles - active comparator design and new user design can help mitigate such challenges in observational studies. To improve validity of study findings, observational studies should be designed in such a way that makes them more closely approximate RCTs. The active comparator design compares the drug of interest to another commonly used agent for the same indication, rather than a ‘non-user’ group. This principle helps select treatment groups similar in treatment indications (both measured and unmeasured characteristics). The new user design includes a cohort of patients from the time of treatment initiation, so that it can assess patients’ pretreatment characteristics and capture all events occurring anytime during follow-up. PMID:25800216

Designing food delivery systems: challenges related to the in vitro methods employed to determine the fate of bioactives in the gut.

PubMed

Arranz, Elena; Corredig, Milena; Guri, Anilda

2016-08-10

An in depth understanding of the underpinning mechanisms that relate to food disruption and processing in the gastrointestinal tract is necessary to achieve optimal intake of nutrients and their bioefficacy. Although in vivo trials can provide insights on physiological responses of nutrients, in vitro assays are often applied as tools to understand specific mechanisms, or as prescreening methods to determine the factors associated with the uptake of food components in the gastrointestinal tract. In vitro assays are also often utilized to design novel or improved food delivery systems. In this review the available approaches to study delivery and uptake of food bioactives and the associated challenges are discussed. For an in depth understanding of food processing in the gastrointestinal tract, it is necessary to apply multidisciplinary methodologies, at the interface between materials science, chemistry, physics and biology.

A Systematic Review of Herbal Medicine for Chemotherapy Induced Peripheral Neuropathy

PubMed Central

Noh, Hyeonseok

2018-01-01

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect in cancer patients. The aim of this review was to assess the effectiveness of herbal medicine in preventing and treating CIPN. Methods Randomised controlled trials were included in this review. Extracting and assessing the data independently, two authors searched 13 databases. Results Twenty-eight trials involving 2174 patients met the inclusion criteria. Although there were some exceptions, the methodological quality was typically low. Seventeen trials reported the incidence rate of CIPN assessed by various tools and 14 showed a significant difference regarding the decrease of the incidence rate between the two groups. For clinical improvement, 12 trials reported it using various tools and 10 showed a significant difference between two groups. Two cases of adverse events occurred in one trial; the other nine trials reported no adverse events. Conclusions We found that herbal medicines in combination with and/or without other therapies potentially have preventive or therapeutic effects on CIPN. However, conclusions cannot be drawn because of the generally low quality of the methodology, the clinical heterogeneity, and the small sample size for each single herbal medicine. Trials that are more rigorous and report sufficient methodological data are needed. PMID:29636782

Hospital recruitment for a pragmatic cluster-randomized clinical trial: Lessons learned from the COMPASS study.

PubMed

Johnson, Anna M; Jones, Sara B; Duncan, Pamela W; Bushnell, Cheryl D; Coleman, Sylvia W; Mettam, Laurie H; Kucharska-Newton, Anna M; Sissine, Mysha E; Rosamond, Wayne D

2018-01-26

Pragmatic randomized clinical trials are essential to determine the effectiveness of interventions in "real-world" clinical practice. These trials frequently use a cluster-randomized methodology, with randomization at the site level. Despite policymakers' increased interest in supporting pragmatic randomized clinical trials, no studies to date have reported on the unique recruitment challenges faced by cluster-randomized pragmatic trials. We investigated key challenges and successful strategies for hospital recruitment in the Comprehensive Post-Acute Stroke Services (COMPASS) study. The COMPASS study is designed to compare the effectiveness of the COMPASS model versus usual care in improving functional outcomes, reducing the numbers of hospital readmissions, and reducing caregiver strain for patients discharged home after stroke or transient ischemic attack. This model integrates early supported discharge planning with transitional care management, including nurse-led follow-up phone calls after 2, 30, and 60 days and an in-person clinic visit at 7-14 days involving a functional assessment and neurological examination. We present descriptive statistics of the characteristics of successfully recruited hospitals compared with all eligible hospitals, reasons for non-participation, and effective recruitment strategies. We successfully recruited 41 (43%) of 95 eligible North Carolina hospitals. Leading, non-exclusive reasons for non-participation included: insufficient staff or financial resources (n = 33, 61%), lack of health system support (n = 16, 30%), and lack of support of individual decision-makers (n = 11, 20%). Successful recruitment strategies included: building and nurturing relationships, engaging team members and community partners with a diverse skill mix, identifying gatekeepers, finding mutually beneficial solutions, having a central institutional review board, sharing published pilot data, and integrating contracts and review board administrators. Although we incorporated strategies based on the best available evidence at the outset of the study, hospital recruitment required three times as much time and considerably more staff than anticipated. To reach our goal, we tailored strategies to individuals, hospitals, and health systems. Successful recruitment of a sufficient number and representative mix of hospitals requires considerable preparation, planning, and flexibility. Strategies presented here may assist future trial organizers in implementing cluster-randomized pragmatic trials. Clinicaltrials.gov, NCT02588664 . Registered on 23 October 2015.

Speed Accuracy Tradeoffs in Human Speech Production

DTIC Science & Technology

2017-05-01

for considering Fitts’ law in the domain of speech production is elucidated. Methodological challenges in applying Fitts-style analysis are addressed...order to assess whether articulatory kinematics conform to Fitts’ law. A second, associated goal is to address the methodological challenges inherent in...performing Fitts-style analysis on rtMRI data of speech production. Methodological challenges include segmenting continuous speech into specific motor

Randomized Controlled Trials in Music Therapy: Guidelines for Design and Implementation.

PubMed

Bradt, Joke

2012-01-01

Evidence from randomized controlled trials (RCTs) plays a powerful role in today's healthcare industry. At the same time, it is important that multiple types of evidence contribute to music therapy's knowledge base and that the dialogue of clinical effectiveness in music therapy is not dominated by the biomedical hierarchical model of evidence-based practice. Whether or not one agrees with the hierarchical model of evidence in the current healthcare climate, RCTs can contribute important knowledge to our field. Therefore, it is important that music therapists are prepared to design trials that meet current methodological standards and, equally important, are able to respond appropriately to those design aspects that may not be feasible in music therapy research. To provide practical guidelines to music therapy researchers for the design and implementation of RCTs as well as to enable music therapists to be well-informed consumers of RCT evidence. This article reviews key design aspects of RCTs and discusses how to best implement these standards in music therapy trials. A systematic presentation of basic randomization methods, allocation concealment strategies, issues related to blinding in music therapy trials and strategies for implementation, the use of treatment manuals, types of control groups, outcome selection, and sample size computation is provided. Despite the challenges of meeting all key design demands typical of an RCT, it is possible to design rigorous music therapy RCTs that accurately estimate music therapy treatment benefits.

Independent academic Data Monitoring Committees for clinical trials in cardiovascular and cardiometabolic diseases.

PubMed

Filippatos, Gerasimos S; de Graeff, Pieter; Bax, Jeroen J; Borg, John-Joseph; Cleland, John G F; Dargie, Henry J; Flather, Marcus; Ford, Ian; Friede, Tim; Greenberg, Barry; Henon-Goburdhun, Cécile; Holcomb, Richard; Horst, Bradley; Lekakis, John; Mueller-Velten, Guenther; Papavassiliou, Athanasios G; Prasad, Krishna; Rosano, Giuseppe M C; Severin, Thomas; Sherman, Warren; Stough, Wendy Gattis; Swedberg, Karl; Tavazzi, Luigi; Tousoulis, Dimitris; Vardas, Panagiotis; Ruschitzka, Frank; Anker, Stefan D

2017-04-01

Data Monitoring Committees (DMCs) play a crucial role in the conducting of clinical trials to ensure the safety of study participants and to maintain a trial's scientific integrity. Generally accepted standards exist for DMC composition and operational conduct. However, some relevant issues are not specifically addressed in current guidance documents, resulting in uncertainties regarding optimal approaches for communication between the DMC, steering committee, and sponsors, release of information, and liability protection for DMC members. The Heart Failure Association (HFA) of the European Society of Cardiology (ESC), in collaboration with the Clinical Trials Unit of the European Heart Agency (EHA) of the ESC convened a meeting of international experts in DMCs for cardiovascular and cardiometabolic clinical trials to identify specific issues and develop steps to resolve challenges faced by DMCs.The main recommendations from the meeting relate to methodological consistency, independence, managing conflicts of interest, liability protection, and training of future DMC members. This paper summarizes the key outcomes from this expert meeting, and describes the core set of activities that might be further developed and ultimately implemented by the ESC, HFA, and other interested ESC constituent bodies. The HFA will continue to work with stakeholders in cardiovascular and cardiometabolic clinical research to promote these goals. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

Identifying Items to Assess Methodological Quality in Physical Therapy Trials: A Factor Analysis

PubMed Central

Cummings, Greta G.; Fuentes, Jorge; Saltaji, Humam; Ha, Christine; Chisholm, Annabritt; Pasichnyk, Dion; Rogers, Todd

2014-01-01

Background Numerous tools and individual items have been proposed to assess the methodological quality of randomized controlled trials (RCTs). The frequency of use of these items varies according to health area, which suggests a lack of agreement regarding their relevance to trial quality or risk of bias. Objective The objectives of this study were: (1) to identify the underlying component structure of items and (2) to determine relevant items to evaluate the quality and risk of bias of trials in physical therapy by using an exploratory factor analysis (EFA). Design A methodological research design was used, and an EFA was performed. Methods Randomized controlled trials used for this study were randomly selected from searches of the Cochrane Database of Systematic Reviews. Two reviewers used 45 items gathered from 7 different quality tools to assess the methodological quality of the RCTs. An exploratory factor analysis was conducted using the principal axis factoring (PAF) method followed by varimax rotation. Results Principal axis factoring identified 34 items loaded on 9 common factors: (1) selection bias; (2) performance and detection bias; (3) eligibility, intervention details, and description of outcome measures; (4) psychometric properties of the main outcome; (5) contamination and adherence to treatment; (6) attrition bias; (7) data analysis; (8) sample size; and (9) control and placebo adequacy. Limitation Because of the exploratory nature of the results, a confirmatory factor analysis is needed to validate this model. Conclusions To the authors' knowledge, this is the first factor analysis to explore the underlying component items used to evaluate the methodological quality or risk of bias of RCTs in physical therapy. The items and factors represent a starting point for evaluating the methodological quality and risk of bias in physical therapy trials. Empirical evidence of the association among these items with treatment effects and a confirmatory factor analysis of these results are needed to validate these items. PMID:24786942

Identifying items to assess methodological quality in physical therapy trials: a factor analysis.

PubMed

Armijo-Olivo, Susan; Cummings, Greta G; Fuentes, Jorge; Saltaji, Humam; Ha, Christine; Chisholm, Annabritt; Pasichnyk, Dion; Rogers, Todd

2014-09-01

Numerous tools and individual items have been proposed to assess the methodological quality of randomized controlled trials (RCTs). The frequency of use of these items varies according to health area, which suggests a lack of agreement regarding their relevance to trial quality or risk of bias. The objectives of this study were: (1) to identify the underlying component structure of items and (2) to determine relevant items to evaluate the quality and risk of bias of trials in physical therapy by using an exploratory factor analysis (EFA). A methodological research design was used, and an EFA was performed. Randomized controlled trials used for this study were randomly selected from searches of the Cochrane Database of Systematic Reviews. Two reviewers used 45 items gathered from 7 different quality tools to assess the methodological quality of the RCTs. An exploratory factor analysis was conducted using the principal axis factoring (PAF) method followed by varimax rotation. Principal axis factoring identified 34 items loaded on 9 common factors: (1) selection bias; (2) performance and detection bias; (3) eligibility, intervention details, and description of outcome measures; (4) psychometric properties of the main outcome; (5) contamination and adherence to treatment; (6) attrition bias; (7) data analysis; (8) sample size; and (9) control and placebo adequacy. Because of the exploratory nature of the results, a confirmatory factor analysis is needed to validate this model. To the authors' knowledge, this is the first factor analysis to explore the underlying component items used to evaluate the methodological quality or risk of bias of RCTs in physical therapy. The items and factors represent a starting point for evaluating the methodological quality and risk of bias in physical therapy trials. Empirical evidence of the association among these items with treatment effects and a confirmatory factor analysis of these results are needed to validate these items. © 2014 American Physical Therapy Association.

The importance of preservation of the ethical principle of equipoise in the design of clinical trials: relative impact of the methodological quality domains on the treatment effect in randomized controlled trials.

PubMed

Djulbegovic, Benjamin; Cantor, Alan; Clarke, Mike

2003-01-01

Previous research has identified methodological problems in the design and conduct of randomized trials that could, if left unaddressed, lead to biased results. In this report we discuss one such problem, inadequate control intervention, and argue that it can be by far the most important design characteristic of randomized trials in overestimating the effect of new treatments. Current guidelines for the design and reporting of randomized trials, such as the Consolidated Standards of Reporting Trials (CONSORT) statement, do not address the choice of the comparator intervention. We argue that an adequate control intervention can be selected if people designing a trial explicitly take into consideration the ethical principle of equipoise, also known as "the uncertainty principle."

Methodological challenges to human medical study.

PubMed

Zhong, Yixin; Liu, Baoyan; Qu, Hua; Xie, Qi

2014-09-01

With the transformation of modern medicinal pattern, medical studies are confronted with methodological challenges. By analyzing two methodologies existing in the study of physical matter system and information system, the article points out that traditional Chinese medicine (TCM), especially the treatment based on syndrome differentiation, embodies information conception of methodological positions, while western medicine represents matter conception of methodological positions. It proposes a new way of thinking about combination of TCM and western medicine by combinating two kinds of methodological methods.

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments

PubMed Central

2011-01-01

Background No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes - the "sentinel lesion approach". Methods/design MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Results Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. Conclusions In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS - the sentinel lesion approach - serving as proof of principle for its future wider applicability. Trial registration ClinicalTrials.gov (NCT00395200). PMID:21366911

Development of a manualized protocol of massage therapy for clinical trials in osteoarthritis.

PubMed

Ali, Ather; Kahn, Janet; Rosenberger, Lisa; Perlman, Adam I

2012-10-04

Clinical trial design of manual therapies may be especially challenging as techniques are often individualized and practitioner-dependent. This paper describes our methods in creating a standardized Swedish massage protocol tailored to subjects with osteoarthritis of the knee while respectful of the individualized nature of massage therapy, as well as implementation of this protocol in two randomized clinical trials. The manualization process involved a collaborative process between methodologic and clinical experts, with the explicit goals of creating a reproducible semi-structured protocol for massage therapy, while allowing some latitude for therapists' clinical judgment and maintaining consistency with a prior pilot study. The manualized protocol addressed identical specified body regions with distinct 30- and 60-min protocols, using standard Swedish strokes. Each protocol specifies the time allocated to each body region. The manualized 30- and 60-min protocols were implemented in a dual-site 24-week randomized dose-finding trial in patients with osteoarthritis of the knee, and is currently being implemented in a three-site 52-week efficacy trial of manualized Swedish massage therapy. In the dose-finding study, therapists adhered to the protocols and significant treatment effects were demonstrated. The massage protocol was manualized, using standard techniques, and made flexible for individual practitioner and subject needs. The protocol has been applied in two randomized clinical trials. This manualized Swedish massage protocol has real-world utility and can be readily utilized both in the research and clinical settings. Clinicaltrials.gov NCT00970008 (18 August 2009).

A Systematic Review of the Effectiveness of Medical Cannabis for Psychiatric, Movement and Neurodegenerative Disorders.

PubMed

Lim, Keane; See, Yuen Mei; Lee, Jimmy

2017-11-30

The discovery of endocannabinoid's role within the central nervous system and its potential therapeutic benefits have brought forth rising interest in the use of cannabis for medical purposes. The present review aimed to synthesize and evaluate the available evidences on the efficacy of cannabis and its derivatives for psychiatric, neurodegenerative and movement disorders. A systematic search of randomized controlled trials of cannabis and its derivatives were conducted via databases (PubMed, Embase and the Cochrane Central Register of Controlled Trials). A total of 24 reports that evaluated the use of medical cannabis for Alzheimer's disease, anorexia nervosa, anxiety, dementia, dystonia, Huntington's disease, Parkinson's disease, post-traumatic stress disorder (PTSD), psychosis and Tourette syndrome were included in this review. Trial quality was assessed with the Cochrane risk of bias tool. There is a lack of evidence on the therapeutic effects of cannabinoids for amyotrophic lateral sclerosis and dystonia. Although trials with positive findings were identified for anorexia nervosa, anxiety, PTSD, psychotic symptoms, agitation in Alzheimer's disease and dementia, Huntington's disease, and Tourette syndrome, and dyskinesia in Parkinson's disease, definitive conclusion on its efficacy could not be drawn. Evaluation of these low-quality trials, as rated on the Cochrane risk of bias tools, was challenged by methodological issues such as inadequate description of allocation concealment, blinding and underpowered sample size. More adequately powered controlled trials that examine the long and short term efficacy, safety and tolerability of cannabis for medical use, and the mechanisms underpinning the therapeutic potential are warranted.

[Defining an ethics for preventive trials].

PubMed

Chippaux, J-P

2008-04-01

Preventive trials (to prevent from infection) or prophylaxis trials (to avoid consequences of the disease) differ from other clinical trials as they apply to healthy subjects or subjects considering themselves as such: the latter do not ask for intervention even less for trial. Moreover, it is generally an experiment which aims at validating a public health intervention, the individual character of which could appear as secondary regarding the collective interest. It concerns many tools or methods: preventive or prophylactic vaccines and drugs, condoms, impregnated bed nets, etc. The field of implementation of preventive trials is large and covers routine immunization (EPI), large-scale control or eradication of endemic diseases or epidemics, for which the concept of individual risk is generally better understood. Preventive trials imply ethical obligations (high individual or collective benefits and absence of risks as there is no immediate therapeutic compensation), methodological adaptations (because the number of subjects is considerably larger than for therapeutic trials) and a sensitive valorization towards a large population who is not asking for the recommended intervention. As regard the benefits, it is also necessary to consider the costs in comparison with the expected efficacy The methodological constraints are important because the demonstration of both safety and efficacy requires a very large number of subjects to validate the product. It is often necessary to use indirect or substitutive markers and indicators (title of protective antibodies rather than definite clinical protection) which need a preliminary validation. Before carrying out a preventive or prophylactic trial, it is advisable to specify the objectives in order to assess the real profits and absence of risks during the trial and after the implementation of the tested product. Preventive trials require a phase of technological transfer to guarantee the application of the validated tools for the benefit of the population at stake. In this respect, if trials for prevention are now well codified both on ethical and methodological aspects, trials for prophylaxis (filariasis with ivermectin, schistosomiasis with praziquantel, malaria with intermittent "preventive" treatment or HIV with antiretroviral treatment, for example) still remain a difficult issue at both ethical and methodological levels.

Cognitive Behavior Therapy for Schizophrenia: Effect Sizes, Clinical Models, and Methodological Rigor

PubMed Central

Wykes, Til; Steel, Craig; Everitt, Brian; Tarrier, Nicholas

2008-01-01

Background: Guidance in the United States and United Kingdom has included cognitive behavior therapy for psychosis (CBTp) as a preferred therapy. But recent advances have widened the CBTp targets to other symptoms and have different methods of provision, eg, in groups. Aim: To explore the effect sizes of current CBTp trials including targeted and nontargeted symptoms, modes of action, and effect of methodological rigor. Method: Thirty-four CBTp trials with data in the public domain were used as source data for a meta-analysis and investigation of the effects of trial methodology using the Clinical Trial Assessment Measure (CTAM). Results: There were overall beneficial effects for the target symptom (33 studies; effect size = 0.400 [95% confidence interval {CI} = 0.252, 0.548]) as well as significant effects for positive symptoms (32 studies), negative symptoms (23 studies), functioning (15 studies), mood (13 studies), and social anxiety (2 studies) with effects ranging from 0.35 to 0.44. However, there was no effect on hopelessness. Improvements in one domain were correlated with improvements in others. Trials in which raters were aware of group allocation had an inflated effect size of approximately 50%–100%. But rigorous CBTp studies showed benefit (estimated effect size = 0.223; 95% CI = 0.017, 0.428) although the lower end of the CI should be noted. Secondary outcomes (eg, negative symptoms) were also affected such that in the group of methodologically adequate studies the effect sizes were not significant. Conclusions: As in other meta-analyses, CBTp had beneficial effect on positive symptoms. However, psychological treatment trials that make no attempt to mask the group allocation are likely to have inflated effect sizes. Evidence considered for psychological treatment guidance should take into account specific methodological detail. PMID:17962231

Commentary on Reconstituting Fibrinogen Concentrate to Maintain Blinding in a Double-blind, Randomized Trial in an Emergency Setting.

PubMed

Bruynseels, Daniel; Solomon, Cristina; Hallam, Angela; Collins, Peter W; Collis, Rachel E; Hamlyn, Vincent; Hall, Judith E

2016-01-01

The gold standard of trial design is the double-blind, placebo-controlled, randomized trial. Intravenous medication, which needs reconstitution by the attending clinician in an emergency situation, can be challenging to incorporate into a suitably blinded study. We have developed a method of blindly reconstituting and administering fibrinogen concentrate (presented as a lyophilized powder), where the placebo is normal saline. Fibrinogen concentrate is increasingly being used early in the treatment of major hemorrhage. Our methodology was designed for a multicenter study investigating the role of fibrinogen concentrate in the treatment of the coagulopathy associated with major obstetric hemorrhage. The method has been verified by a stand-alone pharmaceutical manufacturing unit with an investigational medicinal products license, and to date has successfully been applied 45 times in four study centers. There have been no difficulties in reconstitution and no related adverse events reported. We feel our method is simple to perform and maintains blinding throughout, making it potentially suitable for use in other trials conducted in psychologically high-pressure environments. Although fibrinogen concentrate was the focus of our study, it is likely that the method is applicable to other lyophilized medication with limited shelf life (e.g., antibiotics). Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

A literature review of applied adaptive design methodology within the field of oncology in randomised controlled trials and a proposed extension to the CONSORT guidelines.

PubMed

Mistry, Pankaj; Dunn, Janet A; Marshall, Andrea

2017-07-18

The application of adaptive design methodology within a clinical trial setting is becoming increasingly popular. However the application of these methods within trials is not being reported as adaptive designs hence making it more difficult to capture the emerging use of these designs. Within this review, we aim to understand how adaptive design methodology is being reported, whether these methods are explicitly stated as an 'adaptive design' or if it has to be inferred and to identify whether these methods are applied prospectively or concurrently. Three databases; Embase, Ovid and PubMed were chosen to conduct the literature search. The inclusion criteria for the review were phase II, phase III and phase II/III randomised controlled trials within the field of Oncology that published trial results in 2015. A variety of search terms related to adaptive designs were used. A total of 734 results were identified, after screening 54 were eligible. Adaptive designs were more commonly applied in phase III confirmatory trials. The majority of the papers performed an interim analysis, which included some sort of stopping criteria. Additionally only two papers explicitly stated the term 'adaptive design' and therefore for most of the papers, it had to be inferred that adaptive methods was applied. Sixty-five applications of adaptive design methods were applied, from which the most common method was an adaptation using group sequential methods. This review indicated that the reporting of adaptive design methodology within clinical trials needs improving. The proposed extension to the current CONSORT 2010 guidelines could help capture adaptive design methods. Furthermore provide an essential aid to those involved with clinical trials.

Methodological issues in negative symptom trials.

PubMed

Marder, Stephen R; Daniel, David G; Alphs, Larry; Awad, A George; Keefe, Richard S E

2011-03-01

Individuals from academia, the pharmaceutical industry, and the US Food and Drug Administration used a workshop format to discuss important methodological issues in the design of trials of pharmacological agents for improving negative symptoms in schizophrenia. The issues addressed included the need for a coprimary functional measure for registration trials; the characteristics of individuals who should enter negative symptom trials; the optimal duration for a proof-of-concept or registration trial; the optimal design of a study of a broad-spectrum agent that treats both positive and negative symptoms or a co-medication that is added to an antipsychotic; the relative strengths and weaknesses of available instruments for measuring negative symptoms; the definition of clinically meaningful improvement for these trials; and whether drugs can be approved for a subdomain of negative symptoms.

Methodological Issues in Negative Symptom Trials

PubMed Central

Marder, Stephen R.; Daniel, David G.; Alphs, Larry; Awad, A. George; Keefe, Richard S. E.

2011-01-01

Individuals from academia, the pharmaceutical industry, and the US Food and Drug Administration used a workshop format to discuss important methodological issues in the design of trials of pharmacological agents for improving negative symptoms in schizophrenia. The issues addressed included the need for a coprimary functional measure for registration trials; the characteristics of individuals who should enter negative symptom trials; the optimal duration for a proof-of-concept or registration trial; the optimal design of a study of a broad-spectrum agent that treats both positive and negative symptoms or a co-medication that is added to an antipsychotic; the relative strengths and weaknesses of available instruments for measuring negative symptoms; the definition of clinically meaningful improvement for these trials; and whether drugs can be approved for a subdomain of negative symptoms. PMID:21270473

Clinical trials in crisis: four simple methodologic fixes

PubMed Central

Vickers, Andrew J.

2014-01-01

There is growing consensus that the US clinical trials system is broken, with trial costs and complexity increasing exponentially, and many trials failing to accrue. Yet concerns about the expense and failure rate of randomized trials are only the tip of the iceberg; perhaps what should worry us most is the number of trials that are not even considered because of projected costs and poor accrual. Several initiatives, including the Clinical Trials Transformation Initiative and the “Sensible Guidelines Group” seek to push back against current trends in clinical trials, arguing that all aspects of trials - including design, approval, conduct, monitoring, analysis and dissemination - should be based on evidence rather than contemporary norms. Proposed here are four methodologic fixes for current clinical trials. The first two aim to simplify trials, reducing costs and increasing patient acceptability by dramatically reducing eligibility criteria - often to the single criterion that the consenting physician is uncertain which of the two randomized arms is optimal - and by clinical integration, investment in data infrastructure to bring routinely collected data up to research grade to be used as endpoints in trials. The second two methodologic fixes aim to shed barriers to accrual, either by cluster randomization of clinicians (in the case of modifications to existing treatment) or by early consent, where patients are offered the chance of being randomly selected to be offered a novel intervention if disease progresses at a subsequent point. Such solutions may be partial, or result in a new set of problems of their own. Yet the current crisis in clinical trials mandates innovative approaches: randomized trials have resulted in enormous benefits for patients and we need to ensure that they continue to do so. PMID:25278228

Clinical trials in crisis: Four simple methodologic fixes.

PubMed

Vickers, Andrew J

2014-12-01

There is growing consensus that the US clinical trials system is broken, with trial costs and complexity increasing exponentially, and many trials failing to accrue. Yet, concerns about the expense and failure rate of randomized trials are only the tip of the iceberg; perhaps what should worry us most is the number of trials that are not even considered because of projected costs and poor accrual. Several initiatives, including the Clinical Trials Transformation Initiative and the "Sensible Guidelines Group" seek to push back against current trends in clinical trials, arguing that all aspects of trials-including design, approval, conduct, monitoring, analysis, and dissemination-should be based on evidence rather than contemporary norms. Proposed here are four methodologic fixes for current clinical trials. The first two aim to simplify trials, reducing costs, and increasing patient acceptability by dramatically reducing eligibility criteria-often to the single criterion that the consenting physician is uncertain which of the two randomized arms is optimal-and by clinical integration, investment in data infrastructure to bring routinely collected data up to research grade to be used as endpoints in trials. The second two methodologic fixes aim to shed barriers to accrual, either by cluster randomization of clinicians (in the case of modifications to existing treatment) or by early consent, where patients are offered the chance of being randomly selected to be offered a novel intervention if disease progresses at a subsequent point. Such solutions may be partial, or result in a new set of problems of their own. Yet, the current crisis in clinical trials mandates innovative approaches: randomized trials have resulted in enormous benefits for patients, and we need to ensure that they continue to do so. © The Author(s) 2014.

Use of qualitative methods alongside randomised controlled trials of complex healthcare interventions: methodological study

PubMed Central

Glenton, Claire; Oxman, Andrew D

2009-01-01

Objective To examine the use of qualitative approaches alongside randomised trials of complex healthcare interventions. Design Review of randomised controlled trials of interventions to change professional practice or the organisation of care. Data sources Systematic sample of 100 trials published in English from the register of the Cochrane Effective Practice and Organisation of Care Review Group. Methods Published and unpublished qualitative studies linked to the randomised controlled trials were identified through database searches and contact with authors. Data were extracted from each study by two reviewers using a standard form. We extracted data describing the randomised controlled trials and qualitative studies, the quality of these studies, and how, if at all, the qualitative and quantitative findings were combined. A narrative synthesis of the findings was done. Results 30 of the 100 trials had associated qualitative work and 19 of these were published studies. 14 qualitative studies were done before the trial, nine during the trial, and four after the trial. 13 studies reported an explicit theoretical basis and 11 specified their methodological approach. Approaches to sampling and data analysis were poorly described. For most cases (n=20) we found no indication of integration of qualitative and quantitative findings at the level of either analysis or interpretation. The quality of the qualitative studies was highly variable. Conclusions Qualitative studies alongside randomised controlled trials remain uncommon, even where relatively complex interventions are being evaluated. Most of the qualitative studies were carried out before or during the trials with few studies used to explain trial results. The findings of the qualitative studies seemed to be poorly integrated with those of the trials and often had major methodological shortcomings. PMID:19744976

Quality of reporting in oncology phase II trials: A 5-year assessment through systematic review.

PubMed

Langrand-Escure, Julien; Rivoirard, Romain; Oriol, Mathieu; Tinquaut, Fabien; Rancoule, Chloé; Chauvin, Frank; Magné, Nicolas; Bourmaud, Aurélie

2017-01-01

Phase II clinical trials are a cornerstone of the development in experimental treatments They work as a "filter" for phase III trials confirmation. Surprisingly the attrition ratio in Phase III trials in oncology is significantly higher than in any other medical specialty. This suggests phase II trials in oncology fail to achieve their goal. Objective The present study aims at estimating the quality of reporting in published oncology phase II clinical trials. A literature review was conducted among all phase II and phase II/III clinical trials published during a 5-year period (2010-2015). All articles electronically published by three randomly-selected oncology journals with Impact-Factors>4 were included: Journal of Clinical Oncology, Annals of Oncology and British Journal of Cancer. Quality of reporting was assessed using the Key Methodological Score. 557 articles were included. 315 trials were single-arm studies (56.6%), 193 (34.6%) were randomized and 49 (8.8%) were non-randomized multiple-arm studies. The Methodological Score was equal to 0 (lowest level), 1, 2, 3 (highest level) respectively for 22 (3.9%), 119 (21.4%), 270 (48.5%) and 146 (26.2%) articles. The primary end point is almost systematically reported (90.5%), while sample size calculation is missing in 66% of the articles. 3 variables were independently associated with reporting of a high standard: presence of statistical design (p-value <0.001), multicenter trial (p-value = 0.012), per-protocol analysis (p-value <0.001). Screening was mainly performed by a sole author. The Key Methodological Score was based on only 3 items, making grey zones difficult to translate. This literature review highlights the existence of gaps concerning the quality of reporting. It therefore raised the question of the suitability of the methodology as well as the quality of these trials, reporting being incomplete in the corresponding articles.

Quality of reporting in oncology phase II trials: A 5-year assessment through systematic review

PubMed Central

Langrand-Escure, Julien; Rivoirard, Romain; Oriol, Mathieu; Tinquaut, Fabien; Rancoule, Chloé; Chauvin, Frank; Magné, Nicolas; Bourmaud, Aurélie

2017-01-01

Background Phase II clinical trials are a cornerstone of the development in experimental treatments They work as a "filter" for phase III trials confirmation. Surprisingly the attrition ratio in Phase III trials in oncology is significantly higher than in any other medical specialty. This suggests phase II trials in oncology fail to achieve their goal. Objective The present study aims at estimating the quality of reporting in published oncology phase II clinical trials. Data sources A literature review was conducted among all phase II and phase II/III clinical trials published during a 5-year period (2010–2015). Study eligibility criteria All articles electronically published by three randomly-selected oncology journals with Impact-Factors>4 were included: Journal of Clinical Oncology, Annals of Oncology and British Journal of Cancer. Intervention Quality of reporting was assessed using the Key Methodological Score. Results 557 articles were included. 315 trials were single-arm studies (56.6%), 193 (34.6%) were randomized and 49 (8.8%) were non-randomized multiple-arm studies. The Methodological Score was equal to 0 (lowest level), 1, 2, 3 (highest level) respectively for 22 (3.9%), 119 (21.4%), 270 (48.5%) and 146 (26.2%) articles. The primary end point is almost systematically reported (90.5%), while sample size calculation is missing in 66% of the articles. 3 variables were independently associated with reporting of a high standard: presence of statistical design (p-value <0.001), multicenter trial (p-value = 0.012), per-protocol analysis (p-value <0.001). Limitations Screening was mainly performed by a sole author. The Key Methodological Score was based on only 3 items, making grey zones difficult to translate. Conclusions & implications of key findings This literature review highlights the existence of gaps concerning the quality of reporting. It therefore raised the question of the suitability of the methodology as well as the quality of these trials, reporting being incomplete in the corresponding articles. PMID:29216190

Methodological Reporting Quality of Randomized Controlled Trials in 3 Leading Diabetes Journals From 2011 to 2013 Following CONSORT Statement: A System Review.

PubMed

Zhai, Xiao; Wang, Yiran; Mu, Qingchun; Chen, Xiao; Huang, Qin; Wang, Qijin; Li, Ming

2015-07-01

To appraise the current reporting methodological quality of randomized clinical trials (RCTs) in 3 leading diabetes journals.We systematically searched the literature for RCTs in Diabetes Care, Diabetes and Diabetologia from 2011 to 2013.Characteristics were extracted based on Consolidated Standards of Reporting Trials (CONSORT) statement. Generation of allocation, concealment of allocation, intention-to-treat (ITT) analysis and handling of dropouts were defined as primary outcome and "low risk of bias." Sample size calculation, type of intervention, country, number of patients, funding source were also revealed and descriptively reported. Trials were compared among journals, study years, and other characters.A total of 305 RCTs were enrolled in this study. One hundred eight (35.4%) trials reported adequate generation of allocation, 87 (28.5%) trials reported adequate concealment of allocation, 53 (23.8%) trials used ITT analysis, and 130 (58.3%) trials were adequate in handling of dropouts. Only 15 (4.9%) were "low risk of bias" trials. Studies at a large scale (n > 100) or from European presented with more "low risk of bias" trials than those at a small scale (n ≤ 100) or from other regions. No improvements were found in these 3 years.This study shows that methodological reporting quality of RCTs in the major diabetes journals remains suboptimal. It can be further improved to meet and keep up with the standards of the CONSORT statement.

Challenges and Ideas from a Research Program on High Quality, Evidence-Based Practice in School Mental Health

PubMed Central

Weist, Mark D.; Youngstrom, Eric A.; Stephan, Sharon; Lever, Nancy; Fowler, Johnathan; Taylor, Leslie; McDaniel, Heather; Chappelle, Lori; Paggeot, Samantha; Hoagwood, Kimberly

2013-01-01

Objective Reviews the progression of a research program designed to develop, implement and study the implementation of “achievable” evidence-based practices (EBPs) in schools. Reviews challenges encountered and ideas to overcome them to enhance this avenue of research. Method Presents two federally funded randomized controlled trials involving comparison of a four-component targeted intervention (Quality Assessment and Improvement, Family Engagement and Empowerment, Modular Evidence-Based Practice, Implementation Support) versus a comparison intervention focused on Personal Wellness. In both studies primary aims focused on changes in clinician attitudes and behavior, including the delivery of high quality, evidence-based practices and secondary aims focused on student level impacts. Results A number of challenges, many not reported in the literature are reviewed, and ideas for overcoming them are presented. Conclusions Given the reality that the majority of youth mental health services are delivered in schools and the potential of school mental health (SMH) services to provide a continuum of mental health care from promotion to intervention, it is critical that the field consider and address the logistical and methodological challenges associated with implementing and studying EBP implementation by clinicians. PMID:24063310

Challenges and ideas from a research program on high-quality, evidence-based practice in school mental health.

PubMed

Weist, Mark D; Youngstrom, Eric A; Stephan, Sharon; Lever, Nancy; Fowler, Johnathan; Taylor, Leslie; McDaniel, Heather; Chappelle, Lori; Paggeot, Samantha; Hoagwood, Kimberly

2014-01-01

This article reviews the progression of a research program designed to develop, implement, and study the implementation of "achievable" evidence-based practices (EBPs) in schools. We review challenges encountered and ideas to overcome them to enhance this avenue of research. The article presents two federally funded randomized controlled trials involving comparison of a four-component targeted intervention (Quality Assessment and Improvement, Family Engagement and Empowerment, Modular Evidence-Based Practice, Implementation Support) versus a comparison intervention focused on personal wellness. In both studies, primary aims focused on changes in clinician attitudes and behavior, including the delivery of high-quality EBPs and secondary aims focused on student-level impacts. A number of challenges, many not reported in the literature, are reviewed, and ideas for overcoming them are presented. Given the reality that the majority of youth mental health services are delivered in schools and the potential of school mental health services to provide a continuum of mental health care from promotion to intervention, it is critical that the field consider and address the logistical and methodological challenges associated with implementing and studying EBP implementation by clinicians.

A multichannel model-based methodology for extubation readiness decision of patients on weaning trials.

PubMed

Casaseca-de-la-Higuera, Pablo; Simmross-Wattenberg, Federico; Martín-Fernández, Marcos; Alberola-López, Carlos

2009-07-01

Discontinuation of mechanical ventilation is a challenging task that involves a number of subtle clinical issues. The gradual removal of the respiratory support (referred to as weaning) should be performed as soon as autonomous respiration can be sustained. However, the prediction rate of successful extubation is still below 25% based on previous studies. Construction of an automatic system that provides information on extubation readiness is thus desirable. Recent works have demonstrated that the breathing pattern variability is a useful extubation readiness indicator, with improving performance when multiple respiratory signals are jointly processed. However, the existing methods for predictor extraction present several drawbacks when length-limited time series are to be processed in heterogeneous groups of patients. In this paper, we propose a model-based methodology for automatic readiness prediction. It is intended to deal with multichannel, nonstationary, short records of the breathing pattern. Results on experimental data yield an 87.27% of successful readiness prediction, which is in line with the best figures reported in the literature. A comparative analysis shows that our methodology overcomes the shortcomings of so far proposed methods when applied to length-limited records on heterogeneous groups of patients.

Interventions to address parenting and parental substance abuse: conceptual and methodological considerations.

PubMed

Neger, Emily N; Prinz, Ronald J

2015-07-01

Parental substance abuse is a serious problem affecting the well-being of children and families. The co-occurrence of parental substance abuse and problematic parenting is recognized as a major public health concern. This review focuses on 21 outcome studies that tested dual treatment of substance abuse and parenting. A summary of theoretical conceptualizations of the connections between substance abuse and parenting provides a backdrop for the review. Outcomes of the dual treatment studies were generally positive with respect to reduction of parental substance use and improvement of parenting. Research in this area varied in methodological rigor and needs to overcome challenges regarding design issues, sampling frame, and complexities inherent in such a high-risk population. This area of work can be strengthened by randomized controlled trials, use of mixed-methods outcome measures, consideration of parent involvement with child protective services, involvement of significant others in treatment, provision of concrete supports for treatment attendance and facilitative public policies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Recommendations for research design and reporting in computer-assisted diagnosis to facilitate meta-analysis.

PubMed

Eadie, Leila H; Taylor, Paul; Gibson, Adam P

2012-04-01

Computer-assisted diagnosis (CAD) describes a diverse, heterogeneous range of applications rather than a single entity. The aims and functions of CAD systems vary considerably and comparing studies and systems is challenging due to methodological and design differences. In addition, poor study quality and reporting can reduce the value of some publications. Meta-analyses of CAD are therefore difficult and may not provide reliable conclusions. Aiming to determine the major sources of heterogeneity and thereby what CAD researchers could change to allow this sort of assessment, this study reviews a sample of 147 papers concerning CAD used with imaging for cancer diagnosis. It discusses sources of variability, including the goal of the CAD system, learning methodology, study population, design, outcome measures, inclusion of radiologists, and study quality. Based upon this evidence, recommendations are made to help researchers optimize the quality and comparability of their trial design and reporting. Copyright © 2011 Elsevier Inc. All rights reserved.

Interventions to Address Parenting and Parental Substance Abuse: Conceptual and Methodological Considerations

PubMed Central

Neger, Emily N.; Prinz, Ronald J.

2015-01-01

Parental substance abuse is a serious problem affecting the well-being of children and families. The co-occurrence of parental substance abuse and problematic parenting is recognized as a major public health concern. This review focuses on 21 outcome studies that tested dual treatment of substance abuse and parenting. A summary of theoretical conceptualizations of the connections between substance abuse and parenting provides a backdrop for the review. Outcomes of the dual treatment studies were generally positive with respect to reduction of parental substance use and improvement of parenting. Research in this area varied in methodological rigor and needs to overcome challenges regarding design issues, sampling frame, and complexities inherent in such a high-risk population. This area of work can be strengthened by randomized controlled trials, use of mixed-methods outcome measures, consideration of parent involvement with child protective services, involvement of significant others in treatment, provision of concrete supports for treatment attendance and facilitative public policies. PMID:25939033

Collecting and validating experiential expertise is doable but poses methodological challenges.

PubMed

Burda, Marika H F; van den Akker, Marjan; van der Horst, Frans; Lemmens, Paul; Knottnerus, J André

2016-04-01

To give an overview of important methodological challenges in collecting, validating, and further processing experiential expertise and how to address these challenges. Based on our own experiences in studying the concept, operationalization, and contents of experiential expertise, we have formulated methodological issues regarding the inventory and application of experiential expertise. The methodological challenges can be categorized in six developmental research stages, comprising the conceptualization of experiential expertise, methods to harvest experiential expertise, the validation of experiential expertise, evaluation of the effectiveness, how to translate experiential expertise into acceptable guidelines, and how to implement these. The description of methodological challenges and ways to handle those are illustrated using diabetes mellitus as an example. Experiential expertise can be defined and operationalized in terms of successful illness-related behaviors and translated into recommendations regarding life domains. Pathways have been identified to bridge the gaps between the world of patients' daily lives and the medical world. Copyright © 2016 Elsevier Inc. All rights reserved.

Harmonized clinical trial methodologies for localized cutaneous leishmaniasis and potential for extensive network with capacities for clinical evaluation

PubMed Central

Grogl, Max; Boni, Marina; Carvalho, Edgar M.; Chebli, Houda; Cisse, Mamoudou; Diro, Ermias; Fernandes Cota, Gláucia; Erber, Astrid C.; Gadisa, Endalamaw; Handjani, Farhad; Khamesipour, Ali; Llanos-Cuentas, Alejandro; López Carvajal, Liliana; Grout, Lise; Lmimouni, Badre Eddine; Mokni, Mourad; Nahzat, Mohammad Sami; Ben Salah, Afif; Ozbel, Yusuf; Pascale, Juan Miguel; Rizzo Molina, Nidia; Rode, Joelle; Romero, Gustavo; Ruiz-Postigo, José Antonio; Gore Saravia, Nancy; Soto, Jaime; Uzun, Soner; Mashayekhi, Vahid; Vélez, Ivan Dario; Vogt, Florian; Zerpa, Olga; Arana, Byron

2018-01-01

Introduction Progress with the treatment of cutaneous leishmaniasis (CL) has been hampered by inconsistent methodologies used to assess treatment effects. A sizable number of trials conducted over the years has generated only weak evidence backing current treatment recommendations, as shown by systematic reviews on old-world and new-world CL (OWCL and NWCL). Materials and methods Using a previously published guidance paper on CL treatment trial methodology as the reference, consensus was sought on key parameters including core eligibility and outcome measures, among OWCL (7 countries, 10 trial sites) and NWCL (7 countries, 11 trial sites) during two separate meetings. Results Findings and level of consensus within and between OWCL and NWCL sites are presented and discussed. In addition, CL trial site characteristics and capacities are summarized. Conclusions The consensus reached allows standardization of future clinical research across OWCL and NWCL sites. We encourage CL researchers to adopt and adapt as required the proposed parameters and outcomes in their future trials and provide feedback on their experience. The expertise afforded between the two sets of clinical sites provides the basis for a powerful consortium with potential for extensive, standardized assessment of interventions for CL and faster approval of candidate treatments. PMID:29329311

Planning strategies for the avoidance of pitfalls in intervention research.

PubMed

Pruitt, R H; Privette, A B

2001-08-01

With the exception of large clinical trials, few studies in nursing and other social sciences test interventions. The discipline of nursing needs to maintain a full range of research designs for continued knowledge development. Intervention research presents unique opportunities and challenges for the novice as well as the seasoned researcher. Some of these methodological challenges include the complex nature of human subjects and interventions, including many factors that interfere with the study variables. Preliminary studies often reveal challenges that may not always be predicted or reflected in research texts. These challenges may be as important as the study results for success in future research efforts. Difficulties encountered in intervention research and suggested strategies for maintaining the integrity of the study are addressed. These challenges include maintaining an adequate sample size, intervention demands, measuring variables, timing issues, and experiencing unexpected events. Strategies presented include the importance of extensive planning, minimizing subject expectations and rewarding efforts, attention to control group members, incorporating retention strategies, expanding knowledge of variables and the study population, preliminary studies as well as anticipating unexpected events. The need for enhanced communication among nurse researchers, educators and clinicians is addressed. In the current health care arena, nurse researchers must understand organizational dynamics and marketing strategies. Collaborative research efforts can increase the visibility of nursing research as well as funding opportunities.

Association between exogenous testosterone and cardiovascular events: an overview of systematic reviews.

PubMed

Onasanya, Oluwadamilola; Iyer, Geetha; Lucas, Eleanor; Lin, Dora; Singh, Sonal; Alexander, G Caleb

2016-11-01

Given the conflicting evidence regarding the association between exogenous testosterone and cardiovascular events, we systematically assessed published systematic reviews for evidence of the association between exogenous testosterone and cardiovascular events. We searched PubMed, MEDLINE, Embase, Cochrane Collaboration Clinical Trials, ClinicalTrials.gov, and the US Food and Drug Administration website for systematic reviews of randomised controlled trials published up to July 19, 2016. Two independent reviewers screened 954 full texts from 29 335 abstracts to identify systematic reviews of randomised controlled trials in which the cardiovascular effects of exogenous testosterone on men aged 18 years or older were examined. We extracted data for study characteristics, analytic methods, and key findings, and applied the AMSTAR (A Measurement Tool to Assess Systematic Reviews) checklist to assess methodological quality of each review. Our primary outcome measure was the direction and magnitude of association between exogenous testosterone and cardiovascular events. We identified seven reviews and meta-analyses, which had substantial clinical heterogeneity, differing statistical methods, and variable methodological quality and quality of data abstraction. AMSTAR scores ranged from 3 to 9 out of 11. Six systematic reviews that each included a meta-analysis showed no significant association between exogenous testosterone and cardiovascular events, with summary estimates ranging from 1·07 to 1·82 and imprecise confidence intervals. Two of these six meta-analyses showed increased risk in subgroup analyses of oral testosterone and men aged 65 years or older during their first treatment year. One meta-analysis showed a significant association between exogenous testosterone and cardiovascular events, in men aged 18 years or older generally, with a summary estimate of 1·54 (95% CI 1·09-2·18). Our optimal information size analysis showed that any randomised controlled trial aiming to detect a true difference in cardiovascular risk between treatment groups receiving exogenous testosterone and their controls (with a two-sided p value of 0·05 and a power of 80%) would require at least 17 664 participants in each trial group. Therefore, given the challenge of adequately powering clinical trials for rare outcomes, rigorous observational studies are needed to clarify the association between testosterone-replacement therapy and major adverse cardiovascular outcomes. Copyright © 2016 Elsevier Ltd. All rights reserved.

The design and methodology of premature ejaculation interventional studies

PubMed Central

2016-01-01

Large well-designed clinical efficacy and safety randomized clinical trials (RCTs) are required to achieve regulatory approval of new drug treatments. The objective of this article is to make recommendations for the criteria for defining and selecting the clinical trial study population, design and efficacy outcomes measures which comprise ideal premature ejaculation (PE) interventional trial methodology. Data on clinical trial design, epidemiology, definitions, dimensions and psychological impact of PE was reviewed, critiqued and incorporated into a series of recommendations for standardisation of PE clinical trial design, outcome measures and reporting using the principles of evidence based medicine. Data from PE interventional studies are only reliable, interpretable and capable of being generalised to patients with PE, when study populations are defined by the International Society for Sexual Medicine (ISSM) multivariate definition of PE. PE intervention trials should employ a double-blind RCT methodology and include placebo control, active standard drug control, and/or dose comparison trials. Ejaculatory latency time (ELT) and subject/partner outcome measures of control, personal/partner/relationship distress and other study-specific outcome measures should be used as outcome measures. There is currently no published literature which identifies a clinically significant threshold response to intervention. The ISSM definition of PE reflects the contemporary understanding of PE and represents the state-of-the-art multi-dimensional definition of PE and is recommended as the basis of diagnosis of PE for all PE clinical trials. PMID:27652224

78 FR 13874 - Watershed Modeling To Assess the Sensitivity of Streamflow, Nutrient, and Sediment Loads to...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-01

... an improved understanding of methodological challenges associated with integrating existing tools and... methodological challenges associated with integrating existing tools (e.g., climate models, downscaling... sensitivity to methodological choices such as different approaches for downscaling global climate change...

Using GRADE as a framework to guide research on the sexual and reproductive health and rights (SRHR) of women living with HIV - methodological opportunities and challenges.

PubMed

Siegfried, Nandi; Narasimhan, Manjulaa; Kennedy, Caitlin E; Welbourn, Alice; Yuvraj, Anandi

2017-09-01

In March 2016, WHO reviewed evidence to develop global recommendations on the sexual and reproductive health and rights (SRHR) of women living with HIV. Systematic reviews and a global survey of women living with HIV informed the guideline development decision-making process. New recommendations covered abortion, Caesarean section, safe disclosure, and empowerment and self-efficacy interventions. Identification of key research gaps is part of the WHO guidelines development process, but consistent methods to do so are lacking. Our method aimed to ensure consistency and comprised the systematic application of a framework based on GRADE (Grading of Recommendations, Assessment, Development and Evaluation) to the process. The framework incorporates the strength and quality rating of recommendations and the priorities reported by women in the survey to inform research prioritisation. For each gap, we also articulated: (1) the most appropriate and robust study design to answer the question; (2) alternative pragmatic designs if the ideal design is not feasible; and (3) the methodological challenges facing researchers through identifying potential biases. We found 12 research gaps and identified five appropriate study designs to address the related questions: (1) Cross-sectional surveys; (2) Qualitative interview-driven studies; (3) Registries; (4) Randomised controlled trials; and (5) Medical record audit. Methodological challenges included selection, recruitment, misclassification, measurement and contextual biases, and confounding. In conclusion, a framework based on GRADE can provide a systematic approach to identifying research gaps from a WHO guideline. Incorporation of the priorities of women living with HIV into the framework systematically ensures that women living with HIV can shape future policy decisions affecting their lives. Implementation science and participatory research are appropriate over-arching approaches to enhance uptake of interventions and to ensure inclusion of women living with HIV at all stages of the research process.

Methodological quality of randomised controlled trials in burns care. A systematic review.

PubMed

Danilla, Stefan; Wasiak, Jason; Searle, Susana; Arriagada, Cristian; Pedreros, Cesar; Cleland, Heather; Spinks, Anneliese

2009-11-01

To evaluate the methodological quality of published randomised controlled trials (RCTs) in burn care treatment and management. Using a predetermined search strategy we searched Ovid MEDLINE (1950 to January 2008) database to identify all English RCTs related to burn care. Full text studies identified were reviewed for key demographic and methodological characteristics. Methodological trial quality was assessed using the Jadad scale. A total of 257 studies involving 14,535 patients met the inclusion criteria. The median Jadad score was 2 (out of a best possible score of 5). Information was given in the introduction and discussion sections of most RCTs, although insufficient detail was provided on randomisation, allocation concealment, and blinding. The number of RCTs increased between 1950 and 2008 (Spearman's rho=0.6129, P<0.001), although the reporting quality did not improve over the same time period (P=0.1896) and was better in RCTs with larger sample sizes (median Jadad score, 4 vs. 2 points, P<0.0001). Methodological quality did not correlate with journal impact factor (P=0.2371). The reporting standards of RCTs are highly variable and less than optimal in most cases. The advent of evidence-based medicine heralds a new approach to burns care and systematic steps are needed to improve the quality of RCTs in this field. Identifying and reviewing the existing number of RCTs not only highlights the need for burn clinicians to conduct more trials, but may also encourage burn health clinicians to consider the importance of conducting trials that follow appropriate, evidence-based standards.

Methodology for a randomised controlled trial of preschool vision screening. A new approach with the 'ALSPAC' project.

PubMed

Williams, C; Harrad, R A; Harvey, I; Frankel, S; Golding, J

1996-06-01

We present the methodology of a population-based Randomised Controlled Trial, comparing an intensive programme of primary preschool vision screening by orthoptists with the usual non-specialist screening. The aims of the trial are to compare the effectiveness and costs of intensive orthoptic screening with non-specialist measures. The orthoptic screening programme will be evaluated both as a composite package and in terms of the screening value of the individual tests at specific ages. This trial is nested within a large population-based longitudinal study. Additional demographic and developmental data on the children in the trial are therefore available. The results of the trial will be used to help clarify which methods of preschool ophthalmic population screening are best in terms of disease detection and cost efficiency.

How completely are physiotherapy interventions described in reports of randomised trials?

PubMed

Yamato, Tiê P; Maher, Chris G; Saragiotto, Bruno T; Hoffmann, Tammy C; Moseley, Anne M

2016-06-01

Incomplete descriptions of interventions are a common problem in reports of randomised controlled trials. To date no study has evaluated the completeness of the descriptions of physiotherapy interventions. To evaluate the completeness of the descriptions of physiotherapy interventions in a random sample of reports of randomised controlled trials (RCTs). A random sample of 200 reports of RCTs from the PEDro database. We included full text papers, written in English, and reporting trials with two arms. We included trials evaluating any type of physiotherapy interventions and subdisciplines. The methodological quality was evaluated using the PEDro scale and completeness of intervention description using the Template for Intervention Description and Replication (TIDieR) checklist. The proportion and 95% confidence interval were calculated for intervention and control groups, and used to present the relationship between completeness and methodological quality, and subdisciplines. Completeness of intervention reporting in physiotherapy RCTs was poor. For intervention groups, 46 (23%) trials did not describe at least half of the items. Reporting was worse for control groups, 149 (75%) trials described less than half of the items. There was no clear difference in the completeness across subdisciplines or methodological quality. Our sample were restricted to trials published in English in 2013. Descriptions of interventions in physiotherapy RCTs are typically incomplete. Authors and journals should aim for more complete descriptions of interventions in physiotherapy trials. Copyright © 2016 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

Clinical Trials of Potential Cognitive-Enhancing Drugs in Schizophrenia: What Have We Learned So Far?

PubMed Central

Keefe, Richard S. E.; Buchanan, Robert W.; Marder, Stephen R.; Schooler, Nina R.; Dugar, Ashish; Zivkov, Milana; Stewart, Michelle

2013-01-01

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website “www.clinicaltrials.gov” using the terms “schizophrenia AND cognition,” “schizophrenia AND neurocognition,” “schizophrenia AND neurocognitive tests,” “schizophrenia AND MATRICS,” “schizophrenia AND MCCB,” “schizophrenia AND BACS,” “schizophrenia AND COGSTATE,” and “schizophrenia AND CANTAB” and “first-episode schizophrenia AND cognition.” The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia. PMID:22114098

False confessions, expert testimony, and admissibility.

PubMed

Watson, Clarence; Weiss, Kenneth J; Pouncey, Claire

2010-01-01

The confession of a criminal defendant serves as a prosecutor's most compelling piece of evidence during trial. Courts must preserve a defendant's constitutional right to a fair trial while upholding the judicial interests of presenting competent and reliable evidence to the jury. When a defendant seeks to challenge the validity of that confession through expert testimony, the prosecution often contests the admissibility of the expert's opinion. Depending on the content and methodology of the expert's opinion, testimony addressing the phenomenon of false confessions may or may not be admissible. This article outlines the scientific and epistemological bases of expert testimony on false confession, notes the obstacles facing its admissibility, and provides guidance to the expert in formulating opinions that will reach the judge or jury. We review the 2006 New Jersey Superior Court decision in State of New Jersey v. George King to illustrate what is involved in the admissibility of false-confession testimony and use the case as a starting point in developing a best-practice approach to working in this area.

Current-reported outcome domains in studies of adults with a focus on the treatment of tinnitus: protocol for a systematic review

PubMed Central

Hall, Deborah A; Szczepek, Agnieszka J; Kennedy, Veronica; Haider, Haúla

2015-01-01

Introduction In Europe alone, over 70 million people experience tinnitus. Despite its considerable socioeconomic relevance, progress in developing successful treatments has been limited. Clinical effectiveness is judged according to change in primary outcome measures, but because tinnitus is a subjective condition, the definition of outcomes is challenging and it remains unclear which distinct aspects of tinnitus (ie, ‘domains’) are most relevant for assessment. The development of a minimum outcome reporting standard would go a long way towards addressing these problems. In 2006, a consensus meeting recommended using 1 of 4 questionnaires for tinnitus severity as an outcome in clinical trials, in part because of availability in different language translations. Our initiative takes an approach motivated by clinimetrics, first by determining what to measure before seeking to determine how to measure it. Agreeing on the domains that contribute to tinnitus severity (ie, ‘what’) is the first step towards achieving a minimum outcome reporting standard for tinnitus that has been reached via a methodologically rigorous and transparent process. Methods and analysis Deciding what should be the core set of outcomes requires a great deal of discussion and so lends itself well to international effort. This protocol lays out the first-step methodology in defining a Core Domain Set for clinical trials of tinnitus by establishing existing knowledge and practice with respect to which outcome domains have been measured and which instruments used in recent registered and published clinical trials. Ethics and dissemination No ethical issues are foreseen. Findings will be reported at national and international ear, nose and throat (ENT) and audiology conferences and in a peer-reviewed journal, using PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analysis) guidelines. Trial registration number The systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525. PMID:26560061

From multidimensional neuropsychological outcomes to a cognitive complication rate: The International Subarachnoid Aneurysm Trial

PubMed Central

Scott, Richard B; Eccles, Fiona; Lloyd, Andrew; Carpenter, Katherine

2008-01-01

Background The neuropsychological arm of the International Subarachnoid Aneurysm Trial (N-ISAT) evaluated the cognitive outcome of 573 patients at 12 months following subarachnoid haemorrhage (SAH). The assessment included 29 psychometric measures, yielding a substantial and complex body of data. We have explored alternative and optimal methodologies for analysing and summarising these data to enable the estimation of a cognitive complication rate (CCR). Any differences in cognitive outcome between the two arms of the trial are not however reported here. Methods All individual test scores were transformed into z-scores and a 5th percentile cut-off for impairment was established. A principal components analysis (PCA) was applied to these data to mathematically transform correlated test scores into a smaller number of uncorrelated principal components, or cognitive 'domains'. These domains formed the basis for grouping and weighting individual patients' impaired scores on individual measures. In order to increase the sample size, a series of methods for handling missing data were applied. Results We estimated a 34.1% CCR in all those patients seen face-to-face, rising to 37.4% CCR with the inclusion of patients who were unable to attend assessment for reason related to the index SAH. This group demonstrated significantly more self and carer/relative rated disability on a Health Related Quality of Life questionnaire, than patients classified as having no functionally significant cognitive deficits. Conclusion Evaluating neuropsychological outcome in a large RCT involves unique methodological and organizational challenges. We have demonstrated how these problems may be addressed by re-classifying interval data from 29 measures into a dichotomous CCR. We have presented a 'sliding scale' of undifferentiated individual cognitive impairments, and then on the basis of PCA-derived cognitive 'domains', included consideration of the distribution of impairments in these terms. In order to maximize sample size we have suggested ways for patients who did not complete the entire protocol to be included in the overall CCR. ISAT trial registration ISRCTN49866681 PMID:18341689

Challenges and impact of conducting vaccine trials in Asia and Africa

PubMed Central

Kochhar, Sonali

2013-01-01

Immunization is one of the most beneficial and cost-effective disease prevention measures. There are global efforts to develop new vaccines for disease control. The vaccine clinical trials must be conducted in the countries where they will be used. This has led to vaccine trials being conducted across Asia and Africa where there is a high burden of infectious diseases. The setup and successful conduct of International standard GCP vaccine trials across trial centers located in resource constrained settings are challenging. The challenges, ethical considerations and impact of the implementation of clinical trials in low-resource settings are highlighted here to help vaccine development programs successfully conduct such trials. PMID:23321645

Identifying research priorities for effective retention strategies in clinical trials.

PubMed

Kearney, Anna; Daykin, Anne; Shaw, Alison R G; Lane, Athene J; Blazeby, Jane M; Clarke, Mike; Williamson, Paula; Gamble, Carrol

2017-08-31

The failure to retain patients or collect primary-outcome data is a common challenge for trials and reduces the statistical power and potentially introduces bias into the analysis. Identifying strategies to minimise missing data was the second highest methodological research priority in a Delphi survey of the Directors of UK Clinical Trial Units (CTUs) and is important to minimise waste in research. Our aim was to assess the current retention practices within the UK and priorities for future research to evaluate the effectiveness of strategies to reduce attrition. Seventy-five chief investigators of NIHR Health Technology Assessment (HTA)-funded trials starting between 2009 and 2012 were surveyed to elicit their awareness about causes of missing data within their trial and recommended practices for improving retention. Forty-seven CTUs registered within the UKCRC network were surveyed separately to identify approaches and strategies being used to mitigate missing data across trials. Responses from the current practice surveys were used to inform a subsequent two-round Delphi survey with registered CTUs. A consensus list of retention research strategies was produced and ranked by priority. Fifty out of seventy-five (67%) chief investigators and 33/47 (70%) registered CTUs completed the current practice surveys. Seventy-eight percent of trialists were aware of retention challenges and implemented strategies at trial design. Patient-initiated withdrawal was the most common cause of missing data. Registered CTUs routinely used newsletters, timeline of participant visits, and telephone reminders to mitigate missing data. Whilst 36 out of 59 strategies presented had been formally or informally evaluated, some frequently used strategies, such as site initiation training, have had no research to inform practice. Thirty-five registered CTUs (74%) participated in the Delphi survey. Research into the effectiveness of site initiation training, frequency of patient contact during a trial, the use of routinely collected data, the frequency and timing of reminders, triggered site training and the time needed to complete questionnaires was deemed critical. Research into the effectiveness of Christmas cards for site staff was not of critical importance. The surveys of current practices demonstrates that a variety of strategies are being used to mitigate missing data but with little evidence to support their use. Six retention strategies were deemed critically important within the Delphi survey and should be a primary focus of future retention research.

A Randomized Study of How Physicians Interpret Research Funding Disclosures

PubMed Central

Kesselheim, Aaron S.; Robertson, Christopher T.; Myers, Jessica A.; Rose, Susannah L.; Gillet, Victoria; Ross, Kathryn M.; Glynn, Robert J.; Joffe, Steven; Avorn, Jerry

2012-01-01

BACKGROUND The effects of clinical-trial funding on the interpretation of trial results are poorly understood. We examined how such support affects physicians’ reactions to trials with a high, medium, or low level of methodologic rigor. METHODS We presented 503 board-certified internists with abstracts that we designed describing clinical trials of three hypothetical drugs. The trials had high, medium, or low methodologic rigor, and each report included one of three support disclosures: funding from a pharmaceutical company, NIH funding, or none. For both factors studied (rigor and funding), one of the three possible variations was randomly selected for inclusion in the abstracts. Follow-up questions assessed the physicians’ impressions of the trials’ rigor, their confidence in the results, and their willingness to prescribe the drugs. RESULTS The 269 respondents (53.5% response rate) perceived the level of study rigor accurately. Physicians reported that they would be less willing to prescribe drugs tested in low-rigor trials than those tested in medium-rigor trials (odds ratio, 0.64; 95% confidence interval [CI], 0.46 to 0.89; P = 0.008) and would be more willing to prescribe drugs tested in high-rigor trials than those tested in medium-rigor trials (odds ratio, 3.07; 95% CI, 2.18 to 4.32; P<0.001). Disclosure of industry funding, as compared with no disclosure of funding, led physicians to downgrade the rigor of a trial (odds ratio, 0.63; 95% CI, 0.46 to 0.87; P = 0.006), their confidence in the results (odds ratio, 0.71; 95% CI, 0.51 to 0.98; P = 0.04), and their willingness to prescribe the hypothetical drugs (odds ratio, 0.68; 95% CI, 0.49 to 0.94; P = 0.02). Physicians were half as willing to prescribe drugs studied in industry-funded trials as they were to prescribe drugs studied in NIH-funded trials (odds ratio, 0.52; 95% CI, 0.37 to 0.71; P<0.001). These effects were consistent across all levels of methodologic rigor. CONCLUSIONS Physicians discriminate among trials of varying degrees of rigor, but industry sponsorship negatively influences their perception of methodologic quality and reduces their willingness to believe and act on trial findings, independently of the trial’s quality. These effects may influence the translation of clinical research into practice. PMID:22992075

Quantitative assessment of dynamic PET imaging data in cancer imaging.

PubMed

Muzi, Mark; O'Sullivan, Finbarr; Mankoff, David A; Doot, Robert K; Pierce, Larry A; Kurland, Brenda F; Linden, Hannah M; Kinahan, Paul E

2012-11-01

Clinical imaging in positron emission tomography (PET) is often performed using single-time-point estimates of tracer uptake or static imaging that provides a spatial map of regional tracer concentration. However, dynamic tracer imaging can provide considerably more information about in vivo biology by delineating both the temporal and spatial pattern of tracer uptake. In addition, several potential sources of error that occur in static imaging can be mitigated. This review focuses on the application of dynamic PET imaging to measuring regional cancer biologic features and especially in using dynamic PET imaging for quantitative therapeutic response monitoring for cancer clinical trials. Dynamic PET imaging output parameters, particularly transport (flow) and overall metabolic rate, have provided imaging end points for clinical trials at single-center institutions for years. However, dynamic imaging poses many challenges for multicenter clinical trial implementations from cross-center calibration to the inadequacy of a common informatics infrastructure. Underlying principles and methodology of PET dynamic imaging are first reviewed, followed by an examination of current approaches to dynamic PET image analysis with a specific case example of dynamic fluorothymidine imaging to illustrate the approach. Copyright © 2012 Elsevier Inc. All rights reserved.

[Science in a crisis. Medical countermeasures in Ebola virus disease, 2016: lessons learned and perspectives].

PubMed

Malvy, D

2016-10-01

In 2013, the world began to witness an unprecedented Ebola epidemic in West Africa that was smoldering by early 2016. Under this urgent circumstance, the global scientific community organized and made progress in identifying potential preventive countermeasures and therapeutics and accelerated the development of those promising interventions. Trials of experimental interventions soon emerged as a key component of the global response. Hence, an interdisciplinary issue ensued concerning how best to assess clinical safety and effectiveness of potential interventions prior to or concurrent with their broad use in humans. Key issues rely on the close collaboration between research and clinical teams involved in care in the field. Indeed, it is of prime importance to consider cultural dimensions when aiming to build trust within communities and flexibility to adapt trial procedures to field constraints. Trials implemented during the outbreak crisis illustrates challenging inputs for producing scientific and ethical gains for the benefits of vulnerable populations in the context of an international emerging or re-emerging infectious disease event. This includes rapid implementation of clinical research studies from the early phase of the next global outbreak on the basis of practical and ready-to-apply innovative methodological framework built during interepidemic periods.

Perioperative ketorolac in high risk breast cancer patients. Rationale, feasibility and methodology of a prospective randomized placebo-controlled trial.

PubMed

Forget, Patrice; Berlière, Martine; van Maanen, Aline; Duhoux, Francois P; Machiels, Jean-Pascal; Coulie, Pierre G; Bouche, Gauthier; De Kock, Marc

2013-10-01

Ketorolac, a NSAID routinely used during surgery proposed to have anticancer effects, is a promising way to improve postoperative oncological outcome. This effect may be particularly prominent in patients with elevated preoperative inflammatory scores, like the neutrophil:lymphocyte ratio. In this paper, we describe the rationale, the preliminary analyses in our patients, the feasibility and the methodology of a prospective randomized trial called "Ketorolac in Breast Cancer trial" (KBCt) (NCT01806259). Copyright © 2013 Elsevier Ltd. All rights reserved.

Psychosocial interventions for post-traumatic stress disorder in refugees and asylum seekers resettled in high-income countries: Systematic review and meta-analysis

PubMed Central

Nosè, Michela; Ballette, Francesca; Bighelli, Irene; Turrini, Giulia; Purgato, Marianna; Tol, Wietse; Priebe, Stefan; Barbui, Corrado

2017-01-01

Treatment of post-traumatic stress disorder (PTSD) in refugees and asylum seekers resettled in high-income countries presents specific challenges. This systematic review examined the effectiveness of psychosocial interventions for this group. We searched the Cochrane Central Register of randomised trials, CINAHL, EMBASE, PILOTS, PsycINFO, PubMed and Web of Science up to July 2016. Studies included randomised and controlled clinical trials comparing psychosocial interventions with waiting list or treatment as usual in adult refugees and asylum seekers with PTSD resettled in high-income countries. PTSD symptoms post-intervention was the primary outcome. We computed standardized mean differences (SMD) with 95% confidence intervals (CI). This study is registered with PROSPERO: CRD42015027843. Twelve studies were included in the meta-analysis. Psychosocial interventions were effective in decreasing PTSD symptoms relative to control groups (SMD -1·03, 95% CI -1·55 to -0·51; number needed to treat 4·4; I2 86%; 95% CI 77 to 91). Narrative exposure therapy, a manualized short-term variant of cognitive behavioural therapy with a trauma focus, was the best-supported intervention (5 RCTs, 187 participants, SMD -0·78, 95% CI -1·18 to -0·38, I2 37%; 95% CI 0 to 77). Methodological quality of the included studies was limited. Overall, psychosocial interventions for asylum seekers and refugees with PTSD resettled in high-income countries were found to provide significant benefits in reducing PTSD symptoms. Yet, the number of studies is small and their methodological quality limited, so that more rigorous trials should be conducted in the future. PMID:28151992

Psychosocial interventions for post-traumatic stress disorder in refugees and asylum seekers resettled in high-income countries: Systematic review and meta-analysis.

PubMed

Nosè, Michela; Ballette, Francesca; Bighelli, Irene; Turrini, Giulia; Purgato, Marianna; Tol, Wietse; Priebe, Stefan; Barbui, Corrado

2017-01-01

Treatment of post-traumatic stress disorder (PTSD) in refugees and asylum seekers resettled in high-income countries presents specific challenges. This systematic review examined the effectiveness of psychosocial interventions for this group. We searched the Cochrane Central Register of randomised trials, CINAHL, EMBASE, PILOTS, PsycINFO, PubMed and Web of Science up to July 2016. Studies included randomised and controlled clinical trials comparing psychosocial interventions with waiting list or treatment as usual in adult refugees and asylum seekers with PTSD resettled in high-income countries. PTSD symptoms post-intervention was the primary outcome. We computed standardized mean differences (SMD) with 95% confidence intervals (CI). This study is registered with PROSPERO: CRD42015027843. Twelve studies were included in the meta-analysis. Psychosocial interventions were effective in decreasing PTSD symptoms relative to control groups (SMD -1·03, 95% CI -1·55 to -0·51; number needed to treat 4·4; I2 86%; 95% CI 77 to 91). Narrative exposure therapy, a manualized short-term variant of cognitive behavioural therapy with a trauma focus, was the best-supported intervention (5 RCTs, 187 participants, SMD -0·78, 95% CI -1·18 to -0·38, I2 37%; 95% CI 0 to 77). Methodological quality of the included studies was limited. Overall, psychosocial interventions for asylum seekers and refugees with PTSD resettled in high-income countries were found to provide significant benefits in reducing PTSD symptoms. Yet, the number of studies is small and their methodological quality limited, so that more rigorous trials should be conducted in the future.

Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making.

PubMed

Yap, Christina; Billingham, Lucinda J; Cheung, Ying Kuen; Craddock, Charlie; O'Quigley, John

2017-12-15

The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate, or stop early), using all the accumulated information. After specifying a model with favorable statistical properties, we utilize the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgments. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified continual reassessment method is illustrated in an acute myeloid leukemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose update. In the illustrated trial, the seamless, clear transition for each dose recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators. Clin Cancer Res; 23(24); 7440-7. ©2017 AACR . ©2017 American Association for Cancer Research.

The Study of HIV and Antenatal Care Integration in Pregnancy in Kenya: Design, Methods, and Baseline Results of a Cluster-Randomized Controlled Trial

PubMed Central

Turan, Janet M.; Steinfeld, Rachel L.; Onono, Maricianah; Bukusi, Elizabeth A.; Woods, Meghan; Shade, Starley B.; Washington, Sierra; Marima, Reson; Penner, Jeremy; Ackers, Marta L.; Mbori-Ngacha, Dorothy; Cohen, Craig R.

2012-01-01

Background Despite strong evidence for the effectiveness of anti-retroviral therapy for improving the health of women living with HIV and for the prevention of mother-to-child transmission (PMTCT), HIV persists as a major maternal and child health problem in sub-Saharan Africa. In most settings antenatal care (ANC) services and HIV treatment services are offered in separate clinics. Integrating these services may result in better uptake of services, reduction of the time to treatment initiation, better adherence, and reduction of stigma. Methodology/Principal Findings A prospective cluster randomized controlled trial design was used to evaluate the effects of integrating HIV treatment into ANC clinics at government health facilities in rural Kenya. Twelve facilities were randomized to provide either fully integrated services (ANC, PMTCT, and HIV treatment services all delivered in the ANC clinic) or non-integrated services (ANC clinics provided ANC and basic PMTCT services and referred clients to a separate HIV clinic for HIV treatment). During June 2009– March 2011, 1,172 HIV-positive pregnant women were enrolled in the study. The main study outcomes are rates of maternal enrollment in HIV care and treatment, infant HIV testing uptake, and HIV-free infant survival. Baseline results revealed that the intervention and control cohorts were similar with respect to socio-demographics, male partner HIV testing, sero-discordance of the couple, obstetric history, baseline CD4 count, and WHO Stage. Challenges faced while conducting this trial at low-resource rural health facilities included frequent staff turnover, stock-outs of essential supplies, transportation challenges, and changes in national guidelines. Conclusions/Significance This is the first randomized trial of ANC and HIV service integration to be conducted in rural Africa. It is expected that the study will provide critical evidence regarding the implementation and effectiveness of this service delivery strategy, with important implications for programs striving to eliminate vertical transmission of HIV and improve maternal health. Trial Registration ClinicalTrials.gov NCT00931216 NCT00931216. PMID:22970177

Evaluation of the Cochrane tool for assessing risk of bias in randomized clinical trials: overview of published comments and analysis of user practice in Cochrane and non-Cochrane reviews.

PubMed

Jørgensen, Lars; Paludan-Müller, Asger S; Laursen, David R T; Savović, Jelena; Boutron, Isabelle; Sterne, Jonathan A C; Higgins, Julian P T; Hróbjartsson, Asbjørn

2016-05-10

The Cochrane risk of bias tool for randomized clinical trials was introduced in 2008 and has frequently been commented on and used in systematic reviews. We wanted to evaluate the tool by reviewing published comments on its strengths and challenges and by describing and analysing how the tool is applied to both Cochrane and non-Cochrane systematic reviews. A review of published comments (searches in PubMed, The Cochrane Methodology Register and Google Scholar) and an observational study (100 Cochrane and 100 non-Cochrane reviews from 2014). Our review included 68 comments, 15 of which were categorised as major. The main strengths of the tool were considered to be its aim (to assess trial conduct and not reporting), its developmental basis (wide consultation, empirical and theoretical evidence) and its transparent procedures. The challenges of the tool were mainly considered to be its choice of core bias domains (e.g. not involving funding/conflicts of interest) and issues to do with implementation (i.e. modest inter-rater agreement) and terminology. Our observational study found that the tool was used in all Cochrane reviews (100/100) and was the preferred tool in non-Cochrane reviews (31/100). Both types of reviews frequently implemented the tool in non-recommended ways. Most Cochrane reviews planned to use risk of bias assessments as basis for sensitivity analyses (70 %), but only a minority conducted such analyses (19 %) because, in many cases, few trials were assessed as having "low" risk of bias for all standard domains (6 %). The judgement of at least one risk of bias domain as "unclear" was found in 89 % of included randomized clinical trials (1103/1242). The Cochrane tool has become the standard approach to assess risk of bias in randomized clinical trials but is frequently implemented in a non-recommended way. Based on published comments and how it is applied in practice in systematic reviews, the tool may be further improved by a revised structure and more focused guidance.

Methodological reporting quality of randomized controlled trials: A survey of seven core journals of orthopaedics from Mainland China over 5 years following the CONSORT statement.

PubMed

Zhang, J; Chen, X; Zhu, Q; Cui, J; Cao, L; Su, J

2016-11-01

In recent years, the number of randomized controlled trials (RCTs) in the field of orthopaedics is increasing in Mainland China. However, randomized controlled trials (RCTs) are inclined to bias if they lack methodological quality. Therefore, we performed a survey of RCT to assess: (1) What about the quality of RCTs in the field of orthopedics in Mainland China? (2) Whether there is difference between the core journals of the Chinese department of orthopedics and Orthopaedics Traumatology Surgery & Research (OTSR). This research aimed to evaluate the methodological reporting quality according to the CONSORT statement of randomized controlled trials (RCTs) in seven key orthopaedic journals published in Mainland China over 5 years from 2010 to 2014. All of the articles were hand researched on Chongqing VIP database between 2010 and 2014. Studies were considered eligible if the words "random", "randomly", "randomization", "randomized" were employed to describe the allocation way. Trials including animals, cadavers, trials published as abstracts and case report, trials dealing with subgroups analysis, or trials without the outcomes were excluded. In addition, eight articles selected from Orthopaedics Traumatology Surgery & Research (OTSR) between 2010 and 2014 were included in this study for comparison. The identified RCTs are analyzed using a modified version of the Consolidated Standards of Reporting Trials (CONSORT), including the sample size calculation, allocation sequence generation, allocation concealment, blinding and handling of dropouts. A total of 222 RCTs were identified in seven core orthopaedic journals. No trials reported adequate sample size calculation, 74 (33.4%) reported adequate allocation generation, 8 (3.7%) trials reported adequate allocation concealment, 18 (8.1%) trials reported adequate blinding and 16 (7.2%) trials reported handling of dropouts. In OTSR, 1 (12.5%) trial reported adequate sample size calculation, 4 (50.0%) reported adequate allocation generation, 1 (12.5%) trials reported adequate allocation concealment, 2 (25.0%) trials reported adequate blinding and 5 (62.5%) trials reported handling of dropouts. There were statistical differences as for sample size calculation and handling of dropouts between papers from Mainland China and OTSR (P<0.05). The findings of this study show that the methodological reporting quality of RCTs in seven core orthopaedic journals from the Mainland China is far from satisfaction and it needs to further improve to keep up with the standards of the CONSORT statement. Level III case control. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Methodological reporting of randomized clinical trials in respiratory research in 2010.

PubMed

Lu, Yi; Yao, Qiuju; Gu, Jie; Shen, Ce

2013-09-01

Although randomized controlled trials (RCTs) are considered the highest level of evidence, they are also subject to bias, due to a lack of adequately reported randomization, and therefore the reporting should be as explicit as possible for readers to determine the significance of the contents. We evaluated the methodological quality of RCTs in respiratory research in high ranking clinical journals, published in 2010. We assessed the methodological quality, including generation of the allocation sequence, allocation concealment, double-blinding, sample-size calculation, intention-to-treat analysis, flow diagrams, number of medical centers involved, diseases, funding sources, types of interventions, trial registration, number of times the papers have been cited, journal impact factor, journal type, and journal endorsement of the CONSORT (Consolidated Standards of Reporting Trials) rules, in RCTs published in 12 top ranking clinical respiratory journals and 5 top ranking general medical journals. We included 176 trials, of which 93 (53%) reported adequate generation of the allocation sequence, 66 (38%) reported adequate allocation concealment, 79 (45%) were double-blind, 123 (70%) reported adequate sample-size calculation, 88 (50%) reported intention-to-treat analysis, and 122 (69%) included a flow diagram. Multivariate logistic regression analysis revealed that journal impact factor ≥ 5 was the only variable that significantly influenced adequate allocation sequence generation. Trial registration and journal impact factor ≥ 5 significantly influenced adequate allocation concealment. Medical interventions, trial registration, and journal endorsement of the CONSORT statement influenced adequate double-blinding. Publication in one of the general medical journal influenced adequate sample-size calculation. The methodological quality of RCTs in respiratory research needs improvement. Stricter enforcement of the CONSORT statement should enhance the quality of RCTs.

Using discrete choice experiments within a cost-benefit analysis framework: some considerations.

PubMed

McIntosh, Emma

2006-01-01

A great advantage of the stated preference discrete choice experiment (SPDCE) approach to economic evaluation methodology is its immense flexibility within applied cost-benefit analyses (CBAs). However, while the use of SPDCEs in healthcare has increased markedly in recent years there has been a distinct lack of equivalent CBAs in healthcare using such SPDCE-derived valuations. This article outlines specific issues and some practical suggestions for consideration relevant to the development of CBAs using SPDCE-derived benefits. The article shows that SPDCE-derived CBA can adopt recent developments in cost-effectiveness methodology including the cost-effectiveness plane, appropriate consideration of uncertainty, the net-benefit framework and probabilistic sensitivity analysis methods, while maintaining the theoretical advantage of the SPDCE approach. The concept of a cost-benefit plane is no different in principle to the cost-effectiveness plane and can be a useful tool for reporting and presenting the results of CBAs.However, there are many challenging issues to address for the advancement of CBA methodology using SPCDEs within healthcare. Particular areas for development include the importance of accounting for uncertainty in SPDCE-derived willingness-to-pay values, the methodology of SPDCEs in clinical trial settings and economic models, measurement issues pertinent to using SPDCEs specifically in healthcare, and the importance of issues such as consideration of the dynamic nature of healthcare and the resulting impact this has on the validity of attribute definitions and context.

Type 1 Diabetes TrialNet--an international collaborative clinical trials network.

PubMed

Skyler, Jay S; Greenbaum, Carla J; Lachin, John M; Leschek, Ellen; Rafkin-Mervis, Lisa; Savage, Peter; Spain, Lisa

2008-12-01

Type 1 Diabetes TrialNet is an international consortium of clinical research centers aimed at the prevention or delay of type 1 diabetes (T1D). The fundamental goal of TrialNet is to counter the T1D disease process by immune modulation and/or enhancement of beta cell proliferation and regeneration. To achieve this goal, TrialNet researchers are working to better understand the natural history of the disease, to identify persons at risk, and to clinically evaluate novel therapies that balance potential risks and benefits. The particular focus is on studies of preventive measures. In addition, TrialNet evaluates therapies in individuals with newly diagnosed T1D with preserved beta cell function to help determine the risk/benefit profile and gain an initial assessment of potential efficacy in preservation of beta cell function, so that promising agents can be studied in prevention trials. In addition, TrialNet evaluates methodologies that enhance the conduct of its clinical trials, which includes tests of outcome assessment methodology, the evaluation of surrogate markers, and mechanistic studies laying the foundation for future clinical trials.

Conducting Research with LGB People of Color: Methodological Challenges and Strategies

ERIC Educational Resources Information Center

DeBlaere, Cirleen; Brewster, Melanie E.; Sarkees, Anthony; Moradi, Bonnie

2010-01-01

Methodological barriers have been highlighted as a primary reason for the limited research with lesbian, gay, and bisexual (LGB) people of color. Thus, strategies for anticipating and addressing potential methodological barriers are needed. To address this need, this article discusses potential challenges associated with conducting research with…

Review of Recent Methodological Developments in Group-Randomized Trials: Part 2-Analysis.

PubMed

Turner, Elizabeth L; Prague, Melanie; Gallis, John A; Li, Fan; Murray, David M

2017-07-01

In 2004, Murray et al. reviewed methodological developments in the design and analysis of group-randomized trials (GRTs). We have updated that review with developments in analysis of the past 13 years, with a companion article to focus on developments in design. We discuss developments in the topics of the earlier review (e.g., methods for parallel-arm GRTs, individually randomized group-treatment trials, and missing data) and in new topics, including methods to account for multiple-level clustering and alternative estimation methods (e.g., augmented generalized estimating equations, targeted maximum likelihood, and quadratic inference functions). In addition, we describe developments in analysis of alternative group designs (including stepped-wedge GRTs, network-randomized trials, and pseudocluster randomized trials), which require clustering to be accounted for in their design and analysis.

Cluster randomized trials utilizing primary care electronic health records: methodological issues in design, conduct, and analysis (eCRT Study)

PubMed Central

2014-01-01

Background There is growing interest in conducting clinical and cluster randomized trials through electronic health records. This paper reports on the methodological issues identified during the implementation of two cluster randomized trials using the electronic health records of the Clinical Practice Research Datalink (CPRD). Methods Two trials were completed in primary care: one aimed to reduce inappropriate antibiotic prescribing for acute respiratory infection; the other aimed to increase physician adherence with secondary prevention interventions after first stroke. The paper draws on documentary records and trial datasets to report on the methodological experience with respect to research ethics and research governance approval, general practice recruitment and allocation, sample size calculation and power, intervention implementation, and trial analysis. Results We obtained research governance approvals from more than 150 primary care organizations in England, Wales, and Scotland. There were 104 CPRD general practices recruited to the antibiotic trial and 106 to the stroke trial, with the target number of practices being recruited within six months. Interventions were installed into practice information systems remotely over the internet. The mean number of participants per practice was 5,588 in the antibiotic trial and 110 in the stroke trial, with the coefficient of variation of practice sizes being 0.53 and 0.56 respectively. Outcome measures showed substantial correlations between the 12 months before, and after intervention, with coefficients ranging from 0.42 for diastolic blood pressure to 0.91 for proportion of consultations with antibiotics prescribed, defining practice and participant eligibility for analysis requires careful consideration. Conclusions Cluster randomized trials may be performed efficiently in large samples from UK general practices using the electronic health records of a primary care database. The geographical dispersal of trial sites presents a difficulty for research governance approval and intervention implementation. Pretrial data analyses should inform trial design and analysis plans. Trial registration Current Controlled Trials ISRCTN 47558792 and ISRCTN 35701810 (both registered on 17 March 2010). PMID:24919485

Critical appraisal of clinical trials in multiple system atrophy: Toward better quality.

PubMed

Castro Caldas, Ana; Levin, Johannes; Djaldetti, Ruth; Rascol, Olivier; Wenning, Gregor; Ferreira, Joaquim J

2017-10-01

Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause. Although many clinical trials have been conducted, there is still no treatment that cures the disease or slows its progression. We sought to assess the clinical trials, methodology, and quality of reporting of clinical trails conducted in MSA patients. We conducted a systematic review of all trials with at least 1 MSA patient subject to any pharmacological/nonpharmacological interventions. Two independent reviewers evaluated the methodological characteristics and quality of reporting of trials. A total of 60 clinical trials were identified, including 1375 MSA patients. Of the trials, 51% (n = 31) were single-arm studies. A total of 28% (n = 17) had a parallel design, half of which (n = 13) were placebo controlled. Of the studies, 8 (13.3%) were conducted in a multicenter setting, 3 of which were responsible for 49.3% (n = 678) of the total included MSA patients. The description of primary outcomes was unclear in 60% (n = 40) of trials. Only 10 (16.7%) clinical trials clearly described the randomization process. Blinding of the participants, personnel, and outcome assessments were at high risk of bias in the majority of studies. The number of dropouts/withdrawals was high (n = 326, 23.4% among the included patients). Overall, the design and quality of reporting of the reviewed studies is unsatisfactory. The most frequent clinical trials were small and single centered. Inadequate reporting was related to the information on the randomization process, sequence generation, allocation concealment, blinding of participants, and sample size calculations. Although improved during the recent years, methodological quality and trial design need to be optimized to generate more informative results. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Development of Pain Endpoint Models for Use in Prostate Cancer Clinical Trials and Drug Approval

DTIC Science & Technology

2017-10-01

publication delineating key methodological components of pain studies in prostate cancer. KEYWORDS Pain, metastatic castrate resistant prostate cancer...pain palliation and pain progression in prostate cancer clinical trials that are feasible, methodologically rigorous, and meet regulatory...requirements for drug approval and labeling. The primary aim of this award is to conduct an observational longitudinal study in men with castrate-resistant

Bayesian methodology for the design and interpretation of clinical trials in critical care medicine: a primer for clinicians.

PubMed

Kalil, Andre C; Sun, Junfeng

2014-10-01

To review Bayesian methodology and its utility to clinical decision making and research in the critical care field. Clinical, epidemiological, and biostatistical studies on Bayesian methods in PubMed and Embase from their inception to December 2013. Bayesian methods have been extensively used by a wide range of scientific fields, including astronomy, engineering, chemistry, genetics, physics, geology, paleontology, climatology, cryptography, linguistics, ecology, and computational sciences. The application of medical knowledge in clinical research is analogous to the application of medical knowledge in clinical practice. Bedside physicians have to make most diagnostic and treatment decisions on critically ill patients every day without clear-cut evidence-based medicine (more subjective than objective evidence). Similarly, clinical researchers have to make most decisions about trial design with limited available data. Bayesian methodology allows both subjective and objective aspects of knowledge to be formally measured and transparently incorporated into the design, execution, and interpretation of clinical trials. In addition, various degrees of knowledge and several hypotheses can be tested at the same time in a single clinical trial without the risk of multiplicity. Notably, the Bayesian technology is naturally suited for the interpretation of clinical trial findings for the individualized care of critically ill patients and for the optimization of public health policies. We propose that the application of the versatile Bayesian methodology in conjunction with the conventional statistical methods is not only ripe for actual use in critical care clinical research but it is also a necessary step to maximize the performance of clinical trials and its translation to the practice of critical care medicine.

[Methodological quality evaluation of randomized controlled trials for traditional Chinese medicines for treatment of sub-health].

PubMed

Zhao, Jun; Liao, Xing; Zhao, Hui; Li, Zhi-Geng; Wang, Nan-Yue; Wang, Li-Min

2016-11-01

To evaluate the methodological quality of the randomized controlled trials(RCTs) for traditional Chinese medicines for treatment of sub-health, in order to provide a scientific basis for the improvement of clinical trials and systematic review. Such databases as CNKI, CBM, VIP, Wanfang, EMbase, Medline, Clinical Trials, Web of Science and Cochrane Library were searched for RCTS for traditional Chinese medicines for treatment of sub-health between the time of establishment and February 29, 2016. Cochrane Handbook 5.1 was used to screen literatures and extract data, and CONSORT statement and CONSORT for traditional Chinese medicine statement were adopted as the basis for quality evaluation. Among the 72 RCTs included in this study, 67 (93.05%) trials described the inter-group baseline data comparability, 39(54.17%) trials described the unified diagnostic criteria, 28(38.89%) trials described the unified standards of efficacy, 4 (5.55%) trials mentioned the multi-center study, 19(26.38%) trials disclosed the random distribution method, 6(8.33%) trials used the random distribution concealment, 15(20.83%) trials adopted the method of blindness, 3(4.17%) study reported the sample size estimation in details, 5 (6.94%) trials showed a sample size of more than two hundred, 19(26.38%) trials reported the number of withdrawal, defluxion cases and those lost to follow-up, but only 2 trials adopted the ITT analysis,10(13.89%) trials reported the follow-up results, none of the trial reported the test registration and the test protocol, 48(66.7%) trials reported all of the indicators of expected outcomes, 26(36.11%) trials reported the adverse reactions and adverse events, and 4(5.56%) trials reported patient compliance. The overall quality of these randomized controlled trials for traditional Chinese medicines for treatment of sub-health is low, with methodological defects in different degrees. Therefore, it is still necessary to emphasize the correct application of principles such as blindness, randomization and control in RCTs, while requiring reporting in accordance with international standards. Copyright© by the Chinese Pharmaceutical Association.

Effectiveness of the Comprehensive Approach to Rehabilitation (CARe) methodology: design of a cluster randomized controlled trial.

PubMed

Bitter, Neis A; Roeg, Diana P K; van Nieuwenhuizen, Chijs; van Weeghel, Jaap

2015-07-22

There is an increasing amount of evidence for the effectiveness of rehabilitation interventions for people with severe mental illness (SMI). In the Netherlands, a rehabilitation methodology that is well known and often applied is the Comprehensive Approach to Rehabilitation (CARe) methodology. The overall goal of the CARe methodology is to improve the client's quality of life by supporting the client in realizing his/her goals and wishes, handling his/her vulnerability and improving the quality of his/her social environment. The methodology is strongly influenced by the concept of 'personal recovery' and the 'strengths case management model'. No controlled effect studies have been conducted hitherto regarding the CARe methodology. This study is a two-armed cluster randomized controlled trial (RCT) that will be executed in teams from three organizations for sheltered and supported housing, which provide services to people with long-term severe mental illness. Teams in the intervention group will receive the multiple-day CARe methodology training from a specialized institute and start working according the CARe Methodology guideline. Teams in the control group will continue working in their usual way. Standardized questionnaires will be completed at baseline (T0), and 10 (T1) and 20 months (T2) post baseline. Primary outcomes are recovery, social functioning and quality of life. The model fidelity of the CARe methodology will be assessed at T1 and T2. This study is the first controlled effect study on the CARe methodology and one of the few RCTs on a broad rehabilitation method or strength-based approach. This study is relevant because mental health care organizations have become increasingly interested in recovery and rehabilitation-oriented care. The trial registration number is ISRCTN77355880 .

Identifying additional studies for a systematic review of retention strategies in randomised controlled trials: making contact with trials units and trial methodologists.

PubMed

Brueton, Valerie; Tierney, Jayne F; Stenning, Sally; Rait, Greta

2017-08-22

Search strategies for systematic reviews aim to identify all evidence relevant to the research question posed. Reports of methodological research can be difficult to find leading to biased results in systematic reviews of research methodology. Evidence suggests that contact with investigators can help to identify unpublished research. To identify additional eligible randomised controlled trials (RCTs) for a Cochrane systematic review of strategies to improve retention in RCTs, we conducted a survey of UK clinical trials units (CTUs) and made contact with RCT methodologists. Key contacts for all UK CTUs were sent a personalised email with a short questionnaire and summary protocol of the Cochrane methodology review. The questionnaire asked whether a RCT evaluating strategies to improve retention embedded in a RCT had ever been conducted by the CTU. Questions about the stage of completion and publication of such RCTs were included. The summary protocol outlined the aims, eligibility criteria, examples of types of retention strategies, and the primary outcome for the systematic review. Personal communication with RCT methodologists and presentations of preliminary results of the review at conferences were also used to identify additional eligible RCTs. We checked the results of our standard searches to see if eligible studies identified through these additional methods were also found using our standard searches. We identified 14 of the 38 RCTs included in the Cochrane methodology review by contacting trials units and methodologists. Eleven of the 14 RCTs identified by these methods were either published in grey literature, in press or unpublished. Three remaining RCTs were fully published at the time. Six of the RCTs identified were not found through any other searches. The RCTs identified represented data for 6 of 14 RCTs of incentive strategies (52% of randomised participants included in the review), and 6 of 14 RCTs of communication strategies (52% of randomised participants included in the Cochrane review). Data were unavailable for two of the RCTs identified. Methodological evaluations embedded in RCTs may be unpublished, published in the grey literature or where published, poorly indexed in bibliographic databases. To identify such studies and minimise selection bias in systematic reviews of methodological evaluations, reviewers should consider contacting CTUs and trial methodologists.

Documenting Sociolinguistic Variation in Lesser-Studied Indigenous Communities: Challenges and Practical Solutions

ERIC Educational Resources Information Center

Mansfield, John; Stanford, James

2017-01-01

Documenting sociolinguistic variation in lesser-studied languages presents methodological challenges, but also offers important research opportunities. In this paper we examine three key methodological challenges commonly faced by researchers who are outsiders to the community. We then present practical solutions for successful variationist…

Registration status and methodological reporting of randomized controlled trials in obesity research: A review.

PubMed

Byrne, Jillian L S; Yee, Tamara; O'Connor, Kathleen; Dyson, Michele P; Ball, Geoff D C

2017-04-01

To assess registration and reporting details of randomized controlled trials (RCTs) published from 2011 to 2016 across four obesity journals. All issues from four leading obesity journals were searched systematically for RCTs from January 2011 to June 2016. Data on registration status were extracted from manuscripts, online trial registries, and a trial database; corresponding authors were contacted for registration details, when necessary. The methodological reporting of RCTs was assessed on specific criteria from the Consolidated Standards of Reporting Trials. A total of 223 RCTs were reviewed. Three-quarters (n = 170) were registered publicly; 94 (55.3%) reported registration details in the manuscript, and 82 (48.2%) were registered prospectively. Newer RCTs were more likely to be registered prospectively than older RCTs (2014-2016: 57.3% vs. 2011-2013: 39.2%; c 2  = 5.5, P = 0.02). Assessment on the Consolidated Standards of Reporting Trials demonstrated that less than half of all studies reported data collection dates (n = 108; 48.4%) or included "randomized trial" in the title (n = 89; 39.9%). The methodological reporting of RCTs published in obesity journals is suboptimal, despite current guidelines and policies. To complement existing standards, editorial boards should incorporate mandatory fields within the online manuscript submission process to enhance the quality, transparency, and comprehensiveness of reporting RCTs in obesity journals. © 2017 The Obesity Society.

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments.

PubMed

Connick, Peter; Kolappan, Madhan; Patani, Rickie; Scott, Michael A; Crawley, Charles; He, Xiao-Ling; Richardson, Karen; Barber, Kelly; Webber, Daniel J; Wheeler-Kingshott, Claudia A M; Tozer, Daniel J; Samson, Rebecca S; Thomas, David L; Du, Ming-Qing; Luan, Shi L; Michell, Andrew W; Altmann, Daniel R; Thompson, Alan J; Miller, David H; Compston, Alastair; Chandran, Siddharthan

2011-03-02

No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes--the "sentinel lesion approach". MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS--the sentinel lesion approach--serving as proof of principle for its future wider applicability. ClinicalTrials.gov (NCT00395200).

Diabetes in rural towns: effectiveness of continuing education and feedback for healthcare providers in altering diabetes outcomes at a population level: protocol for a cluster randomised controlled trial.

PubMed

Paul, Christine L; Piterman, Leon; Shaw, Jonathan; Kirby, Catherine; Sanson-Fisher, Robert W; Carey, Mariko L; Robinson, Jennifer; McElduff, Patrick; Thepwongsa, Isaraporn

2013-03-13

Type 2 diabetes is one of the fastest growing chronic diseases internationally. The health complications associated with type 2 diabetes can be prevented, delayed, or improved via early diagnosis and effective management. This research aims to examine the impact of a primarily web-based educational intervention on the diabetes care provided by general practitioners (GPs) in rural areas, and subsequent patient outcomes. A population-level approach to outcome assessment is used, via whole-town de-identified pathology records. The study uses a cluster randomised controlled trial with rural communities as the unit of analysis. Towns from four Australian states were selected and matched on factors including rurality, population size, proportion of the population who were Indigenous Australians, and socio-economic status. Eleven pairs of towns from two states were suitable for the trial, and one town from each pair was randomised to the experimental group. GPs in the towns allocated to the experimental group are offered an intervention package comprising education on best practice diabetes care via an on-line active learning module, a moderated discussion forum, access to targeted and specialist advice through an on-line request form, and town-based performance feedback on diabetes monitoring and outcomes. The package is offered via repeated direct mail. The benefits of the outcomes of the trial are described along with the challenges and limitations associated with the methodology. Australian New Zealand Clinical Trials Registry: ACTRN12611000553976.

Clinical trials: the challenge of recruitment and retention of participants.

PubMed

Gul, Raisa B; Ali, Parveen A

2010-01-01

This article, based on the available literature, attempts to discuss the importance of recruitment and retention of research participants, the associated barriers and challenges, and various strategies to overcome these barriers. The inability to recruit and retain the required participants in a research project poses serious threats to both the internal and the external validity of a research study. Despite serious implications, the issues of recruitment and retention do not receive due attention in research and publications. Literature suggests a lack of coordinated efforts to collect information on the outcomes of recruitment experiences in clinical trials and population studies. Studies often mention the number of participants who refuse to participate; however, the majority of the studies often fail to mention the specific reasons insufficient recruitment or retention of the participants. A methodological paper. Various participant-, context-, environment- and research-related factors are examined that affect the phenomenon of recruitment and retention of the participants in a study. Delayed or inefficient recruitment also has financial and ethical implications. Although there are many pieces of information scattered throughout academic journals on recruitment and retention of participants in research, few authors have dealt with the issue holistically. It is imperative for researchers to understand the importance of recruitment and retention of research participants, the associated barriers and challenges, and various strategies to overcome these barriers. Appropriate recording and reporting of the problems faced while recruiting and retaining the participants in research studies can help not only in understating the challenge, but will also help in devising the strategies to overcome this problem. This article was an attempt to synthesise and review the available literature on recruitment and retention issues, which demand extensive theoretical and conceptual thinking as part of the research design. An understanding of the challenges and issues related to recruitment and retention can help researchers to think ahead about the strategies to overcome these issues and consequently save the time and energy of the participants, researchers and funding agencies.

Bench-to-bedside review: The MET syndrome – the challenges of researching and adopting medical emergency teams

PubMed Central

Tee, Augustine; Calzavacca, Paolo; Licari, Elisa; Goldsmith, Donna; Bellomo, Rinaldo

2008-01-01

Studies of hospital performance highlight the problem of 'failure to rescue' in acutely ill patients. This is a deficiency strongly associated with serious adverse events, cardiac arrest, or death. Rapid response systems (RRSs) and their efferent arm, the medical emergency team (MET), provide early specialist critical care to patients affected by the 'MET syndrome': unequivocal physiological instability or significant hospital staff concern for patients in a non-critical care environment. This intervention aims to prevent serious adverse events, cardiac arrests, and unexpected deaths. Though clinically logical and relatively simple, its adoption poses major challenges. Furthermore, research about the effectiveness of RRS is difficult to conduct. Sceptics argue that inadequate evidence exists to support its widespread application. Indeed, supportive evidence is based on before-and-after studies, observational investigations, and inductive reasoning. However, implementing a complex intervention like RRS poses enormous logistic, political, cultural, and financial challenges. In addition, double-blinded randomised controlled trials of RRS are simply not possible. Instead, as in the case of cardiac arrest and trauma teams, change in practice may be slow and progressive, even in the absence of level I evidence. It appears likely that the accumulation of evidence from different settings and situations, though methodologically imperfect, will increase the rationale and logic of RRS. A conclusive randomised controlled trial is unlikely to occur. All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident. Arthur Schopenhauer (1788–1860), German philosopher PMID:18254927

78 FR 68449 - Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-14

... RFA-HS14-002, Addressing Methodological Challenges in Research for Patients With Multiple Chronic... applications for the ``AHRQ RFA-HS14-002, Addressing Methodological Challenges in Research for Patients With...

Herbal Medicine for Xerostomia in Cancer Patients: A Systematic Review of Randomized Controlled Trials.

PubMed

Park, Bongki; Noh, Hyeonseok; Choi, Dong-Jun

2018-06-01

Xerostomia (dry mouth) causes many clinical problems, including oral infections, speech difficulties, and impaired chewing and swallowing of food. Many cancer patients have complained of xerostomia induced by cancer therapy. The aim of this systematic review is to assess the efficacy of herbal medicine for the treatment of xerostomia in cancer patients. Randomized controlled trials investigating the use of herbal medicines to treat xerostomia in cancer patients were included. We searched the following 12 databases without restrictions on time or language. The risk of bias was assessed using the Cochrane Risk of Bias Tool. Twenty-five randomized controlled trials involving 1586 patients met the inclusion criteria. A total of 24 formulas were examined in the included trials. Most of the included trials were insufficiently reported in the methodology section. Five formulas were shown to significantly improve the salivary flow rate compared to comparators. Regarding the grade of xerostomia, all formulas with the exception of a Dark Plum gargle solution with normal saline were significantly effective in reducing the severity of dry mouth. Adverse events were reported in 4 trials, and adverse effects of herbal medicine were reported in 3 trials. We found herbal medicines had potential benefits for improving salivary function and reducing the severity of dry mouth in cancer patients. However, methodological limitations and a relatively small sample size reduced the strength of the evidence. More high-quality trials reporting sufficient methodological data are warranted to enforce the strength of evidence regarding the effectiveness of herbal medicines.

Tai Chi for Essential Hypertension

PubMed Central

Wang, Jie; Feng, Bo; Yang, Xiaochen; Liu, Wei; Teng, Fei; Li, Shengjie; Xiong, Xingjiang

2013-01-01

Objectives. To assess the current clinical evidence of Tai Chi for essential hypertension (EH). Search Strategy. 7 electronic databases were searched until 20 April, 2013. Inclusion Criteria. We included randomized trials testing Tai Chi versus routine care or antihypertensive drugs. Trials testing Tai Chi combined with antihypertensive drugs versus antihypertensive drugs were also included. Data Extraction and Analyses. Study selection, data extraction, quality assessment, and data analyses were conducted according to the Cochrane standards. Results. 18 trials were included. Methodological quality of the trials was low. 14 trials compared Tai Chi with routine care. 1 trial compared Tai Chi with antihypertensive drugs. Meta-analysis all showed significant effect of TaiChi in lowering blood pressure (BP). 3 trials compared Tai Chi plus antihypertensive drugs with antihypertensive drugs. Positive results in BP were found in the other 2 combination groups. Most of the trials did not report adverse events, and the safety of Tai Chi is still uncertain. Conclusions. There is some encouraging evidence of Tai Chi for EH. However, due to poor methodological quality of included studies, the evidence remains weak. Rigorously designed trials are needed to confirm the evidence. PMID:23986780

Cluster randomized trials utilizing primary care electronic health records: methodological issues in design, conduct, and analysis (eCRT Study).

PubMed

Gulliford, Martin C; van Staa, Tjeerd P; McDermott, Lisa; McCann, Gerard; Charlton, Judith; Dregan, Alex

2014-06-11

There is growing interest in conducting clinical and cluster randomized trials through electronic health records. This paper reports on the methodological issues identified during the implementation of two cluster randomized trials using the electronic health records of the Clinical Practice Research Datalink (CPRD). Two trials were completed in primary care: one aimed to reduce inappropriate antibiotic prescribing for acute respiratory infection; the other aimed to increase physician adherence with secondary prevention interventions after first stroke. The paper draws on documentary records and trial datasets to report on the methodological experience with respect to research ethics and research governance approval, general practice recruitment and allocation, sample size calculation and power, intervention implementation, and trial analysis. We obtained research governance approvals from more than 150 primary care organizations in England, Wales, and Scotland. There were 104 CPRD general practices recruited to the antibiotic trial and 106 to the stroke trial, with the target number of practices being recruited within six months. Interventions were installed into practice information systems remotely over the internet. The mean number of participants per practice was 5,588 in the antibiotic trial and 110 in the stroke trial, with the coefficient of variation of practice sizes being 0.53 and 0.56 respectively. Outcome measures showed substantial correlations between the 12 months before, and after intervention, with coefficients ranging from 0.42 for diastolic blood pressure to 0.91 for proportion of consultations with antibiotics prescribed, defining practice and participant eligibility for analysis requires careful consideration. Cluster randomized trials may be performed efficiently in large samples from UK general practices using the electronic health records of a primary care database. The geographical dispersal of trial sites presents a difficulty for research governance approval and intervention implementation. Pretrial data analyses should inform trial design and analysis plans. Current Controlled Trials ISRCTN 47558792 and ISRCTN 35701810 (both registered on 17 March 2010).

Trials, tribulations, and triumphs of insider researchers

NASA Astrophysics Data System (ADS)

McBride, S.; Tilley, E. N.; Becker, J.; Orchiston, C.; Johnston, D. M.

2016-12-01

Is there merit in "insider" research? An insider researcher, in the social science context, is someone who conducts their research and provides their observations and perspectives on a project, sector or disaster setting which they are intimately familiar with. One strength of insider research is the unique insights and awareness that are gained as a consequence of the experience of working within the research setting. This could also be considered the most significant criticism of insider research, one that is fraught with bias and subjectivity. So, given their potential biases, can an insider develop worthwhile research? The trials and tribulations of an insider are many. Given the insider position, traditional observer empirical research is not ideal, so this research necessitates exploring different research theoretical perspectives, including the use of critical theory and constructivism. Constructivism-based research permits the researcher to use their unique perspectives and knowledge to `construct' knowledge through their research. However, using constructivist theoretical perspectives and methods may be a complex and challenging endeavor for those better acquainted with empirical methods. Further, ethical restrictions can create further complexities to insider research. Compounding the complexities of methodologies and theoretical perspective, an insiders' perspective can be difficult to manage, given their embedded viewpoint, and may include professional and emotional risks for the researcher. Given its many challenges, insider research is not a frequent pathway of academic examination, particularly in emergency management and natural hazards research. Triumphs of insider research endeavors become clear once ways to address methodological and ethical issues are resolved. I will explore these solutions in my presentation. Further, insider researchers laid the foundation for the contemporary emergency management discipline but this research has been largely been overlooked in the discourse. The triumph of insider research is how influential they may be to a sector; one historical piece of research assisted in the development of an entire sector. Finally, I explore my research pathway, as an insider, to research the communication lessons from the Canterbury Earthquake Sequence.

Characterizing implementation strategies using a systems engineering survey and interview tool: a comparison across 10 prevention programs for drug abuse and HIV sexual risk behavior.

PubMed

Czaja, Sara J; Valente, Thomas W; Nair, Sankaran N; Villamar, Juan A; Brown, C Hendricks

2016-05-17

Although many behavioral interventions have proven to be efficacious, new methodologies are required beyond efficacy trials to understand how to adopt, implement with fidelity, and sustain behavioral interventions in community settings. In this paper, we present a new approach, based on systems engineering concepts and methods, for characterizing implementation strategies that are used to deliver evidence-based behavioral interventions in health and social service settings. We demonstrate the use of this approach with implementation strategies, used or being used for broader dissemination of 10 evidence-based prevention program projects focused on the prevention of drug or HIV sex risk behaviors. The results indicate that there are wide variations in intervention approaches and that there are challenges in program implementation including maintaining program fidelity, serving community needs, and adequate resources. The results also indicate that implementation requires a committed partnership between the program developers, implementation researchers, and community partners. In addition, there is a need for adaptability within programs to meet community needs, resources, and priorities while maintaining program fidelity. Our methodological approach enabled us to highlight challenges associated with the community implementation of health risk prevention interventions. We also demonstrate how comprehensive descriptions of interventions facilitate understanding of the requirements of program implementation and decisions about the feasibility of implementing a program in community settings.

A pragmatic trial in the Rio de Janeiro subway to capture smokers for a quitline: methodological challenges and opportunities.

PubMed

Szklo, André Salem; da Silva Freire Coutinho, Evandro; Reichenheim, Michael Eduardo

2012-01-01

According to the World Health Organization, smoking is an important cause of death worldwide. To encourage smoking cessation, persuasive messages can be used to raise smokers' risk perception. This article discusses challenges and solutions in designing a study to evaluate the effect of two different communication strategies ("gains from quitting" vs. "losses from continuing smoking") in encouraging calls to a quitline. The authors conducted an intervention study in two subway stations for 4 weeks, considering only 1 strategy per station. Large posters containing non-age-specific images and texts, on the basis of the theme"shortness of breath," were displayed on central dividing columns on the boarding platforms. Call rates from the selected stations, and respective rate ratios, overall and per study week, were calculated. Passengers who were smokers, exposed to the positive-content message, called on average 1.7 times more often than did those exposed to the negative-content message (p = .01). Moreover, call rate ratios did not decline over the 4 weeks of the study (p = .40). The effectiveness findings suggest that antismoking campaigns could use positive-content messages in order to recruit a larger smoker population. The proposed methodology can also be used to evaluate effectiveness of messages for "capturing" individuals with other health problems (e.g., alcohol abuse), thereby increasing its potential impact.

Effect of periodontal treatment on preterm birth rate: a systematic review of meta-analyses.

PubMed

López, Néstor J; Uribe, Sergio; Martinez, Benjamín

2015-02-01

Preterm birth is a major cause of neonatal morbidity and mortality in both developed and developing countries. Preterm birth is a highly complex syndrome that includes distinct clinical subtypes in which many different causes may be involved. The results of epidemiological, molecular, microbiological and animal-model studies support a positive association between maternal periodontal disease and preterm birth. However, the results of intervention studies carried out to determine the effect of periodontal treatment on reducing the risk of preterm birth are controversial. This systematic review critically analyzes the methodological issues of meta-analyses of the studies to determine the effect of periodontal treatment to reduce preterm birth. The quality of the individual randomized clinical trials selected is of highest relevance for a systematic review. This article describes the methodological features that should be identified a priori and assessed individually to determine the quality of a randomized controlled trial performed to evaluate the effect of periodontal treatment on pregnancy outcomes. The AMSTAR and the PRISMA checklist tools were used to assess the quality of the six meta-analyses selected, and the bias domain of the Cochrane Collaboration's Tool was applied to evaluate each of the trials included in the meta-analyses. In addition, the methodological characteristics of each clinical trial were assessed. The majority of the trials included in the meta-analyses have significant methodological flaws that threaten their internal validity. The lack of effect of periodontal treatment on preterm birth rate concluded by four meta-analyses, and the positive effect of treatment for reducing preterm birth risk concluded by the remaining two meta-analyses are not based on consistent scientific evidence. Well-conducted randomized controlled trials using rigorous methodology, including appropriate definition of the exposure, adequate control of confounders for preterm birth and application of effective periodontal interventions to eliminate periodontal infection, are needed to confirm the positive association between periodontal disease and preterm birth. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The trials methodological research agenda: results from a priority setting exercise

PubMed Central

2014-01-01

Background Research into the methods used in the design, conduct, analysis, and reporting of clinical trials is essential to ensure that effective methods are available and that clinical decisions made using results from trials are based on the best available evidence, which is reliable and robust. Methods An on-line Delphi survey of 48 UK Clinical Research Collaboration registered Clinical Trials Units (CTUs) was undertaken. During round one, CTU Directors were asked to identify important topics that require methodological research. During round two, their opinion about the level of importance of each topic was recorded, and during round three, they were asked to review the group’s average opinion and revise their previous opinion if appropriate. Direct reminders were sent to maximise the number of responses at each round. Results are summarised using descriptive methods. Results Forty one (85%) CTU Directors responded to at least one round of the Delphi process: 25 (52%) responded in round one, 32 (67%) responded in round two, 24 (50%) responded in round three. There were only 12 (25%) who responded to all three rounds and 18 (38%) who responded to both rounds two and three. Consensus was achieved amongst CTU Directors that the top three priorities for trials methodological research were ‘Research into methods to boost recruitment in trials’ (considered the highest priority), ‘Methods to minimise attrition’ and ‘Choosing appropriate outcomes to measure’. Fifty other topics were included in the list of priorities and consensus was reached that two topics, ‘Radiotherapy study designs’ and ‘Low carbon trials’, were not priorities. Conclusions This priority setting exercise has identified the research topics felt to be most important to the key stakeholder group of Directors of UKCRC registered CTUs. The use of robust methodology to identify these priorities will help ensure that this work informs the trials methodological research agenda, with a focus on topics that will have most impact and relevance. PMID:24456928

Critical reflections on methodological challenge in arts and dementia evaluation and research.

PubMed

Gray, Karen; Evans, Simon Chester; Griffiths, Amanda; Schneider, Justine

2017-01-01

Methodological rigour, or its absence, is often a focus of concern for the emerging field of evaluation and research around arts and dementia. However, this paper suggests that critical attention should also be paid to the way in which individual perceptions, hidden assumptions and underlying social and political structures influence methodological work in the field. Such attention will be particularly important for addressing methodological challenges relating to contextual variability, ethics, value judgement and signification identified through a literature review on this topic. Understanding how, where and when evaluators and researchers experience such challenges may help to identify fruitful approaches for future evaluation.

Practical Issues of Conducting a Q Methodology Study: Lessons Learned From a Cross-cultural Study.

PubMed

Stone, Teresa Elizabeth; Maguire, Jane; Kang, Sook Jung; Cha, Chiyoung

This article advances nursing research by presenting the methodological challenges experienced in conducting a multination Q-methodology study. This article critically analyzes the relevance of the methodology for cross-cultural and nursing research and the challenges that led to specific responses by the investigators. The use of focus groups with key stakeholders supplemented the Q-analysis results. The authors discuss practical issues and shared innovative approaches and provide best-practice suggestions on the use of this flexible methodology. Q methodology has the versatility to explore complexities of contemporary nursing practice and cross-cultural health research.

Launching a Novel Preclinical Infrastructure: Comparative Oncology Trials Consortium Directed Therapeutic Targeting of TNFα to Cancer Vasculature

PubMed Central

Mazcko, Christina; Hanna, Engy; Kachala, Stefan; LeBlanc, Amy; Newman, Shelley; Vail, David; Henry, Carolyn; Thamm, Douglas; Sorenmo, Karin; Hajitou, Amin; Pasqualini, Renata; Arap, Wadih

2009-01-01

Background Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial of the Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturally develop in pet dogs into the development path of new human drugs. Trials are designed to address questions challenging in conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuable addition to successful studies of cancer biology and novel therapeutic drug, imaging and device development. Methodology/Principal Findings Through this established infrastructure, the first trial of the COTC (COTC001) evaluated a targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to αV integrins on tumor endothelium. Trial progress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for the consortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (5×1012 transducing units intravenous) of RGD-A-TNF. This demonstrated selective targeting of tumor-associated vasculature and sparing of normal tissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the defined optimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), and disease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST). Conclusions/Significance The first study of the COTC has demonstrated the utility and efficiency of the established infrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. The preclinical evaluation of RGD-A-TNF within this network provided valuable and necessary data to complete the design of first-in-man studies. PMID:19330034

Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: a methodological overview.

PubMed

Jensen, Jakob Solgaard; Bielefeldt, Andreas Ørsted; Hróbjartsson, Asbjørn

2017-07-01

Active placebos are control interventions that mimic the side effects of the experimental interventions in randomized trials and are sometimes used to reduce the risk of unblinding. We wanted to assess how often randomized clinical drug trials use active placebo control groups; to provide a catalog, and a characterization, of such trials; and to analyze methodological arguments for and against the use of active placebo. An overview consisting of three thematically linked substudies. In an observational substudy, we assessed the prevalence of active placebo groups based on a random sample of 200 PubMed indexed placebo-controlled randomized drug trials published in October 2013. In a systematic review, we identified and characterized trials with active placebo control groups irrespective of publication time. In a third substudy, we reviewed publications with substantial methodological comments on active placebo groups (searches in PubMed, The Cochrane Library, Google Scholar, and HighWirePress). The prevalence of trials with active placebo groups published in 2013 was 1 out of 200 (95% confidence interval: 0-2), 0.5% (0-1%). We identified and characterized 89 randomized trials (published 1961-2014) using active placebos, for example, antihistamines, anticholinergic drugs, and sedatives. Such trials typically involved a crossover design, the experimental intervention had noticeable side effects, and the outcomes were patient-reported. The use of active placebos was clustered in specific research settings and did not appear to reflect consistently the side effect profile of the experimental intervention, for example, selective serotonin reuptake inhibitors were compared with active placebos in pain trials but not in depression trials. We identified and analyzed 25 methods publications with substantial comments. The main argument for active placebo was to reduce risk of unblinding; the main argument against was the risk of unintended therapeutic effect. Pharmacological active placebo control interventions are rarely used in randomized clinical trials, but they constitute a methodological tool which merits serious consideration. We suggest that active placebos are used more often in trials of drugs with noticeable side effects, especially in situations where the expected therapeutic effects are modest and the risk of bias due to unblinding is high. Copyright © 2017 Elsevier Inc. All rights reserved.

In Defense of the Randomized Controlled Trial for Health Promotion Research

PubMed Central

Rosen, Laura; Manor, Orly; Engelhard, Dan; Zucker, David

2006-01-01

The overwhelming evidence about the role lifestyle plays in mortality, morbidity, and quality of life has pushed the young field of modern health promotion to center stage. The field is beset with intense debate about appropriate evaluation methodologies. Increasingly, randomized designs are considered inappropriate for health promotion research. We have reviewed criticisms against randomized trials that raise philosophical and practical issues, and we will show how most of these criticisms can be overcome with minor design modifications. By providing rebuttal to arguments against randomized trials, our work contributes to building a sound methodological base for health promotion research. PMID:16735622

Sincere but naive: methodological queries concerning the British Columbia polygamy reference trial.

PubMed

Ashley, Sean Matthew

2014-11-01

Academics frequently serve as expert witnesses in legal cases, yet their role as transmitters of social scientific knowledge remains under-examined. The present study analyzes the deployment of social science within British Columbia's polygamy reference trial where research is used to support the assertion that polygamy is inherently harmful to society. Within the trial record and the written decision, the protection of monogamy as an institution is performed in part through the marginalization of qualitative methodology and the concurrent privileging of quantitative studies that purportedly demonstrate widespread social harms associated with the practice of polygyny.

Implementation Considerations for Multisite Clinical Trials with Cognitive Neuroscience Tasks

PubMed Central

Keefe, Richard S. E.; Harvey, Philip D.

2008-01-01

Multisite clinical trials aimed at cognitive enhancement across various neuropsychiatric conditions have employed standard neuropsychological tests as outcome measures. While these tests have enjoyed wide clinical use and have proven reliable and predictive of functional disability, a number of implementation challenges have arisen when these tests are used in clinical trials. These issues are likely to be magnified in future studies when cognitive neuroscience (CN) procedures are explored in these trials, because in their current forms CN procedures are less standardized and more difficult to teach and monitor. For multisite trials, we anticipate that the most challenging issues will include assuring tester competence, monitoring tester performance, specific challenges with complex assessment methods, and having resources available for adequate monitoring of data quality. Suggestions for overcoming these implementation challenges are offered. PMID:18495645

Estimating Health-State Utility for Economic Models in Clinical Studies: An ISPOR Good Research Practices Task Force Report.

PubMed

Wolowacz, Sorrel E; Briggs, Andrew; Belozeroff, Vasily; Clarke, Philip; Doward, Lynda; Goeree, Ron; Lloyd, Andrew; Norman, Richard

Cost-utility models are increasingly used in many countries to establish whether the cost of a new intervention can be justified in terms of health benefits. Health-state utility (HSU) estimates (the preference for a given state of health on a cardinal scale where 0 represents dead and 1 represents full health) are typically among the most important and uncertain data inputs in cost-utility models. Clinical trials represent an important opportunity for the collection of health-utility data. However, trials designed primarily to evaluate efficacy and safety often present challenges to the optimal collection of HSU estimates for economic models. Careful planning is needed to determine which of the HSU estimates may be measured in planned trials; to establish the optimal methodology; and to plan any additional studies needed. This report aimed to provide a framework for researchers to plan the collection of health-utility data in clinical studies to provide high-quality HSU estimates for economic modeling. Recommendations are made for early planning of health-utility data collection within a research and development program; design of health-utility data collection during protocol development for a planned clinical trial; design of prospective and cross-sectional observational studies and alternative study types; and statistical analyses and reporting. Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Health technology assessment of public health interventions: an analysis of characteristics and comparison of methods-study protocol.

PubMed

Mathes, Tim; Willms, Gerald; Polus, Stephanie; Stegbauer, Constance; Messer, Melanie; Klingler, Corinna; Ehrenreich, Heidi; Niebuhr, Dea; Marckmann, Georg; Gerhardus, Ansgar; Pieper, Dawid

2018-05-23

Conducting a health technology assessment (HTA) of public health interventions (PHIs) poses some challenges. PHIs are often complex interventions, which affect the number and degree of interactions of the aspects to be assessed. Randomized controlled trials on PHIs are rare as they are difficult to conduct because of ethical or feasibility issues. The aim of this study is to provide an overview of the methodological characteristics and to compare the applied assessment methods in HTAs on PHIs. We will systematically search HTA agencies for HTAs on PHIs published between 2012 and 2016. We will identify the HTAs by screening the webpages of members of international HTA organizations. One reviewer will screen the list of HTAs on the webpages of members of international HTA organization, and a second review will double-check the excluded records. For this methodological review, we define a PHI as a population-based intervention on health promotion or for primary prevention of chronic or non-chronic diseases. Only full HTA reports will be included. At maximum, we will include a sample of 100 HTAs. In the case that we identify more than 100 relevant HTAs, we will perform a random selection. We will extract data on effectiveness, safety and economic as well as on social, cultural, ethical and legal aspects in a priori piloted standardized tables. We will not assess the risk of bias as we focus on exploring methodological features. Data extraction will be performed by one reviewer and verified by a second. We will synthesize data using tables and in a structured narrative way. Our analysis will provide a comprehensive and current overview of methods applied in HTAs on PHIs. We will discuss approaches that may be promising to overcome the challenges of evaluating PHIs.

Modified versus standard intention-to-treat reporting: are there differences in methodological quality, sponsorship, and findings in randomized trials? A cross-sectional study.

PubMed

Montedori, Alessandro; Bonacini, Maria Isabella; Casazza, Giovanni; Luchetta, Maria Laura; Duca, Piergiorgio; Cozzolino, Francesco; Abraha, Iosief

2011-02-28

Randomized controlled trials (RCTs) that use the modified intention-to-treat (mITT) approach are increasingly being published. Such trials have a preponderance of post-randomization exclusions, industry sponsorship, and favourable findings, and little is known whether in terms of these items mITT trials are different with respect to trials that report a standard intention-to-treat. To determine differences in the methodological quality, sponsorship, authors' conflicts of interest, and findings among trials with different "types" of intention-to-treat, we undertook a cross-sectional study of RCTs published in 2006 in three general medical journals (the Journal of the American Medical Association, the New England Journal of Medicine and the Lancet) and three specialty journals (Antimicrobial Agents and Chemotherapy, the American Heart Journal and the Journal of Clinical Oncology). Trials were categorized based on the "type" of intention-to-treat reporting as follows: ITT, trials reporting the use of standard ITT approach; mITT, trials reporting the use of a "modified intention-to-treat" approach; and "no ITT", trials not reporting the use of any intention-to-treat approach. Two pairs of reviewers independently extracted the data in duplicate. The strength of the associations between the "type" of intention-to-treat reporting and the quality of reporting (sample size calculation, flow-chart, lost to follow-up), the methodological quality of the trials (sequence generation, allocation concealment, and blinding), the funding source, and the findings was determined. Odds ratios (OR) were calculated with 95% confidence intervals (CI). Of the 367 RCTs included, 197 were classified as ITT, 56 as mITT, and 114 as "no ITT" trials. The quality of reporting and the methodological quality of the mITT trials were similar to those of the ITT trials; however, the mITT trials were more likely to report post-randomization exclusions (adjusted OR 3.43 [95%CI, 1.70 to 6.95]; P < 0.001). We found a strong association between trials classified as mITT and for-profit agency sponsorship (adjusted OR 7.41 [95%CI, 3.14 to 17.48]; P < .001) as well as the presence of authors' conflicts of interest (adjusted OR 5.14 [95%CI, 2.12 to 12.48]; P < .001). There was no association between mITT reporting and favourable results; in general, however, trials with for-profit agency sponsorship were significantly associated with favourable results (adjusted OR 2.30; [95%CI, 1.28 to 4.16]; P = 0.006). We found that the mITT trials were significantly more likely to perform post-randomization exclusions and were strongly associated with industry funding and authors' conflicts of interest.

A methodology for assessing the effect of correlations among muscle synergy activations on task-discriminating information.

PubMed

Delis, Ioannis; Berret, Bastien; Pozzo, Thierry; Panzeri, Stefano

2013-01-01

Muscle synergies have been hypothesized to be the building blocks used by the central nervous system to generate movement. According to this hypothesis, the accomplishment of various motor tasks relies on the ability of the motor system to recruit a small set of synergies on a single-trial basis and combine them in a task-dependent manner. It is conceivable that this requires a fine tuning of the trial-to-trial relationships between the synergy activations. Here we develop an analytical methodology to address the nature and functional role of trial-to-trial correlations between synergy activations, which is designed to help to better understand how these correlations may contribute to generating appropriate motor behavior. The algorithm we propose first divides correlations between muscle synergies into types (noise correlations, quantifying the trial-to-trial covariations of synergy activations at fixed task, and signal correlations, quantifying the similarity of task tuning of the trial-averaged activation coefficients of different synergies), and then uses single-trial methods (task-decoding and information theory) to quantify their overall effect on the task-discriminating information carried by muscle synergy activations. We apply the method to both synchronous and time-varying synergies and exemplify it on electromyographic data recorded during performance of reaching movements in different directions. Our method reveals the robust presence of information-enhancing patterns of signal and noise correlations among pairs of synchronous synergies, and shows that they enhance by 9-15% (depending on the set of tasks) the task-discriminating information provided by the synergy decompositions. We suggest that the proposed methodology could be useful for assessing whether single-trial activations of one synergy depend on activations of other synergies and quantifying the effect of such dependences on the task-to-task differences in muscle activation patterns.

Effectiveness of physical therapy interventions for children with cerebral palsy: A systematic review

PubMed Central

Anttila, Heidi; Autti-Rämö, Ilona; Suoranta, Jutta; Mäkelä, Marjukka; Malmivaara, Antti

2008-01-01

Background To assess the effectiveness of physical therapy (PT) interventions on functioning in children with cerebral palsy (CP). Methods A search was made in Medline, Cinahl, PEDro and the Cochrane library for the period 1990 to February 2007. Only randomized controlled trials (RCTs) on PT interventions in children with diagnosed CP were included. Two reviewers independently assessed the methodological quality and extracted the data. The outcomes measured in the trials were classified using the International Classification of Functioning, Disability and Health (ICF). Results Twenty-two trials were identified. Eight intervention categories were distinguished. Four trials were of high methodological quality. Moderate evidence of effectiveness was established for two intervention categories: effectiveness of upper extremity treatments on attained goals and active supination, and of prehensile hand treatment and neurodevelopmental therapy (NDT) or NDT twice a week on developmental status, and of constraint-induced therapy on amount and quality of hand use. Moderate evidence of ineffectiveness was found of strength training on walking speed and stride length. Conflicting evidence was found for strength training on gross motor function. For the other intervention categories the evidence was limited due to low methodological quality and the statistically insignificant results of the studies. Conclusion Due to limitations in methodological quality and variations in population, interventions and outcomes, mostly limited evidence on the effectiveness of most PT interventions is available through RCTs. Moderate evidence was found for some effectiveness of upper extremity training. Well-designed trials are needed especially for focused PT interventions. PMID:18435840

Challenges in recruitment and retention of clinical trial subjects.

PubMed

Kadam, Rashmi Ashish; Borde, Sanghratna Umakant; Madas, Sapna Amol; Salvi, Sundeep Santosh; Limaye, Sneha Saurabh

2016-01-01

Successful recruitment of patients is known to be one of the most challenging aspects in conduct of randomized controlled trials. Inadequate patient retention during conduct of trial affects conclusive results. To assess the level of challenges faced by Indian investigators in recruitment and retention of trial subjects. We developed a survey questionnaire on challenges encountered by investigators in subject recruitment and retention which was hosted on a web portal. Seventy-three investigators from India participated in the survey. The frequently encountered challenges in subject recruitment were complexity of study protocol (38%), lack of awareness about clinical trials in patients (37%), and sociocultural issues related to trial participation (37%). About 63% of participants strongly agreed that creating a positive awareness about clinical trials among people through press and media, having a dedicated clinical research coordinator for trial (50.7%), and designing a recruitment strategy prior to study initiation (46.6%) would enhance recruitment. Almost 50.7% of participants agreed that interacting with medical community in vicinity of the study site and educating patients about clinical trials during routine outpatient department visits (46.6%) would enhance recruitment. Experiencing a serious adverse event, subject's fear for study procedures (47%) and side effects (44%) were thought to have a moderate effect on subject retention. Our survey has put forth factors related to negative publicity by media, lack of patient education about clinical trials; complex study designs are barriers to clinical trial recruitment in India. It is essential to devise innovative and effective strategies focusing on education of public and mass media about clinical research in India.

Economic Evaluation of Adolescent Addiction Programs: Methodological Challenges and Recommendations

PubMed Central

Homer, Jenny F.; Drummond, Michael F.; French, Michael T.

2008-01-01

This paper identifies and describes several methodological challenges encountered in economic evaluations of substance abuse interventions for adolescents. Topics include study design, the choice of perspective, the estimation of costs and outcomes, and the generalizability of results. Recommendations are offered for confronting these challenges using examples from adolescent addiction research. PMID:19027640

Troubling the Boundaries: Overcoming Methodological Challenges in a Multi-Sectoral and Multi-Jurisdictional HIV/HCV Policy Scoping Review

ERIC Educational Resources Information Center

Hare, Kathleen A.; Dubé, Anik; Marshall, Zack; Gahagan, Jacqueline; Harris, Gregory E.; Tucker, Maryanne; Dykeman, Margaret; MacDonald, Jo-Ann

2016-01-01

Policy scoping reviews are an effective method for generating evidence-informed policies. However, when applying guiding methodological frameworks to complex policy evidence, numerous, unexpected challenges can emerge. This paper details five challenges experienced and addressed by a policy trainee-led, multi-disciplinary research team, while…

Observational studies of the association between glucose-lowering medications and cardiovascular outcomes: addressing methodological limitations.

PubMed

Patorno, Elisabetta; Patrick, Amanda R; Garry, Elizabeth M; Schneeweiss, Sebastian; Gillet, Victoria G; Bartels, Dorothee B; Masso-Gonzalez, Elvira; Seeger, John D

2014-11-01

Recent years have witnessed a growing body of observational literature on the association between glucose-lowering treatments and cardiovascular disease. However, many of the studies are based on designs or analyses that inadequately address the methodological challenges involved. We reviewed recent observational literature on the association between glucose-lowering medications and cardiovascular outcomes and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We describe and illustrate these methodological issues and their impact on observed associations, providing examples from the reviewed literature. We suggest approaches that may be employed to manage these methodological challenges. From the evaluation of 81 publications of observational investigations assessing the association between glucose-lowering treatments and cardiovascular outcomes, we identified the following methodological challenges: 1) handling of temporality in administrative databases; 2) handling of risks that vary with time and treatment duration; 3) definitions of the exposure risk window; 4) handling of exposures that change over time; and 5) handling of confounding by indication. Most of these methodological challenges may be suitably addressed through application of appropriate methods. Observational research plays an increasingly important role in the evaluation of the clinical effects of diabetes treatment. Implementation of appropriate research methods holds the promise of reducing the potential for spurious findings and the risk that the spurious findings will mislead the medical community about risks and benefits of diabetes medications.

76 FR 22404 - Analgesic Clinical Trials Innovation, Opportunities, and Networks (ACTION) Initiative

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-21

..., but not limited to, specific research designs and methodological features so as to inform the future... clinical trials. Many experts in analgesic drug development believe that it is the design of the clinical trials that is at fault in this situation and that better trial designs will yield more successful...

Establishment of Requirements and Methodology for the Development and Implementation of GreyMatters, a Memory Clinic Information System.

PubMed

Tapuria, Archana; Evans, Matt; Curcin, Vasa; Austin, Tony; Lea, Nathan; Kalra, Dipak

2017-01-01

The aim of the paper is to establish the requirements and methodology for the development process of GreyMatters, a memory clinic system, outlining the conceptual, practical, technical and ethical challenges, and the experiences of capturing clinical and research oriented data along with the implementation of the system. The methodology for development of the information system involved phases of requirements gathering, modeling and prototype creation, and 'bench testing' the prototype with experts. The standard Institute of Electrical and Electronics Engineers (IEEE) recommended approach for the specifications of software requirements was adopted. An electronic health record (EHR) standard, EN13606 was used, and clinical modelling was done through archetypes and the project complied with data protection and privacy legislation. The requirements for GreyMatters were established. Though the initial development was complex, the requirements, methodology and standards adopted made the construction, deployment, adoption and population of a memory clinic and research database feasible. The electronic patient data including the assessment scales provides a rich source of objective data for audits and research and to establish study feasibility and identify potential participants for the clinical trials. The establishment of requirements and methodology, addressing issues of data security and confidentiality, future data compatibility and interoperability and medico-legal aspects such as access controls and audit trails, led to a robust and useful system. The evaluation supports that the system is an acceptable tool for clinical, administrative, and research use and forms a useful part of the wider information architecture.

mHealth in psychiatry: time for methodological change.

PubMed

Nicholas, Jennifer; Boydell, Katherine; Christensen, Helen

2016-05-01

A multitude of mental health apps are available to consumers through the Apple and Google app stores. However, evidence supporting the effectiveness of mHealth is scant. We argue this gap between app availability and research evidence is primarily due to unsuitable knowledge translation practices and therefore suggest abandoning the randomised controlled trial as the primary app evaluation paradigm. Alternative evaluation methodologies such as iterative participatory research and single case designs are better aligned with mHealth translational needs. A further challenge to the use of mobile technology in mental health is the dissemination of information about app quality to consumers. Strategies to facilitate successful dissemination of quality resources must consider several factors, such as target audience and context. In practice, structured solutions to inform consumers of evidence-informed apps could range from the development of consumer used tools to app accreditation portals. Consumer enthusiasm for apps represents an opportunity to increase access and support for psychiatric populations. However, adoption of alternative research methodologies and the development of dissemination strategies are vital before this opportunity can be substantially seized. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

School-Based Methylphenidate Placebo Protocols: Methodological and Practical Issues.

ERIC Educational Resources Information Center

Hyman, Irwin A.; Wojtowicz, Alexandra; Lee, Kee Duk; Haffner, Mary Elizabeth; Fiorello, Catherine A.; And Others

1998-01-01

Focuses on methodological issues involved in choosing instruments to monitor behavior, once a comprehensive evaluation has suggested trials on Ritalin. Case examples illustrate problems of teacher compliance in filling out measures, supplying adequate placebos, and obtaining physical cooperation. Emerging school-based methodologies are discussed…

Efficacy and safety of Suanzaoren decoction for primary insomnia: a systematic review of randomized controlled trials

PubMed Central

2013-01-01

Background Insomnia is a widespread human health problem, but there currently are the limitations of conventional therapies available. Suanzaoren decoction (SZRD) is a well known classic Chinese herbal prescription for insomnia and has been treating people’s insomnia for more than thousand years. The objective of this study was to evaluate the efficacy and safety of SZRD for insomnia. Methods A systematic literature search was performed for 6 databases up to July of 2012 to identify randomized control trials (RCTs) involving SZRD for insomniac patients. The methodological quality of RCTs was assessed independently using the Cochrane Handbook for Systematic Reviews of Interventions. Results Twelve RCTs with total of 1376 adult participants were identified. The methodological quality of all included trials are no more than 3/8 score. Majority of the RCTs concluded that SZRD was more significantly effective than benzodiazepines for treating insomnia. Despite these positive outcomes, there were many methodological shortcomings in the studies reviewed, including insufficient information about randomization generation and absence of allocation concealment, lack of blinding and no placebo control, absence of intention-to-treat analysis and lack of follow-ups, selective publishing and reporting, and small number of sample sizes. A number of clinical heterogeneity such as diagnosis, intervention, control, and outcome measures were also reviewed. Only 3 trials reported adverse events, whereas the other 9 trials did not provide the safety information. Conclusions Despite the apparent reported positive findings, there is insufficient evidence to support efficacy of SZRD for insomnia due to the poor methodological quality and the small number of trials of the included studies. SZRD seems generally safe, but is insufficient evidence to make conclusions on the safety because fewer studies reported the adverse events. Further large sample-size and well-designed RCTs are needed. PMID:23336848

Mechanistic and Technical Challenges in Studying the Human Microbiome and Cancer Epidemiology.

PubMed

Verma, Mukesh

2017-04-01

This article reviews the significance of the microbiome in cancer epidemiology, mechanistic and technical challenges in the field, and characterization of the microbiome in different tumor types to identify biomarkers of risk, progression, and prognosis. Publications on the microbiome and cancer epidemiology were reviewed to analyze sample collection and processing, microbiome taxa characterization by 16S ribosomal RNA sequencing, and microbiome metabolite characterization (metabotyping) by nuclear magnetic resonance and mass spectrometry. The analysis identified methodology types, research design, sample types, and issues in integrating data from different platforms. Aerodigestive cancer epidemiology studies conducted by different groups demonstrated the significance of microbiome information in developing approaches to improve health. Challenges exist in sample preparation and processing (eg, standardization of methods for collection and analysis). These challenges relate to technology, data integration from "omics" studies, inherent bias in primer selection during 16S ribosomal RNA sequencing, the need for large consortia with well-characterized biospecimens, cause and effect issues, resilience of microbiota to exposure events (requires longitudinal studies), and expanding studies for fungal and viral diversity (most studies used bacterial 16S ribosomal RNA sequencing for microbiota characterization). Despite these challenges, microbiome and cancer epidemiology studies are significant and may facilitate cancer risk assessment, diagnosis, and prognosis. In the future, clinical trials likely will use microbiota modifications to improve the efficacy of existing treatments.

Mechanistic and Technical Challenges in Studying the Human Microbiome and Cancer Epidemiology

PubMed Central

2016-01-01

This article reviews the significance of the microbiome in cancer epidemiology, mechanistic and technical challenges in the field, and characterization of the microbiome in different tumor types to identify biomarkers of risk, progression, and prognosis. Publications on the microbiome and cancer epidemiology were reviewed to analyze sample collection and processing, microbiome taxa characterization by 16S ribosomal RNA sequencing, and microbiome metabolite characterization (metabotyping) by nuclear magnetic resonance and mass spectrometry. The analysis identified methodology types, research design, sample types, and issues in integrating data from different platforms. Aerodigestive cancer epidemiology studies conducted by different groups demonstrated the significance of microbiome information in developing approaches to improve health. Challenges exist in sample preparation and processing (eg, standardization of methods for collection and analysis). These challenges relate to technology, data integration from “omics” studies, inherent bias in primer selection during 16S ribosomal RNA sequencing, the need for large consortia with well-characterized biospecimens, cause and effect issues, resilience of microbiota to exposure events (requires longitudinal studies), and expanding studies for fungal and viral diversity (most studies used bacterial 16S ribosomal RNA sequencing for microbiota characterization). Despite these challenges, microbiome and cancer epidemiology studies are significant and may facilitate cancer risk assessment, diagnosis, and prognosis. In the future, clinical trials likely will use microbiota modifications to improve the efficacy of existing treatments. PMID:27121074

Can we improve the performance and reporting of investigator-initiated clinical trials? Rheumatoid arthritis as an example.

PubMed

Landewé, Robert B M; Smolen, Josef S; Weinblatt, Michael E; Emery, Paul; Dougados, Maxime; Fleischmann, Roy; Aletaha, Daniel; Kavanaugh, Arthur; van der Heijde, Désirée

2014-10-01

Investigator-initiated trials, some of which have been referred to as comparative effectiveness trials, pragmatic trials, or strategy trials, are sometimes considered to be of greater clinical importance than industry-driven trials, because they address important but unresolved clinical questions that differ from the questions asked in industry-driven trials. Regulatory authorities have provided methodological guidance for industry-driven trials for the approval of new treatments, but such guidance is less clear for investigator-initiated trials. The European League Against Rheumatism (EULAR) task force for the update of the recommendations for the management of rheumatoid arthritis has critically looked at the methodological quality and conduct of many investigator-initiated trials, and has identified a number of concerns. In this Viewpoint paper, we highlight commonly encountered issues that are discussed using examples of well-known investigator-initiated trials. These issues cover three themes: (1) design choice (superiority vs non-inferiority designs); (2) statistical power and (3) convenience reporting. Since we acknowledge the importance of investigator-initiated research, we also propose a shortlist of points-to-consider when designing, performing and reporting investigator-initiated trials. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Commentary: considerations for using the 'Trials within Cohorts' design in a clinical trial of an investigational medicinal product.

PubMed

Bibby, Anna C; Torgerson, David J; Leach, Samantha; Lewis-White, Helen; Maskell, Nick A

2018-01-08

The 'trials within cohorts' (TwiC) design is a pragmatic approach to randomised trials in which trial participants are randomly selected from an existing cohort. The design has multiple potential benefits, including the option of conducting multiple trials within the same cohort. To date, the TwiC design methodology been used in numerous clinical settings but has never been applied to a clinical trial of an investigational medicinal product (CTIMP). We have recently secured the necessary approvals to undertake the first CTIMP using the TwiC design. In this paper, we describe some of the considerations and modifications required to ensure such a trial is compliant with Good Clinical Practice and international clinical trials regulations. We advocate using a two-stage consent process and using the consent stages to explicitly differentiate between trial participants and cohort participants who are providing control data. This distinction ensured compliance but had consequences with respect to costings, recruitment and the trial assessment schedule. We have demonstrated that it is possible to secure ethical and regulatory approval for a CTIMP TwiC. By including certain considerations at the trial design stage, we believe this pragmatic and efficient methodology could be utilised in other CTIMPs in future.

Recent advances in treating Parkinson’s disease

PubMed Central

Oertel, Wolfgang H.

2017-01-01

This article summarizes (1) the recent achievements to further improve symptomatic therapy of motor Parkinson’s disease (PD) symptoms, (2) the still-few attempts to systematically search for symptomatic therapy of non-motor symptoms in PD, and (3) the advances in the development and clinical testing of compounds which promise to offer disease modification in already-manifest PD. However, prevention (that is, slowing or stopping PD in a prodromal stage) is still a dream and one reason for this is that we have no consensus on primary endpoints for clinical trials which reflect the progression in prodromal stages of PD, such as in rapid eye movement sleep behavior disorder (RBD) —a methodological challenge to be met in the future. PMID:28357055

Mindfulness Interventions.

PubMed

Creswell, J David

2017-01-03

Mindfulness interventions aim to foster greater attention to and awareness of present moment experience. There has been a dramatic increase in randomized controlled trials (RCTs) of mindfulness interventions over the past two decades. This article evaluates the growing evidence of mindfulness intervention RCTs by reviewing and discussing (a) the effects of mindfulness interventions on health, cognitive, affective, and interpersonal outcomes; (b) evidence-based applications of mindfulness interventions to new settings and populations (e.g., the workplace, military, schools); (c) psychological and neurobiological mechanisms of mindfulness interventions; (d) mindfulness intervention dosing considerations; and (e) potential risks of mindfulness interventions. Methodologically rigorous RCTs have demonstrated that mindfulness interventions improve outcomes in multiple domains (e.g., chronic pain, depression relapse, addiction). Discussion focuses on opportunities and challenges for mindfulness intervention research and on community applications.

Reimbursement challenges with cancer immunotherapeutics

PubMed Central

Kudrin, Alex

2012-01-01

Today the task of cancer vaccine developers is not only to excel in cancer immunology and art of conducting immunotherapy trials but also in the analysis and forecasting the cost-effectiveness of the final product. This article reviews methodology used by EU health-technology bodies in the appraisal of new therapies based on economic and clinical values and different budgetary uncertainties. Increasingly, new oncology treatments were able to access EU market only under provision of risk-sharing agreements with payers and examples of such agreements are given here. Cancer vaccine developers should consider early collection of patient reported outcomes in order to project additional clinical and economic value with immunotherapy. Furthermore, early interaction with different stakeholders including patient organizations, physicians and payer bodies can facilitate market access. PMID:22894969

Challenges in conducting a community-based influenza vaccine trial in a rural community in northern India.

PubMed

Kumar, Rakesh; Amarchand, Ritvik; Narayan, Venkatesh Vinayak; Saha, Siddhartha; Lafond, Kathryn E; Kapoor, Suresh K; Dar, Lalit; Jain, Seema; Krishnan, Anand

2018-04-04

Evidence on influenza vaccine effectiveness from low and middle countries (LMICs) is limited due to limited institutional capacities; lack of adequate resources; and lack of interest by ministries of health for influenza vaccine introduction. There are concerns that the highest ethical standards will be compromised during trials in LMICs leading to mistrust of clinical trials. These factors pose regulatory and operational challenges to researchers in these countries. We conducted a community-based vaccine trial to assess the efficacy of live attenuated influenza vaccine and inactivated influenza vaccine in rural north India. Key regulatory challenges included obtaining regulatory approvals, reporting of adverse events, and compensating subjects for trial-related injuries; all of which were required to be completed in a timely fashion. Key operational challenges included obtaining audio-visual consent; maintaining a low attrition rate; and administering vaccines during a narrow time period before the influenza season, and under extreme heat. We overcame these challenges through advanced planning, and sustaining community engagement. We adapted the trial procedures to cope with field conditions by conducting mock vaccine camps; and planned for early morning vaccination to mitigate threats to the cold chain. These lessons may help investigators to confront similar challenges in other LMICs.

Mobile Phone Apps for Preventing Cancer Through Educational and Behavioral Interventions: State of the Art and Remaining Challenges.

PubMed

Coughlin, Steven; Thind, Herpreet; Liu, Benyuan; Champagne, Nicole; Jacobs, Molly; Massey, Rachael I

2016-05-30

Rapid developments in technology have encouraged the use of mobile phones in smoking cessation, promoting healthy diet, nutrition, and physical activity, sun safety, and cancer screening. Although many apps relating to the prevention of cancer and other chronic diseases are available from major mobile phone platforms, relatively few have been tested in research studies to determine their efficacy. In this paper, we discuss issues related to the development and testing of new apps for preventing cancer through smoking cessation, sun safety, and other healthy behaviors, including key methodologic issues and outstanding challenges. An exploratory literature review was conducted using bibliographic searches in PubMed and CINAHL with relevant search terms (eg, smartphones, smoking cessation, cancer prevention, cancer screening, and carcinogens) to identify papers published in English through October 2015. Only 4 randomized controlled trials of the use of mobile phone apps for smoking cessation and 2 trials of apps for sun safety were identified, indicating that it is premature to conduct a systematic search and meta-analysis of the published literature on this topic. Future studies should utilize randomized controlled trial research designs, larger sample sizes, and longer study periods to better establish the cancer prevention and control capabilities of mobile phone apps. In developing new and refined apps for cancer prevention and control, both health literacy and eHealth literacy should be taken into account. There is a need for culturally appropriate, tailored health messages to increase knowledge and awareness of health behaviors such as smoking cessation, cancer screening, and sun safety. Mobile phone apps are likely to be a useful and low-cost intervention for preventing cancer through behavioral changes.

Mobile Phone Apps for Preventing Cancer Through Educational and Behavioral Interventions: State of the Art and Remaining Challenges

PubMed Central

Champagne, Nicole; Jacobs, Molly; Massey, Rachael I

2016-01-01

Background Rapid developments in technology have encouraged the use of mobile phones in smoking cessation, promoting healthy diet, nutrition, and physical activity, sun safety, and cancer screening. Although many apps relating to the prevention of cancer and other chronic diseases are available from major mobile phone platforms, relatively few have been tested in research studies to determine their efficacy. Objective In this paper, we discuss issues related to the development and testing of new apps for preventing cancer through smoking cessation, sun safety, and other healthy behaviors, including key methodologic issues and outstanding challenges. Methods An exploratory literature review was conducted using bibliographic searches in PubMed and CINAHL with relevant search terms (eg, smartphones, smoking cessation, cancer prevention, cancer screening, and carcinogens) to identify papers published in English through October 2015. Results Only 4 randomized controlled trials of the use of mobile phone apps for smoking cessation and 2 trials of apps for sun safety were identified, indicating that it is premature to conduct a systematic search and meta-analysis of the published literature on this topic. Conclusions Future studies should utilize randomized controlled trial research designs, larger sample sizes, and longer study periods to better establish the cancer prevention and control capabilities of mobile phone apps. In developing new and refined apps for cancer prevention and control, both health literacy and eHealth literacy should be taken into account. There is a need for culturally appropriate, tailored health messages to increase knowledge and awareness of health behaviors such as smoking cessation, cancer screening, and sun safety. Mobile phone apps are likely to be a useful and low-cost intervention for preventing cancer through behavioral changes. PMID:27242162

CONSIDER - Core Outcome Set in IAD Research: study protocol for establishing a core set of outcomes and measurements in incontinence-associated dermatitis research.

PubMed

Van den Bussche, Karen; De Meyer, Dorien; Van Damme, Nele; Kottner, Jan; Beeckman, Dimitri

2017-10-01

This study protocol describes the methodology for the development of a core set of outcomes and a core set of measurements for incontinence-associated dermatitis. Incontinence is a widespread disorder with an important impact on quality of life. One of the most common complications is incontinence-associated dermatitis, resulting from chemical and physical irritation of the skin barrier, triggering inflammation and skin damage. Managing incontinence-associated dermatitis is an important challenge for nurses. Several interventions have been assessed in clinical trials, but heterogeneity in study outcomes complicates the comparability and standardization. To overcome this challenge, the development of a core outcome set, a minimum set of outcomes and measurements to be assessed in clinical research, is needed. A project team, International Steering Committee and panelists will be involved to guide the development of the core outcome set. The framework of the Harmonizing Outcomes Measures for Eczema roadmap endorsed by Cochrane Skin Group Core Outcomes Set Initiative, is used to inform the project design. A systematic literature review, interviews to integrate the patients' perspective and a consensus study with healthcare researchers and providers using the Delphi procedure will be performed. The project was approved by the Ethics review Committee (April 2016). This is the first project that will identify a core outcome set of outcomes and measurements for incontinence-associated dermatitis research. A core outcome set will reduce possible reporting bias, allow results comparisons and statistical pooling across trials and strengthen evidence-based practice and decision-making. This project has been registered in the Core Outcome Measures in Effectiveness Trials (COMET) database and is part of the Cochrane Skin Group Core Outcomes Set Initiative (CSG-COUSIN). © 2016 John Wiley & Sons Ltd.

Methodological Quality of Randomized Clinical Trials of Respiratory Physiotherapy in Coronary Artery Bypass Grafting Patients in the Intensive Care Unit: a Systematic Review

PubMed Central

Lorscheitter, Jaqueline; Stein, Cinara; Plentz, Rodrigo Della Méa

2017-01-01

Objective To assess methodological quality of the randomized controlled trials of physiotherapy in patients undergoing coronary artery bypass grafting in the intensive care unit. Methods The studies published until May 2015, in MEDLINE, Cochrane and PEDro were included. The primary outcome extracted was proper filling of the Cochrane Collaboration's tool's items and the secondary was suitability to the requirements of the CONSORT Statement and its extension. Results From 807 studies identified, 39 were included. Most at CONSORT items showed a better adequacy after the statement's publication. Studies with positive outcomes presented better methodological quality. Conclusion The methodological quality of the studies has been improving over the years. However, many aspects can still be better designed. PMID:28977205

Speed-Accuracy Tradeoffs in Speech Production

DTIC Science & Technology

2017-06-01

imaging data of speech production. A theoretical framework for considering Fitts’ law in the domain of speech production is elucidated. Methodological ...articulatory kinematics conform to Fitts’ law. A second, associated goal is to address the methodological challenges inherent in performing Fitts-style...analysis on rtMRI data of speech production. Methodological challenges include segmenting continuous speech into specific motor tasks, defining key

Beyond the Randomized Controlled Trial: A Review of Alternatives in mHealth Clinical Trial Methods

PubMed Central

Wiljer, David; Cafazzo, Joseph A

2016-01-01

Background Randomized controlled trials (RCTs) have long been considered the primary research study design capable of eliciting causal relationships between health interventions and consequent outcomes. However, with a prolonged duration from recruitment to publication, high-cost trial implementation, and a rigid trial protocol, RCTs are perceived as an impractical evaluation methodology for most mHealth apps. Objective Given the recent development of alternative evaluation methodologies and tools to automate mHealth research, we sought to determine the breadth of these methods and the extent that they were being used in clinical trials. Methods We conducted a review of the ClinicalTrials.gov registry to identify and examine current clinical trials involving mHealth apps and retrieved relevant trials registered between November 2014 and November 2015. Results Of the 137 trials identified, 71 were found to meet inclusion criteria. The majority used a randomized controlled trial design (80%, 57/71). Study designs included 36 two-group pretest-posttest control group comparisons (51%, 36/71), 16 posttest-only control group comparisons (23%, 16/71), 7 one-group pretest-posttest designs (10%, 7/71), 2 one-shot case study designs (3%, 2/71), and 2 static-group comparisons (3%, 2/71). A total of 17 trials included a qualitative component to their methodology (24%, 17/71). Complete trial data collection required 20 months on average to complete (mean 21, SD 12). For trials with a total duration of 2 years or more (31%, 22/71), the average time from recruitment to complete data collection (mean 35 months, SD 10) was 2 years longer than the average time required to collect primary data (mean 11, SD 8). Trials had a moderate sample size of 112 participants. Two trials were conducted online (3%, 2/71) and 7 trials collected data continuously (10%, 7/68). Onsite study implementation was heavily favored (97%, 69/71). Trials with four data collection points had a longer study duration than trials with two data collection points: F4,56=3.2, P=.021, η2=0.18. Single-blinded trials had a longer data collection period compared to open trials: F2,58=3.8, P=.028, η2=0.12. Academic sponsorship was the most common form of trial funding (73%, 52/71). Trials with academic sponsorship had a longer study duration compared to industry sponsorship: F2,61=3.7, P=.030, η2=0.11. Combined, data collection frequency, study masking, sample size, and study sponsorship accounted for 32.6% of the variance in study duration: F4,55=6.6, P<.01, adjusted r2=.33. Only 7 trials had been completed at the time this retrospective review was conducted (10%, 7/71). Conclusions mHealth evaluation methodology has not deviated from common methods, despite the need for more relevant and timely evaluations. There is a need for clinical evaluation to keep pace with the level of innovation of mHealth if it is to have meaningful impact in informing payers, providers, policy makers, and patients. PMID:27613084

Beyond the Randomized Controlled Trial: A Review of Alternatives in mHealth Clinical Trial Methods.

PubMed

Pham, Quynh; Wiljer, David; Cafazzo, Joseph A

2016-09-09

Randomized controlled trials (RCTs) have long been considered the primary research study design capable of eliciting causal relationships between health interventions and consequent outcomes. However, with a prolonged duration from recruitment to publication, high-cost trial implementation, and a rigid trial protocol, RCTs are perceived as an impractical evaluation methodology for most mHealth apps. Given the recent development of alternative evaluation methodologies and tools to automate mHealth research, we sought to determine the breadth of these methods and the extent that they were being used in clinical trials. We conducted a review of the ClinicalTrials.gov registry to identify and examine current clinical trials involving mHealth apps and retrieved relevant trials registered between November 2014 and November 2015. Of the 137 trials identified, 71 were found to meet inclusion criteria. The majority used a randomized controlled trial design (80%, 57/71). Study designs included 36 two-group pretest-posttest control group comparisons (51%, 36/71), 16 posttest-only control group comparisons (23%, 16/71), 7 one-group pretest-posttest designs (10%, 7/71), 2 one-shot case study designs (3%, 2/71), and 2 static-group comparisons (3%, 2/71). A total of 17 trials included a qualitative component to their methodology (24%, 17/71). Complete trial data collection required 20 months on average to complete (mean 21, SD 12). For trials with a total duration of 2 years or more (31%, 22/71), the average time from recruitment to complete data collection (mean 35 months, SD 10) was 2 years longer than the average time required to collect primary data (mean 11, SD 8). Trials had a moderate sample size of 112 participants. Two trials were conducted online (3%, 2/71) and 7 trials collected data continuously (10%, 7/68). Onsite study implementation was heavily favored (97%, 69/71). Trials with four data collection points had a longer study duration than trials with two data collection points: F4,56=3.2, P=.021, η(2)=0.18. Single-blinded trials had a longer data collection period compared to open trials: F2,58=3.8, P=.028, η(2)=0.12. Academic sponsorship was the most common form of trial funding (73%, 52/71). Trials with academic sponsorship had a longer study duration compared to industry sponsorship: F2,61=3.7, P=.030, η(2)=0.11. Combined, data collection frequency, study masking, sample size, and study sponsorship accounted for 32.6% of the variance in study duration: F4,55=6.6, P<.01, adjusted r(2)=.33. Only 7 trials had been completed at the time this retrospective review was conducted (10%, 7/71). mHealth evaluation methodology has not deviated from common methods, despite the need for more relevant and timely evaluations. There is a need for clinical evaluation to keep pace with the level of innovation of mHealth if it is to have meaningful impact in informing payers, providers, policy makers, and patients.

The reduction of intoxication and disorder in premises licensed to serve alcohol: An exploratory randomised controlled trial

PubMed Central

2010-01-01

Background Licensed premises offer a valuable point of intervention to reduce alcohol-related harm. Objective To describe the research design for an exploratory trial examining the feasibility and acceptability of a premises-level intervention designed to reduce severe intoxication and related disorder. The study also aims to assess the feasibility of a potential future large scale effectiveness trial and provide information on key trial design parameters including inclusion criteria, premises recruitment methods, strategies to implement the intervention and trial design, outcome measures, data collection methods and intra-cluster correlations. Design A randomised controlled trial in licensed premises that had experienced at least one assault in the year preceding the intervention, documented in police or hospital Emergency Department (ED) records. Premises were recruited from four study areas by piloting four recruitment strategies of varying intensity. Thirty two licensed premises were grouped into matched pairs to reduce potential bias and randomly allocated to the control or intervention condition. The study included a nested process evaluation to provide information on intervention acceptability and implementation. Outcome measures included police-recorded violent incidents, assault-related attendances at each premises' local ED and patron Breath Alcohol Concentration assessed on exiting and entering study premises. Results The most successful recruitment method involved local police licensing officers and yielded a 100% success rate. Police-records of violence provided the most appropriate source of data about disorder at the premises level. Conclusion The methodology of an exploratory trial is presented and despite challenges presented by the study environment it is argued an exploratory trial is warranted. Initial investigations in recruitment methods suggest that study premises should be recruited with the assistance of police officers. Police data were of sufficient quality to identify disorder and street surveys are a feasible method for measuring intoxication at the individual level. Trial registration UKCRN 7090; ISRCTN: 80875696 Funding Medical Research Council (G0701758) to Simon Moore, Simon Murphy, Laurence Moore and Jonathan Shepherd PMID:20946634

Quantifying Variation in Gait Features from Wearable Inertial Sensors Using Mixed Effects Models

PubMed Central

Cresswell, Kellen Garrison; Shin, Yongyun; Chen, Shanshan

2017-01-01

The emerging technology of wearable inertial sensors has shown its advantages in collecting continuous longitudinal gait data outside laboratories. This freedom also presents challenges in collecting high-fidelity gait data. In the free-living environment, without constant supervision from researchers, sensor-based gait features are susceptible to variation from confounding factors such as gait speed and mounting uncertainty, which are challenging to control or estimate. This paper is one of the first attempts in the field to tackle such challenges using statistical modeling. By accepting the uncertainties and variation associated with wearable sensor-based gait data, we shift our efforts from detecting and correcting those variations to modeling them statistically. From gait data collected on one healthy, non-elderly subject during 48 full-factorial trials, we identified four major sources of variation, and quantified their impact on one gait outcome—range per cycle—using a random effects model and a fixed effects model. The methodology developed in this paper lays the groundwork for a statistical framework to account for sources of variation in wearable gait data, thus facilitating informative statistical inference for free-living gait analysis. PMID:28245602

Decision making about healthcare-related tests and diagnostic test strategies. Paper 2: a review of methodological and practical challenges.

PubMed

Mustafa, Reem A; Wiercioch, Wojtek; Cheung, Adrienne; Prediger, Barbara; Brozek, Jan; Bossuyt, Patrick; Garg, Amit X; Lelgemann, Monika; Büehler, Diedrich; Schünemann, Holger J

2017-12-01

In this first of a series of five articles, we provide an overview of how and why healthcare-related tests and diagnostic strategies are currently applied. We also describe how our findings can be integrated with existing frameworks for making decisions that guide the use of healthcare-related tests and diagnostic strategies. We searched MEDLINE, references of identified articles, chapters in relevant textbooks, and identified articles citing classic literature on this topic. We provide updated frameworks for the potential roles and applications of tests with suggested definitions and practical examples. We also discuss study designs that are commonly used to assess tests' performance and the effects of tests on people's health. These designs include diagnostic randomized controlled trials and retrospective validation. We describe the utility of these and other currently suggested designs, which questions they can answer and which ones they cannot. In addition, we summarize the challenges unique to decision-making resulting from the use of tests. This overview highlights current challenges in the application of tests in decision-making in healthcare, provides clarifications, and informs the proposed solutions. Copyright © 2017 Elsevier Inc. All rights reserved.

Methodology of Clinical Trials Aimed at Assessing Interventions for Cutaneous Leishmaniasis

PubMed Central

Olliaro, Piero; Vaillant, Michel; Arana, Byron; Grogl, Max; Modabber, Farrokh; Magill, Alan; Lapujade, Olivier; Buffet, Pierre; Alvar, Jorge

2013-01-01

The current evidence-base for recommendations on the treatment of cutaneous leishmaniasis (CL) is generally weak. Systematic reviews have pointed to a general lack of standardization of methods for the conduct and analysis of clinical trials of CL, compounded with poor overall quality of several trials. For CL, there is a specific need for methodologies which can be applied generally, while allowing the flexibility needed to cover the diverse forms of the disease. This paper intends to provide clinical investigators with guidance for the design, conduct, analysis and report of clinical trials of treatments for CL, including the definition of measurable, reproducible and clinically-meaningful outcomes. Having unified criteria will help strengthen evidence, optimize investments, and enhance the capacity for high-quality trials. The limited resources available for CL have to be concentrated in clinical studies of excellence that meet international quality standards. PMID:23556016

Randomization in clinical trials in orthodontics: its significance in research design and methods to achieve it.

PubMed

Pandis, Nikolaos; Polychronopoulou, Argy; Eliades, Theodore

2011-12-01

Randomization is a key step in reducing selection bias during the treatment allocation phase in randomized clinical trials. The process of randomization follows specific steps, which include generation of the randomization list, allocation concealment, and implementation of randomization. The phenomenon in the dental and orthodontic literature of characterizing treatment allocation as random is frequent; however, often the randomization procedures followed are not appropriate. Randomization methods assign, at random, treatment to the trial arms without foreknowledge of allocation by either the participants or the investigators thus reducing selection bias. Randomization entails generation of random allocation, allocation concealment, and the actual methodology of implementing treatment allocation randomly and unpredictably. Most popular randomization methods include some form of restricted and/or stratified randomization. This article introduces the reasons, which make randomization an integral part of solid clinical trial methodology, and presents the main randomization schemes applicable to clinical trials in orthodontics.

Statistical challenges in a regulatory review of cardiovascular and CNS clinical trials.

PubMed

Hung, H M James; Wang, Sue-Jane; Yang, Peiling; Jin, Kun; Lawrence, John; Kordzakhia, George; Massie, Tristan

2016-01-01

There are several challenging statistical problems identified in the regulatory review of large cardiovascular (CV) clinical outcome trials and central nervous system (CNS) trials. The problems can be common or distinct due to disease characteristics and the differences in trial design elements such as endpoints, trial duration, and trial size. In schizophrenia trials, heavy missing data is a big problem. In Alzheimer trials, the endpoints for assessing symptoms and the endpoints for assessing disease progression are essentially the same; it is difficult to construct a good trial design to evaluate a test drug for its ability to slow the disease progression. In CV trials, reliance on a composite endpoint with low event rate makes the trial size so large that it is infeasible to study multiple doses necessary to find the right dose for study patients. These are just a few typical problems. In the past decade, adaptive designs were increasingly used in these disease areas and some challenges occur with respect to that use. Based on our review experiences, group sequential designs (GSDs) have borne many successful stories in CV trials and are also increasingly used for developing treatments targeting CNS diseases. There is also a growing trend of using more advanced unblinded adaptive designs for producing efficacy evidence. Many statistical challenges with these kinds of adaptive designs have been identified through our experiences with the review of regulatory applications and are shared in this article.

Good research practices for comparative effectiveness research: approaches to mitigate bias and confounding in the design of nonrandomized studies of treatment effects using secondary data sources: the International Society for Pharmacoeconomics and Outcomes Research Good Research Practices for Retrospective Database Analysis Task Force Report--Part II.

PubMed

Cox, Emily; Martin, Bradley C; Van Staa, Tjeerd; Garbe, Edeltraut; Siebert, Uwe; Johnson, Michael L

2009-01-01

The goal of comparative effectiveness analysis is to examine the relationship between two variables, treatment, or exposure and effectiveness or outcome. Unlike data obtained through randomized controlled trials, researchers face greater challenges with causal inference with observational studies. Recognizing these challenges, a task force was formed to develop a guidance document on methodological approaches to addresses these biases. The task force was commissioned and a Chair was selected by the International Society for Pharmacoeconomics and Outcomes Research Board of Directors in October 2007. This report, the second of three reported in this issue of the Journal, discusses the inherent biases when using secondary data sources for comparative effectiveness analysis and provides methodological recommendations to help mitigate these biases. The task force report provides recommendations and tools for researchers to mitigate threats to validity from bias and confounding in measurement of exposure and outcome. Recommendations on design of study included: the need for data analysis plan with causal diagrams; detailed attention to classification bias in definition of exposure and clinical outcome; careful and appropriate use of restriction; extreme care to identify and control for confounding factors, including time-dependent confounding. Design of nonrandomized studies of comparative effectiveness face several daunting issues, including measurement of exposure and outcome challenged by misclassification and confounding. Use of causal diagrams and restriction are two techniques that can improve the theoretical basis for analyzing treatment effects in study populations of more homogeneity, with reduced loss of generalizability.

Multi-Step Usage of in Vivo Models During Rational Drug Design and Discovery

PubMed Central

Williams, Charles H.; Hong, Charles C.

2011-01-01

In this article we propose a systematic development method for rational drug design while reviewing paradigms in industry, emerging techniques and technologies in the field. Although the process of drug development today has been accelerated by emergence of computational methodologies, it is a herculean challenge requiring exorbitant resources; and often fails to yield clinically viable results. The current paradigm of target based drug design is often misguided and tends to yield compounds that have poor absorption, distribution, metabolism, and excretion, toxicology (ADMET) properties. Therefore, an in vivo organism based approach allowing for a multidisciplinary inquiry into potent and selective molecules is an excellent place to begin rational drug design. We will review how organisms like the zebrafish and Caenorhabditis elegans can not only be starting points, but can be used at various steps of the drug development process from target identification to pre-clinical trial models. This systems biology based approach paired with the power of computational biology; genetics and developmental biology provide a methodological framework to avoid the pitfalls of traditional target based drug design. PMID:21731440

Coupled variational formulations of linear elasticity and the DPG methodology

NASA Astrophysics Data System (ADS)

Fuentes, Federico; Keith, Brendan; Demkowicz, Leszek; Le Tallec, Patrick

2017-11-01

This article presents a general approach akin to domain-decomposition methods to solve a single linear PDE, but where each subdomain of a partitioned domain is associated to a distinct variational formulation coming from a mutually well-posed family of broken variational formulations of the original PDE. It can be exploited to solve challenging problems in a variety of physical scenarios where stability or a particular mode of convergence is desired in a part of the domain. The linear elasticity equations are solved in this work, but the approach can be applied to other equations as well. The broken variational formulations, which are essentially extensions of more standard formulations, are characterized by the presence of mesh-dependent broken test spaces and interface trial variables at the boundaries of the elements of the mesh. This allows necessary information to be naturally transmitted between adjacent subdomains, resulting in coupled variational formulations which are then proved to be globally well-posed. They are solved numerically using the DPG methodology, which is especially crafted to produce stable discretizations of broken formulations. Finally, expected convergence rates are verified in two different and illustrative examples.

Guidelines for the Design and Conduct of Clinical Studies in Knee Articular Cartilage Repair

PubMed Central

Mithoefer, Kai; Saris, Daniel B.F.; Farr, Jack; Kon, Elizaveta; Zaslav, Kenneth; Cole, Brian J.; Ranstam, Jonas; Yao, Jian; Shive, Matthew; Levine, David; Dalemans, Wilfried; Brittberg, Mats

2011-01-01

Objective: To summarize current clinical research practice and develop methodological standards for objective scientific evaluation of knee cartilage repair procedures and products. Design: A comprehensive literature review was performed of high-level original studies providing information relevant for the design of clinical studies on articular cartilage repair in the knee. Analysis of cartilage repair publications and synopses of ongoing trials were used to identify important criteria for the design, reporting, and interpretation of studies in this field. Results: Current literature reflects the methodological limitations of the scientific evidence available for articular cartilage repair. However, clinical trial databases of ongoing trials document a trend suggesting improved study designs and clinical evaluation methodology. Based on the current scientific information and standards of clinical care, detailed methodological recommendations were developed for the statistical study design, patient recruitment, control group considerations, study endpoint definition, documentation of results, use of validated patient-reported outcome instruments, and inclusion and exclusion criteria for the design and conduct of scientifically sound cartilage repair study protocols. A consensus statement among the International Cartilage Repair Society (ICRS) and contributing authors experienced in clinical trial design and implementation was achieved. Conclusions: High-quality clinical research methodology is critical for the optimal evaluation of current and new cartilage repair technologies. In addition to generally applicable principles for orthopedic study design, specific criteria and considerations apply to cartilage repair studies. Systematic application of these criteria and considerations can facilitate study designs that are scientifically rigorous, ethical, practical, and appropriate for the question(s) being addressed in any given cartilage repair research project. PMID:26069574

Review of Recent Methodological Developments in Group-Randomized Trials: Part 1—Design

PubMed Central

Li, Fan; Gallis, John A.; Prague, Melanie; Murray, David M.

2017-01-01

In 2004, Murray et al. reviewed methodological developments in the design and analysis of group-randomized trials (GRTs). We have highlighted the developments of the past 13 years in design with a companion article to focus on developments in analysis. As a pair, these articles update the 2004 review. We have discussed developments in the topics of the earlier review (e.g., clustering, matching, and individually randomized group-treatment trials) and in new topics, including constrained randomization and a range of randomized designs that are alternatives to the standard parallel-arm GRT. These include the stepped-wedge GRT, the pseudocluster randomized trial, and the network-randomized GRT, which, like the parallel-arm GRT, require clustering to be accounted for in both their design and analysis. PMID:28426295

Review of Recent Methodological Developments in Group-Randomized Trials: Part 1-Design.

PubMed

Turner, Elizabeth L; Li, Fan; Gallis, John A; Prague, Melanie; Murray, David M

2017-06-01

In 2004, Murray et al. reviewed methodological developments in the design and analysis of group-randomized trials (GRTs). We have highlighted the developments of the past 13 years in design with a companion article to focus on developments in analysis. As a pair, these articles update the 2004 review. We have discussed developments in the topics of the earlier review (e.g., clustering, matching, and individually randomized group-treatment trials) and in new topics, including constrained randomization and a range of randomized designs that are alternatives to the standard parallel-arm GRT. These include the stepped-wedge GRT, the pseudocluster randomized trial, and the network-randomized GRT, which, like the parallel-arm GRT, require clustering to be accounted for in both their design and analysis.

Vitamin D and solar ultraviolet radiation in the risk and treatment of tuberculosis.

PubMed

Ralph, Anna P; Ralph, Anna R; Lucas, Robyn M; Norval, Mary

2013-01-01

Improved understanding of the association between tuberculosis and vitamin D is needed to inform clinical practice. Vitamin D has both immunostimulatory and immunosuppressive effects relevant to human antimycobacterial responses. Ultraviolet radiation, the main source of vitamin D, also induces immunomodulation and could affect the relation between vitamin D and tuberculosis. Clinical trials of vitamin D supplementation in patients with tuberculosis have produced largely negative results, prompting the review of dosing regimens-an explanation for low 25-hydroxyvitamin D status in patients with active tuberculosis is also needed. The reporting of vitamin D deficiency needs to address assay inaccuracies, rising thresholds to define sufficiency, and scarce knowledge of the concentrations needed for optimum immune responses. Future research to measure the effect of the inflammatory setting on serum concentrations of 25-hydroxyvitamin D, at tuberculosis diagnosis and during recovery, could help to account for 25-hydroxyvitamin D changes in these concentrations in patients with tuberculosis. Studies into the role of vitamin D supplementation in latent tuberculosis justify clinical trials in this population, but pose methodological challenges. Vitamin D trials in patients with active tuberculosis should be done in well selected populations using adequate vitamin D doses, although such doses remain undefined. Copyright © 2013 Elsevier Ltd. All rights reserved.

Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR).

PubMed

Evans, Scott R; Rubin, Daniel; Follmann, Dean; Pennello, Gene; Huskins, W Charles; Powers, John H; Schoenfeld, David; Chuang-Stein, Christy; Cosgrove, Sara E; Fowler, Vance G; Lautenbach, Ebbing; Chambers, Henry F

2015-09-01

Clinical trials that compare strategies to optimize antibiotic use are of critical importance but are limited by competing risks that distort outcome interpretation, complexities of noninferiority trials, large sample sizes, and inadequate evaluation of benefits and harms at the patient level. The Antibacterial Resistance Leadership Group strives to overcome these challenges through innovative trial design. Response adjusted for duration of antibiotic risk (RADAR) is a novel methodology utilizing a superiority design and a 2-step process: (1) categorizing patients into an overall clinical outcome (based on benefits and harms), and (2) ranking patients with respect to a desirability of outcome ranking (DOOR). DOORs are constructed by assigning higher ranks to patients with (1) better overall clinical outcomes and (2) shorter durations of antibiotic use for similar overall clinical outcomes. DOOR distributions are compared between antibiotic use strategies. The probability that a randomly selected patient will have a better DOOR if assigned to the new strategy is estimated. DOOR/RADAR represents a new paradigm in assessing the risks and benefits of new strategies to optimize antibiotic use. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Feasibility of conducting a randomised controlled trial of a cookstove intervention in rural Malawi

PubMed Central

Kachidiku, J.; Banda, H.; Kapanga, M.; Doyle, J. V.; Banda, E.; Fox, C.; Gordon, S. B.; Mortimer, K.

2014-01-01

BACKGROUND: Exposure to household air pollution (HAP) causes 4 million deaths annually, and strategies to reduce HAP exposure are urgently required. OBJECTIVE: To evaluate the acceptability and feasibility of conducting a trial of a cookstove intervention in rural Malawi. DESIGN: Non-smoking women were randomised to continuing to use an open fire (control) or to using a wood-burning clay cookstove (intervention). Symptom burden, oxygen saturation and exhaled carbon monoxide (eCO) were assessed at baseline and 7-day follow-up. A subset of women underwent HAP exposure monitoring. RESULTS: Of 51 women recruited, 50 (98%) completed the main study. The methodology was acceptable to participants. Headache, back pain and cough were the most commonly reported symptoms at baseline and follow-up. Median eCO was within normal limits, but with a difference of 0.5 parts per million (ppm) in median change of eCO from baseline to follow-up seen between the two groups (P ∙ 0.035). The peak ambient CO concentration detected was 150 ppm. CONCLUSION: This study suggests that a large cookstove intervention trial in Malawi would be feasible with careful community sensitisation. Monitoring exposure to HAP is challenging, and further studies evaluating potential biomarkers of exposure, including eCO, should be undertaken. PMID:24429320

Q methodology in health economics.

PubMed

Baker, Rachel; Thompson, Carl; Mannion, Russell

2006-01-01

The recognition that health economists need to understand the meaning of data if they are to adequately understand research findings which challenge conventional economic theory has led to the growth of qualitative modes of enquiry in health economics. The use of qualitative methods of exploration and description alongside quantitative techniques gives rise to a number of epistemological, ontological and methodological challenges: difficulties in accounting for subjectivity in choices, the need for rigour and transparency in method, and problems of disciplinary acceptability to health economists. Q methodology is introduced as a means of overcoming some of these challenges. We argue that Q offers a means of exploring subjectivity, beliefs and values while retaining the transparency, rigour and mathematical underpinnings of quantitative techniques. The various stages of Q methodological enquiry are outlined alongside potential areas of application in health economics, before discussing the strengths and limitations of the approach. We conclude that Q methodology is a useful addition to economists' methodological armoury and one that merits further consideration and evaluation in the study of health services.

Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews.

PubMed

Song, Fujian; Loke, Yoon K; Walsh, Tanya; Glenny, Anne-Marie; Eastwood, Alison J; Altman, Douglas G

2009-04-03

To investigate basic assumptions and other methodological problems in the application of indirect comparison in systematic reviews of competing healthcare interventions. Survey of published systematic reviews. Inclusion criteria Systematic reviews published between 2000 and 2007 in which an indirect approach had been explicitly used. Identified reviews were assessed for comprehensiveness of the literature search, method for indirect comparison, and whether assumptions about similarity and consistency were explicitly mentioned. The survey included 88 review reports. In 13 reviews, indirect comparison was informal. Results from different trials were naively compared without using a common control in six reviews. Adjusted indirect comparison was usually done using classic frequentist methods (n=49) or more complex methods (n=18). The key assumption of trial similarity was explicitly mentioned in only 40 of the 88 reviews. The consistency assumption was not explicit in most cases where direct and indirect evidence were compared or combined (18/30). Evidence from head to head comparison trials was not systematically searched for or not included in nine cases. Identified methodological problems were an unclear understanding of underlying assumptions, inappropriate search and selection of relevant trials, use of inappropriate or flawed methods, lack of objective and validated methods to assess or improve trial similarity, and inadequate comparison or inappropriate combination of direct and indirect evidence. Adequate understanding of basic assumptions underlying indirect and mixed treatment comparison is crucial to resolve these methodological problems. APPENDIX 1: PubMed search strategy. APPENDIX 2: Characteristics of identified reports. APPENDIX 3: Identified studies. References of included studies.

The effect of docetaxel on developing oedema in patients with breast cancer: a systematic review.

PubMed

Hugenholtz-Wamsteker, W; Robbeson, C; Nijs, J; Hoelen, W; Meeus, M

2016-03-01

Docetaxel is extensively used in chemotherapy for the treatment of breast cancer. Little attention has been given to oedema as a possible side effect of docetaxel-containing therapies. Until now, no review was conducted to evaluate docetaxel-containing therapies versus docetaxel-free therapies on the magnitude of the risk of developing oedema. In this systematic review, we investigated the risk of developing oedema in patients being treated for breast cancer with or without docetaxel. In this systematic literature review, we searched PubMed and Web of Knowledge for studies on breast cancer patients treated with chemotherapy containing docetaxel. We included clinical trials comparing docetaxel versus docetaxel-free chemotherapy. Oedema had to be reported and measured as a key outcome or an adverse effect. Methodological checklists were used to assess the risk of bias within the selected studies. Seven randomised clinical trials were included. Six trials were of moderate methodological quality. All trials showed an increased rate of oedema in the docetaxel-treatment arm. The trial of weakest methodological quality reported the highest incidence of oedema. The results moderately suggest that adjuvant chemotherapy containing docetaxel is related to a significantly increased risk of developing oedema, compared with docetaxel-free chemotherapy. © 2014 John Wiley & Sons Ltd.

Ethics of phase 1 oncology studies: reexamining the arguments and data.

PubMed

Agrawal, Manish; Emanuel, Ezekiel J

2003-08-27

Phase 1 oncology trials are critical to improving the treatment of cancer. Critics have raised 2 fundamental ethical challenges about phase 1 cancer research: the paucity of benefits with substantial risks and poor-quality informed consent. Despite 3 decades of controversy about phase 1 oncology research, there is little critical analysis of the arguments or of the data relevant to these questions. Existing but old data reveal that about 5% of patients in phase 1 trials experience shrinkage of their tumor, with a 0.5% mortality rate. In some notable cases, patients in phase 1 trials have been cured or sustained long-term remissions. Limited data suggest that patients in phase 1 trials may have better quality of life than comparable patients receiving supportive care. More important, the risks and benefits of phase 1 trials are not clearly worse than risk-benefit ratios used by the US Food and Drug Administration to approve chemotherapeutic agents for clinical use. The objections based on informed consent are deficiencies of disclosure, understanding, and voluntariness. The available data do not support the claim that disclosure is deficient. Although studies evaluating patient understanding have substantial methodological problems, they demonstrate that more than 70% of patients understand that they may not directly benefit even when they hope they will personally benefit. Finally, a closer look at issues of voluntariness reveals that patients with advanced cancer who participate in phase 1 research may have a different set of values than do critics and are not coerced. Overall, it appears that phase 1 oncology trials satisfy the requirement for a favorable risk-benefit ratio and that patients who enroll provide adequate informed consent.

A Methodological Analysis of Randomized Clinical Trials of Computer-Assisted Therapies for Psychiatric Disorders: Toward Improved Standards for an Emerging Field

PubMed Central

Kiluk, Brian D.; Sugarman, Dawn E.; Nich, Charla; Gibbons, Carly J.; Martino, Steve; Rounsaville, Bruce J.; Carroll, Kathleen M.

2013-01-01

Objective Computer-assisted therapies offer a novel, cost-effective strategy for providing evidence-based therapies to a broad range of individuals with psychiatric disorders. However, the extent to which the growing body of randomized trials evaluating computer-assisted therapies meets current standards of methodological rigor for evidence-based interventions is not clear. Method A methodological analysis of randomized clinical trials of computer-assisted therapies for adult psychiatric disorders, published between January 1990 and January 2010, was conducted. Seventy-five studies that examined computer-assisted therapies for a range of axis I disorders were evaluated using a 14-item methodological quality index. Results Results indicated marked heterogeneity in study quality. No study met all 14 basic quality standards, and three met 13 criteria. Consistent weaknesses were noted in evaluation of treatment exposure and adherence, rates of follow-up assessment, and conformity to intention-to-treat principles. Studies utilizing weaker comparison conditions (e.g., wait-list controls) had poorer methodological quality scores and were more likely to report effects favoring the computer-assisted condition. Conclusions While several well-conducted studies have indicated promising results for computer-assisted therapies, this emerging field has not yet achieved a level of methodological quality equivalent to those required for other evidence-based behavioral therapies or pharmacotherapies. Adoption of more consistent standards for methodological quality in this field, with greater attention to potential adverse events, is needed before computer-assisted therapies are widely disseminated or marketed as evidence based. PMID:21536689

Statistical lessons learned for designing cluster randomized pragmatic clinical trials from the NIH Health Care Systems Collaboratory Biostatistics and Design Core.

PubMed

Cook, Andrea J; Delong, Elizabeth; Murray, David M; Vollmer, William M; Heagerty, Patrick J

2016-10-01

Pragmatic clinical trials embedded within health care systems provide an important opportunity to evaluate new interventions and treatments. Networks have recently been developed to support practical and efficient studies. Pragmatic trials will lead to improvements in how we deliver health care and promise to more rapidly translate research findings into practice. The National Institutes of Health (NIH) Health Care Systems Collaboratory was formed to conduct pragmatic clinical trials and to cultivate collaboration across research areas and disciplines to develop best practices for future studies. Through a two-stage grant process including a pilot phase (UH2) and a main trial phase (UH3), investigators across the Collaboratory had the opportunity to work together to improve all aspects of these trials before they were launched and to address new issues that arose during implementation. Seven Cores were created to address the various considerations, including Electronic Health Records; Phenotypes, Data Standards, and Data Quality; Biostatistics and Design Core; Patient-Reported Outcomes; Health Care Systems Interactions; Regulatory/Ethics; and Stakeholder Engagement. The goal of this article is to summarize the Biostatistics and Design Core's lessons learned during the initial pilot phase with seven pragmatic clinical trials conducted between 2012 and 2014. Methodological issues arose from the five cluster-randomized trials, also called group-randomized trials, including consideration of crossover and stepped wedge designs. We outlined general themes and challenges and proposed solutions from the pilot phase including topics such as study design, unit of randomization, sample size, and statistical analysis. Our findings are applicable to other pragmatic clinical trials conducted within health care systems. Pragmatic clinical trials using the UH2/UH3 funding mechanism provide an opportunity to ensure that all relevant design issues have been fully considered in order to reliably and efficiently evaluate new interventions and treatments. The integrity and generalizability of trial results can only be ensured if rigorous designs and appropriate analysis choices are an essential part of their research protocols. © The Author(s) 2016.

Methodological Challenges in Studies Examining the Effects of Breakfast on Cognitive Performance and Appetite in Children and Adolescents.

PubMed

Adolphus, Katie; Bellissimo, Nick; Lawton, Clare L; Ford, Nikki A; Rains, Tia M; Totosy de Zepetnek, Julia; Dye, Louise

2017-01-01

Breakfast is purported to confer a number of benefits on diet quality, health, appetite regulation, and cognitive performance. However, new evidence has challenged the long-held belief that breakfast is the most important meal of the day. This review aims to provide a comprehensive discussion of the key methodological challenges and considerations in studies assessing the effect of breakfast on cognitive performance and appetite control, along with recommendations for future research. This review focuses on the myriad challenges involved in studying children and adolescents specifically. Key methodological challenges and considerations include study design and location, sampling and sample section, choice of objective cognitive tests, choice of objective and subjective appetite measures, merits of providing a fixed breakfast compared with ad libitum, assessment and definition of habitual breakfast consumption, transparency of treatment condition, difficulty of isolating the direct effects of breakfast consumption, untangling acute and chronic effects, and influence of confounding variables. These methodological challenges have hampered a clear substantiation of the potential positive effects of breakfast on cognition and appetite control and contributed to the debate questioning the notion that breakfast is the most important meal of the day. © 2017 American Society for Nutrition.

Methodological Challenges in Studies Examining the Effects of Breakfast on Cognitive Performance and Appetite in Children and Adolescents123

PubMed Central

Bellissimo, Nick; Ford, Nikki A; Rains, Tia M

2017-01-01

Breakfast is purported to confer a number of benefits on diet quality, health, appetite regulation, and cognitive performance. However, new evidence has challenged the long-held belief that breakfast is the most important meal of the day. This review aims to provide a comprehensive discussion of the key methodological challenges and considerations in studies assessing the effect of breakfast on cognitive performance and appetite control, along with recommendations for future research. This review focuses on the myriad challenges involved in studying children and adolescents specifically. Key methodological challenges and considerations include study design and location, sampling and sample section, choice of objective cognitive tests, choice of objective and subjective appetite measures, merits of providing a fixed breakfast compared with ad libitum, assessment and definition of habitual breakfast consumption, transparency of treatment condition, difficulty of isolating the direct effects of breakfast consumption, untangling acute and chronic effects, and influence of confounding variables. These methodological challenges have hampered a clear substantiation of the potential positive effects of breakfast on cognition and appetite control and contributed to the debate questioning the notion that breakfast is the most important meal of the day. PMID:28096143

Comparative effectiveness research for the clinician researcher: a framework for making a methodological design choice.

PubMed

Williams, Cylie M; Skinner, Elizabeth H; James, Alicia M; Cook, Jill L; McPhail, Steven M; Haines, Terry P

2016-08-17

Comparative effectiveness research compares two active forms of treatment or usual care in comparison with usual care with an additional intervention element. These types of study are commonly conducted following a placebo or no active treatment trial. Research designs with a placebo or non-active treatment arm can be challenging for the clinician researcher when conducted within the healthcare environment with patients attending for treatment.A framework for conducting comparative effectiveness research is needed, particularly for interventions for which there are no strong regulatory requirements that must be met prior to their introduction into usual care. We argue for a broader use of comparative effectiveness research to achieve translatable real-world clinical research. These types of research design also affect the rapid uptake of evidence-based clinical practice within the healthcare setting.This framework includes questions to guide the clinician researcher into the most appropriate trial design to measure treatment effect. These questions include consideration given to current treatment provision during usual care, known treatment effectiveness, side effects of treatments, economic impact, and the setting in which the research is being undertaken.

Systematic review and meta-analysis in cardiac surgery: a primer.

PubMed

Yanagawa, Bobby; Tam, Derrick Y; Mazine, Amine; Tricco, Andrea C

2018-03-01

The purpose of this article is to review the strengths and weaknesses of systematic reviews and meta-analyses to inform our current understanding of cardiac surgery. A systematic review and meta-analysis of a focused topic can provide a quantitative estimate for the effect of a treatment intervention or exposure. In cardiac surgery, observational studies and small, single-center prospective trials provide most of the clinical outcomes that form the evidence base for patient management and guideline recommendations. As such, meta-analyses can be particularly valuable in synthesizing the literature for a particular focused surgical question. Since the year 2000, there are over 800 meta-analysis-related publications in our field. There are some limitations to this technique, including clinical, methodological and statistical heterogeneity, among other challenges. Despite these caveats, results of meta-analyses have been useful in forming treatment recommendations or in providing guidance in the design of future clinical trials. There is a growing number of meta-analyses in the field of cardiac surgery. Knowledge translation via meta-analyses will continue to guide and inform cardiac surgical practice and our practice guidelines.

Home-based management of severely acute malnutrition: feasibility of ethically designed, community-based randomised clinical trials.

PubMed

Patil, Rajan R

2015-01-01

The Indian Council of Medical Research had, on May 31, 2011, called for research proposals on severely acute malnourished (SAM) children to generate evidence for the development of practical and scalable regimens to medically rehabilitate children suffering from SAM, without serious complications, at the home/community level and/or peripheral inpatient facilities. The primary outcomes of the proposed research study are recovery from SAM in the short term, as well as sustenance of recovery (for at least six months after the initiation of treatment). The secondary outcomes are the acceptability, feasibility and safety of the regimes being tested. It was suggested that the studies be designed as individual or cluster randomised or quasi randomised controlled trials (RCTs). This paper analyses the methodological, operational, and most importantly, ethical challenges and implications of conducting community-based RCTs involving SAM children. The paper dwells in detail on why and how the RCT design is inappropriate and unsuitable for studying the effectiveness of home-based management of SAM children in the community.

Mild cognitive impairment (MCI) - the novel trend of targeting Alzheimer's disease in its early stages - methodological considerations.

PubMed

Pater, C

2011-11-01

While much uncertainty exists in the estimates of the global burden of Alzheimer's disease and about the potential impact of various interventions, there is a widespread acceptance of the fact that the steady increase in the incidence and prevalence of the condition worldwide is becoming a massive public health problem as well as a huge economic burden for all healthcare systems and societies. These heavy demands are further compounded by the poor quality of life of the affected individuals, of their families and of their caregivers. The epidemic proportion of Alzheimer's disease has triggered relentless attempts for development of treatment approaches during the past two decades by a multitude of pharmaceuticals and biotech companies. Commercial development of the acetylcholinesterase inhibitors has, until recently, virtually dominated the field and, although efficacy has been demonstrated for five different products, the longterm clinical results suggested that alternate approaches were warranted. Disease modifying strategies targeting the β- amyloid plaques (e.g., decreasing β-amyloid formation through β- and γ-secretase inhibition, diminishing β-amyloid aggregation through anti-aggregants or enhancement of β-amyloid clearance through active/passive immunization), targeting the neurofibrillary tangles through inhibition of tau protein hyperphosphorilation or, more recently, by increasing mitochondrial permeability, all these potential treatment modalities are facing major methodological challenges during the conduct of a myriad of clinical trials meant to bring the novel therapies to the market. Failure of more than 400 products tested in more than 800 clinical trials to date, with many of these failures occurring in late stage development (phase III) have triggered a paradigm shift toward targeting of the early stages of cognitive deficiencies (mild cognitive impairment- MCI) and a refinement of the investigative methodologies. The great heterogeneity of the disease entity itself (MCI) coupled with inadequate sensitivity, specificity and positive/negative predictive values of the many common diagnostic outcome scales, outcome measures, and of many of the currently used biomarkers expose the drug development professionals to the risk of methodological flaws rendering the products explored ineffective, while very expensive.

Ethical challenges in preclinical Alzheimer’s disease observational studies and trials: results of the Barcelona summit

PubMed Central

Molinuevo, José L.; Cami, Jordi; Carné, Xavier; Carrillo, Maria C.; Georges, Jean; Isaac, Maria B.; Khachaturian, Zaven; Kim, Scott Y. H.; Morris, John C.; Pasquier, Florence; Ritchie, Craig; Sperling, Reisa; Karlawish, Jason

2016-01-01

Alzheimer’s disease (AD) is among the most significant healthcare burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals’ biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants and disclose or not biomarker status with attention to study type (observational studies versus clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants. PMID:26988427

Characteristics of Placebo Responders in Pediatric Clinical Trials of Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Newcorn, Jeffrey H.; Sutton, Virginia K.; Zhang, Shuyu; Wilens, Timothy; Kratochvil, Christopher; Emslie, Graham J.; D'Souza, Deborah N.; Schuh, Leslie M.; Allen, Albert J.

2009-01-01

Objective: Understanding placebo response is a prerequisite to improving clinical trial methodology. Data from placebo-controlled trials of atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) were analyzed to identify demographic and clinical characteristics that might predict placebo…

Depression Prevention Research: Design, Implementation, and Analysis of Randomized Trials.

ERIC Educational Resources Information Center

Munoz, Ricardo F.; And Others

This document contains three papers concerned with prevention intervention research, a new area of depression research which has shown great promise for contributing new knowledge to the understanding of depression. The first paper, "Clinical Trials vs. Prevention Trials: Methodological Issues in Depression Research" (Ricardo F. Munoz), emphasizes…

Methodological and ethical aspects of randomized controlled clinical trials in minors with malignant diseases.

PubMed

Rothenberger, Lillian G; Henschel, Andreas Dirk; Schrey, Dominik; Becker, Andreas; Boos, Joachim

2011-10-01

Due to the new European regulations for pediatric medications, future clinical trials will include an increasing number of minors. It is therefore important to reconsider and evaluate recent methodological and ethical aspects of clinical trials in minors. The following questions were investigated: How are randomized controlled clinical trials (RCTs) performed in practice? Do investigators take into consideration biomedical ethical principles, explicated for example by Beauchamp and Childress, when planning and conducting a trial? The study was conducted in a descriptive manner. A systematic, algorithm-guided search focusing on RCTs in minors with malignant diseases was carried out in PubMed. One-thousand-nine-hundred-sixty-two publications from 2001 to 2005 were randomized in sequence. The first 1,000 publications were screened according to a priori defined inclusion criteria. One hundred seventy-five publications met the criteria and were reviewed using the SIGN methodological checklist (2004), the CONSORT Statement (2001, section Methods, items 3-12) and indicators for ethical aspects. Seventeen publications were checked by two raters. Information on randomization and blinding was often equivocal. The publications were mainly rated positive for the criteria of the SIGN checklist, and mostly rated negative for the additional items of the CONSORT Statement. Regarding the ethical principles, only few contributions were found in the publications. Inter-rater reliability was good. In the publications analyzed, we found only limited information concerning methods and reflections on ethical principles of the trials. Improvements are thus necessary and possible. We suggest how such trials and their respective publications can be optimized for these aspects. Copyright © 2011 Wiley-Liss, Inc.

Mind-body Therapies for Menopausal Symptoms: A Systematic Review

PubMed Central

Innes, Kim E; Selfe, Terry Kit; Vishnu, Abhishek

2010-01-01

Objective To systematically review the peer-reviewed literature regarding the effects of self-administered mind-body therapies on menopausal symptoms. Methods To identify qualifying studies, we searched 10 scientific databases and scanned bibliographies of relevant review papers and all identified articles. The methodological quality of all studies was assessed systematically using predefined criteria. Results Twenty-one papers representing 18 clinical trials from 6 countries met our inclusion criteria, including 12 randomized controlled trials (N=719), 1 non-randomized controlled trial (N=58), and 5 uncontrolled trials (N=105). Interventions included yoga and/or meditation-based programs, tai chi, and other relaxation practices, including muscle relaxation and breath-based techniques, relaxation response training, and low frequency sound-wave therapy. Eight of the nine studies of yoga, tai chi, and meditation-based programs reported improvement in overall menopausal and vasomotor symptoms; six of seven trials indicated improvement in mood and sleep with yoga-based programs, and four studies reported reduced musculoskeletal pain. Results from the remaining nine trials suggest that breath-based and other relaxation therapies also show promise for alleviating vasomotor and other menopausal symptoms, although intergroup findings were mixed. Most studies reviewed suffered methodological or other limitations, complicating interpretation of findings. Conclusions Collectively, findings of these studies suggest that yoga-based and certain other mind-body therapies may be beneficial for alleviating specific menopausal symptoms. However, the limitations characterizing most studies hinder interpretation of findings and preclude firm conclusions regarding efficacy. Additional large, methodologically sound trials are needed to determine the effects of specific mind-body therapies on menopausal symptoms, examine long-term outcomes, and investigate underlying mechanisms. PMID:20167444

Comparative Review of the Treatment Methodologies of Carotid Stenosis

PubMed Central

Bae, Coney; Szuchmacher, Mauricio; Chang, John B.

2015-01-01

The treatment of carotid stenosis entails three methodologies, namely, medical management, carotid angioplasty and stenting (CAS), as well as carotid endarterectomy (CEA). The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) have shown that symptomatic carotid stenosis greater than 70% is best treated with CEA. In asymptomatic patients with carotid stenosis greater than 60%, CEA was more beneficial than treatment with aspirin alone according to the Asymptomatic Carotid Atherosclerosis (ACAS) and Asymptomatic Carotid Stenosis Trial (ACST) trials. When CAS is compared with CEA, the CREST resulted in similar rates of ipsilateral stroke and death rates regardless of symptoms. However, CAS not only increased adverse effects in women, it also amplified stroke rates and death in elderly patients compared with CEA. CAS can maximize its utility in treating focal restenosis after CEA and patients with overwhelming cardiac risk or prior neck irradiation. When performing CEA, using a patch was equated to a more durable result than primary closure, whereas eversion technique is a new methodology deserving a spotlight. Comparing the three major treatment strategies of carotid stenosis has intrinsic drawbacks, as most trials are outdated and they vary in their premises, definitions, and study designs. With the newly codified best medical management including antiplatelet therapies with aspirin and clopidogrel, statin, antihypertensive agents, strict diabetes control, smoking cessation, and life style change, the current trials may demonstrate that asymptomatic carotid stenosis is best treated with best medical therapy. The ongoing trials will illuminate and reshape the treatment paradigm for symptomatic and asymptomatic carotid stenosis. PMID:26417191

The reduction of intoxication and disorder in premises licensed to serve alcohol: an exploratory randomised controlled trial.

PubMed

Moore, Simon C; Brennan, Iain R; Murphy, Simon; Byrne, Ellie; Moore, Susan N; Shepherd, Jonathan P; Moore, Laurence

2010-10-14

Licensed premises offer a valuable point of intervention to reduce alcohol-related harm. To describe the research design for an exploratory trial examining the feasibility and acceptability of a premises-level intervention designed to reduce severe intoxication and related disorder. The study also aims to assess the feasibility of a potential future large scale effectiveness trial and provide information on key trial design parameters including inclusion criteria, premises recruitment methods, strategies to implement the intervention and trial design, outcome measures, data collection methods and intra-cluster correlations. A randomised controlled trial in licensed premises that had experienced at least one assault in the year preceding the intervention, documented in police or hospital Emergency Department (ED) records. Premises were recruited from four study areas by piloting four recruitment strategies of varying intensity. Thirty two licensed premises were grouped into matched pairs to reduce potential bias and randomly allocated to the control or intervention condition. The study included a nested process evaluation to provide information on intervention acceptability and implementation. Outcome measures included police-recorded violent incidents, assault-related attendances at each premises' local ED and patron Breath Alcohol Concentration assessed on exiting and entering study premises. The most successful recruitment method involved local police licensing officers and yielded a 100% success rate. Police-records of violence provided the most appropriate source of data about disorder at the premises level. The methodology of an exploratory trial is presented and despite challenges presented by the study environment it is argued an exploratory trial is warranted. Initial investigations in recruitment methods suggest that study premises should be recruited with the assistance of police officers. Police data were of sufficient quality to identify disorder and street surveys are a feasible method for measuring intoxication at the individual level. UKCRN 7090; ISRCTN: 80875696. Medical Research Council (G0701758) to Simon Moore, Simon Murphy, Laurence Moore and Jonathan Shepherd.

Shortcomings of protocols of drug trials in relation to sponsorship as identified by Research Ethics Committees: analysis of comments raised during ethical review.

PubMed

van Lent, Marlies; Rongen, Gerard A; Out, Henk J

2014-12-10

Submission of study protocols to research ethics committees (RECs) constitutes one of the earliest stages at which planned trials are documented in detail. Previous studies have investigated the amendments requested from researchers by RECs, but the type of issues raised during REC review have not been compared by sponsor type. The objective of this study was to identify recurring shortcomings in protocols of drug trials based on REC comments and to assess whether these were more common among industry-sponsored or non-industry trials. Retrospective analysis of 226 protocols of drug trials approved in 2010-2011 by three RECs affiliated to academic medical centres in The Netherlands. For each protocol, information on sponsorship, number of participating centres, participating countries, study phase, registration status of the study drug, and type and number of subjects was retrieved. REC comments were extracted from decision letters sent to investigators after review and were classified using a predefined checklist that was based on legislation and guidelines on clinical drug research and previous literature. Most protocols received comments regarding participant information and consent forms (n = 182, 80.5%), methodology and statistical analyses (n = 160, 70.8%), and supporting documentation, including trial agreements and certificates of insurance (n = 154, 68.1%). Of the submitted protocols, 122 (54.0%) were non-industry and 104 (46.0%) were industry-sponsored trials. Non-industry trials more often received comments on subject selection (n = 44, 36.1%) than industry-sponsored trials (n = 18, 17.3%; RR, 1.58; 95% CI, 1.01 to 2.47), and on methodology and statistical analyses (n = 95, 77.9% versus n = 65, 62.5%, respectively; RR, 1.18; 95% CI, 1.01 to 1.37). Non-industry trials less often received comments on supporting documentation (n = 72, 59.0%) than industry-sponsored trials (n = 82, 78.8%; RR, 0.83; 95% CI, 0.72 to 0.95). RECs identified important ethical and methodological shortcomings in protocols of both industry-sponsored and non-industry drug trials. Investigators, especially of non-industry trials, should better prepare their research protocols in order to facilitate the ethical review process.

THERACOM: a systematic review of the evidence base for interventions to improve Therapeutic Communications between black and minority ethnic populations and staff in specialist mental health services.

PubMed

Bhui, Kamaldeep; McCabe, Rosemarie; Weich, Scott; Singh, Swaran; Johnson, Mark; Szczepura, Ala

2013-02-25

Black and Minority Ethnic (BME) groups in receipt of specialist mental health care have reported higher rates of detention under the mental health act, less use of psychological therapies, and more dissatisfaction. Although many explanations have been put forward to explain this, a failure of therapeutic communications may explain poorer satisfaction, disengagement from services and ethnic variations in access to less coercive care. Interventions that improve therapeutic communications may offer new approaches to tackle ethnic inequalities in experiences and outcomes. The THERACOM project is an HTA-funded evidence synthesis review of interventions to improve therapeutic communications between black and minority ethnic patients in contact with specialist mental health services and staff providing those services. This article sets out the protocol methods for a necessarily broad review topic, including appropriate search strategies, dilemmas for classifying different types of therapeutic communications and expectations of the types of interventions to improve them. The review methods will accommodate unexpected types of study and interventions. The findings will be reported in 2013, including a synthesis of the quantitative and grey literature. A particular methodological challenge is to identify and rate the quality of many different study types, for example, randomised controlled trials, observational quantitative studies, qualitative studies and case studies, which comprise the full range of hierarchies of evidence. We discuss the preliminary methodological challenges and some solutions. (PROSPERO registration number: CRD42011001661).

THERACOM: a systematic review of the evidence base for interventions to improve Therapeutic Communications between black and minority ethnic populations and staff in specialist mental health services

PubMed Central

2013-01-01

Background Black and Minority Ethnic (BME) groups in receipt of specialist mental health care have reported higher rates of detention under the mental health act, less use of psychological therapies, and more dissatisfaction. Although many explanations have been put forward to explain this, a failure of therapeutic communications may explain poorer satisfaction, disengagement from services and ethnic variations in access to less coercive care. Interventions that improve therapeutic communications may offer new approaches to tackle ethnic inequalities in experiences and outcomes. Methods The THERACOM project is an HTA-funded evidence synthesis review of interventions to improve therapeutic communications between black and minority ethnic patients in contact with specialist mental health services and staff providing those services. This article sets out the protocol methods for a necessarily broad review topic, including appropriate search strategies, dilemmas for classifying different types of therapeutic communications and expectations of the types of interventions to improve them. The review methods will accommodate unexpected types of study and interventions. The findings will be reported in 2013, including a synthesis of the quantitative and grey literature. Discussion A particular methodological challenge is to identify and rate the quality of many different study types, for example, randomised controlled trials, observational quantitative studies, qualitative studies and case studies, which comprise the full range of hierarchies of evidence. We discuss the preliminary methodological challenges and some solutions. (PROSPERO registration number: CRD42011001661). PMID:23442299

Vitex agnus-castus extracts for female reproductive disorders: a systematic review of clinical trials.

PubMed

van Die, M Diana; Burger, Henry G; Teede, Helena J; Bone, Kerry M

2013-05-01

Vitex agnus-castus L. (chaste tree; chasteberry) is a popular herbal treatment, predominantly used for a range of female reproductive conditions in Anglo-American and European practice. The objective of this systematic review was to evaluate the evidence for the efficacy and safety of Vitex extracts from randomised, controlled trials investigating women's health.Eight databases were searched using Latin and common names for Vitex and phytotherapeutic preparations of the herb as a sole agent, together with filters for randomised, controlled trials or clinical trials. Methodological quality was assessed according to the Cochrane risk of bias and Jadad scales, as well as the proposed elaboration of CONSORT for reporting trials on herbal interventions.Thirteen randomised, controlled trials were identified and twelve are included in this review, of which eight investigated premenstrual syndrome, two premenstrual dysphoric disorder, and two latent hyperprolactinaemia. For premenstrual syndrome, seven of eight trials found Vitex extracts to be superior to placebo (5 of 6 studies), pyridoxine (1), and magnesium oxide (1). In premenstrual dysphoric disorder, one study reported Vitex to be equivalent to fluoxetine, while in the other, fluoxetine outperformed Vitex. In latent hyperprolactinaemia, one trial reported it to be superior to placebo for reducing TRH-stimulated prolactin secretion, normalising a shortened luteal phase, increasing mid-luteal progesterone and 17β-oestradiol levels, while the other found Vitex comparable to bromocriptine for reducing serum prolactin levels and ameliorating cyclic mastalgia. Adverse events with Vitex were mild and generally infrequent. The methodological quality of the included studies varied, but was generally moderate-to-high. Limitations include small sample sizes in some studies, heterogeneity of conditions being treated, and a range of reference treatments.Despite some methodological limitations, the results from randomised, controlled trials to date suggest benefits for Vitex extracts in the treatment of premenstrual syndrome, premenstrual dysphoric disorder and latent hyperprolactinaemia. Further research is recommended, and greater transparency in reporting for future trials. Georg Thieme Verlag KG Stuttgart · New York.

Direct Application of Rep-PCR on Type I Sourdough Matrix to Monitor the Dominance and Persistence of a Lactobacillus plantarum Starter Throughout Back-Slopping.

PubMed

Dolci, Paola; Cocolin, Luca

2017-08-01

This study describes the optimization and application of repetitive element-PCR (rep-PCR) technique directly on microbial DNA extracted from type I sourdoughs for fast monitoring of a Lb. plantarum starter strain (P1FMC) throughout daily back-slopping. The challenge was to follow and study the performance of a starter culture directly in sourdoughs without cultivation on selective media. The extraction of good quality microbial DNA suitable for amplification from a complex matrix such as dough was the first target. In addition, the objective to obtain a clear rep-PCR profile referable to a specific starter strain among a microbial community was pursued. Co-inoculum trials, in flour matrix, with Lb. plantarum P1FMC and L. lactis LC71 strains and, subsequently, type I sourdough back-slopping trials were performed. The rep-PCR amplification profiles obtained were clearly referable to that of Lb. plantarum P1FMC starter in both co-inoculum trials (also when it was present with one order of magnitude less with respect to L. lactis LC71) and back-slopping trials where it dominated the fermentation process with loads of 10 8 cfu g -1 and prevailed on the autochthonous microbiota. Thus, the approach proposed in this paper could be considered a methodological advancement, based on a culture-independent one-step rep-PCR, suitable for fast monitoring of starter performance. © 2017 Institute of Food Technologists®.

A pilot study of simple interventions to improve informed consent in clinical research: feasibility, approach, and results.

PubMed

Kass, Nancy E; Taylor, Holly A; Ali, Joseph; Hallez, Kristina; Chaisson, Lelia

2015-02-01

Research suggests that participants do not always adequately understand studies. While some consent interventions increase understanding, methodologic challenges have been raised in studying consent outside of actual trial settings. This study examined the feasibility of testing two consent interventions in actual studies and measured effectiveness of interventions in improving understanding. Participants enrolling in any of eight ongoing clinical trials were sequentially assigned to one of three different informed consent strategies for enrollment in their clinical trial. Control participants received standard consent procedures for their trial. Participants in the first intervention arm received a bulleted fact sheet summarizing key study information. Participants in the second intervention arm received the bulleted fact sheet and also engaged in a feedback Q&A session. Later, patients answered closed- and open-ended questions to assess patient understanding and literacy. Descriptive statistics, Wilcoxon -Mann -Whitney and Kruskal-Wallis tests were generated to assess correlations; regression analysis determined predictors of understanding. 144 participants enrolled. Using regression analysis, participants receiving the second intervention scored 7.6 percentage points higher (p = .02) on open-ended questions about understanding than participants in the control, although unadjusted comparisons did not reach statistical significance. Our study supports the hypothesis that patients receiving both bulleted fact sheets and a Q&A session had higher understanding compared to standard consent. Fact sheets and short structured dialog are quick to administer and easy to replicate across studies and should be tested in larger samples. © The Author(s) 2014.

COMBAT: Initial experience with a randomized clinical trial of plasma-based resuscitation in the field for traumatic hemorrhagic shock

PubMed Central

Chapman, Michael P.; Moore, Ernest E.; Chin, Theresa L; Ghasabyan, Arsen; Chandler, James; Stringham, John; Gonzalez, Eduardo; Moore, Hunter B.; Banerjee, Anirban; Silliman, Christopher C; Sauaia, Angela

2015-01-01

The existing evidence shows great promise for plasma as the first resuscitation fluid in both civilian and military trauma. We embarked on the Control of Major Bleeding After Trauma (COMBAT) trial with the support of the Department of Defense, in order to determine if plasma-first resuscitation yields hemostatic and survival benefits. The methodology of the COMBAT study represents not only three years of development work, but the integration of nearly two-decades of technical experience with the design and implementation of other clinical trials and studies. Herein, we describe the key features of the study design, critical personnel and infrastructural elements, and key innovations. We will also briefly outline the systems engineering challenges entailed by this study. COMBAT is a randomized, placebo controlled, semi-blinded prospective Phase IIB clinical trial, conducted in a ground ambulance fleet based at a Level I trauma center, and part of a multicenter collaboration. The primary objective of COMBAT is to determine the efficacy of field resuscitation with plasma first, compared to standard of care (normal saline). To date we have enrolled 30 subjects in the COMBAT study. The ability to achieve intervention with a hemostatic resuscitation agent in the closest possible temporal proximity to injury is critical and represents an opportunity to forestall the evolution of the “bloody vicious cycle”. Thus, the COMBAT model for deploying plasma in first response units should serve as a model for RCTs of other hemostatic resuscitative agents. PMID:25784527

Reasons for Ineligibility in Phase 1 and 2A HIV Vaccine Clinical Trials at Kenya Aids Vaccine Initiative (KAVI), Kenya

PubMed Central

Omosa-Manyonyi, Gloria S.; Jaoko, Walter; Anzala, Omu; Ogutu, Hilda; Wakasiaka, Sabina; Malogo, Roselyn; Nyange, Jacqueline; Njuguna, Pamela; Ndinya-Achola, Jeckoniah; Bhatt, Kirana; Farah, Bashir; Oyaro, Micah; Schmidt, Claudia; Priddy, Frances; Fast, Patricia

2011-01-01

Background With the persistent challenges towards controlling the HIV epidemic, there is an ongoing need for research into HIV vaccines and drugs. Sub-Saharan African countries - worst affected by the HIV pandemic - have participated in the conduct of clinical trials for HIV vaccines. In Kenya, the Kenya AIDS Vaccine Initiative (KAVI) at the University of Nairobi has conducted HIV vaccine clinical trials since 2001. Methodology Participants were recruited after an extensive informed consent process followed by screening to determine eligibility. Screening included an assessment of risk behavior, medical history and physical examination, and if clinically healthy, laboratory testing. In the absence of locally derived laboratory reference ranges, the ranges used in these trials were derived from populations in the West. Principal findings Two hundred eighty-one participants were screened between 2003 and 2006 for two clinical trials. Of these, 167 (59.4%) met the inclusion/exclusion criteria. Overall, laboratory abnormalities based on the non-indigenous laboratory references used were the most frequent reasons (61.4%) for ineligibility. Medical abnormalities contributed 30.7% of the total reasons for ineligibility. Based on the laboratory reference intervals now developed from East and Southern Africa, those ineligible due to laboratory abnormalities would have been 46.3%. Of the eligible participants, 18.6% declined enrolment. Conclusions Participant recruitment for HIV vaccine clinical trials is a rigorous and time-consuming exercise. Over 61% of the screening exclusions in clinically healthy people were due to laboratory abnormalities. It is essential that laboratory reference ranges generated from local populations for laboratory values be used in the conduct of clinical trials to avoid unnecessary exclusion of willing participants and to avoid over-reporting of adverse events for enrolled participants. Trial registration Protocol IAVI VRC V001 [1]. ClinicalTrials.gov NCT00124007 Protocol IAVI 010 [2] (registration with ClincalTrials.gov is in progress) Protocols IAVI 002 and IAVI 004 are Phase 1 trials only mentioned in introductory paragraphs; details will not be reported. Registration was not required when they were conducted. PMID:21283743

The Sexunzipped trial: young people's views of participating in an online randomized controlled trial.

PubMed

Nicholas, Angela; Bailey, Julia V; Stevenson, Fiona; Murray, Elizabeth

2013-12-12

Incidence of sexually transmitted infections (STIs) among young people in the United Kingdom is increasing. The Internet can be a suitable medium for delivery of sexual health information and sexual health promotion, given its high usage among young people, its potential for creating a sense of anonymity, and ease of access. Online randomized controlled trials (RCTs) are increasingly being used to evaluate online interventions, but while there are many advantages to online methodologies, they can be associated with a number of problems, including poor engagement with online interventions, poor trial retention, and concerns about the validity of data collected through self-report online. We conducted an online feasibility trial that tested the effects of the Sexunzipped website for sexual health compared to an information-only website. This study reports on a qualitative evaluation of the trial procedures, describing participants' experiences and views of the Sexunzipped online trial including methods of recruitment, incentives, methods of contact, and sexual health outcome measurement. Our goal was to determine participants' views of the acceptability and validity of the online trial methodology used in the pilot RCT of the Sexunzipped intervention. We used three qualitative data sources to assess the acceptability and validity of the online pilot RCT methodology: (1) individual interviews with 22 participants from the pilot RCT, (2) 133 emails received by the trial coordinator from trial participants, and (3) 217 free-text comments from the baseline and follow-up questionnaires. Interviews were audio-recorded and transcribed verbatim. An iterative, thematic analysis of all three data sources was conducted to identify common themes related to the acceptability and feasibility of the online trial methodology. Interview participants found the trial design, including online recruitment via Facebook, online registration, email communication with the researchers, and online completion of sexual health questionnaires to be highly acceptable and preferable to traditional methods. Incentives might assist in recruiting those who would not otherwise participate. Participants generally enjoyed taking part in sexual health research online and found the questionnaire itself thought-provoking. Completing the sexual health questionnaires online encouraged honesty in responding that might not be achieved with other methods. The majority of interview participants also thought that receiving and returning a urine sample for chlamydia testing via post was acceptable. These findings provide strong support for the use of online research methods for sexual health research, emphasizing the importance of careful planning and execution of all trial procedures including recruitment, respondent validation, trial related communication, and methods to maximize follow-up. Our findings suggest that sexual health outcome measurement might encourage reflection on current behavior, sometimes leading to behavior change. International Standard Randomized Controlled Trial Number (ISRCTN): 55651027; http://www.controlled-trials.com/isrctn/pf/55651027 (Archived by WebCite at http://www.webcitation.org/6LbkxdPKf).

Grey literature in meta-analyses of randomized trials of health care interventions.

PubMed

Hopewell, S; McDonald, S; Clarke, M; Egger, M

2007-04-18

The inclusion of grey literature (i.e. literature that has not been formally published) in systematic reviews may help to overcome some of the problems of publication bias, which can arise due to the selective availability of data. To review systematically research studies, which have investigated the impact of grey literature in meta-analyses of randomized trials of health care interventions. We searched the Cochrane Methodology Register (The Cochrane Library Issue 3, 2005), MEDLINE (1966 to 20 May 2005), the Science Citation Index (June 2005) and contacted researchers who may have carried out relevant studies. A study was considered eligible for this review if it compared the effect of the inclusion and exclusion of grey literature on the results of a cohort of meta-analyses of randomized trials. Data were extracted from each report independently by two reviewers. The main outcome measure was an estimate of the impact of trials from the grey literature on the pooled effect estimates of the meta-analyses. Information was also collected on the area of health care, the number of meta-analyses, the number of trials, the number of trial participants, the year of publication of the trials, the language and country of publication of the trials, the number and type of grey and published literature, and methodological quality. Five studies met the inclusion criteria. All five studies showed that published trials showed an overall greater treatment effect than grey trials. This difference was statistically significant in one of the five studies. Data could be combined for three of the five studies. This showed that, on average, published trials showed a 9% greater treatment effect than grey trials (ratio of odds ratios for grey versus published trials 1.09; 95% CI 1.03-1.16). Overall there were more published trials included in the meta-analyses than grey trials (median 224 (IQR 108-365) versus 45(IQR 40-102)). Published trials had more participants on average. The most common types of grey literature were abstracts (55%) and unpublished data (30%). There is limited evidence to show whether grey trials are of poorer methodological quality than published trials. This review shows that published trials tend to be larger and show an overall greater treatment effect than grey trials. This has important implications for reviewers who need to ensure they identify grey trials, in order to minimise the risk of introducing bias into their review.

Cost collection and analysis for health economic evaluation.

PubMed

Smith, Kristine A; Rudmik, Luke

2013-08-01

To improve the understanding of common health care cost collection, estimation, analysis, and reporting methodologies. Ovid MEDLINE (1947 to December 2012), Cochrane Central register of Controlled Trials, Database of Systematic Reviews, Health Technology Assessment, and National Health Service Economic Evaluation Database. This article discusses the following cost collection methods: defining relevant resources, quantification of consumed resources, and resource valuation. It outlines the recommendations for cost reporting in economic evaluations and reviews the techniques on how to handle cost data uncertainty. Last, it discusses the controversial topics of future costs and patient productivity losses. Health care cost collection and estimation can be challenging, and an organized approach is required to optimize accuracy of economic evaluation outcomes. Understanding health care cost collection and estimation techniques will improve both critical appraisal and development of future economic evaluations.

Benefits and challenges of using the cohort multiple randomised controlled trial design for testing an intervention for depression.

PubMed

Viksveen, Petter; Relton, Clare; Nicholl, Jon

2017-07-06

Trials which test the effectiveness of interventions compared with the status quo frequently encounter challenges. The cohort multiple randomised controlled trial (cmRCT) design is an innovative approach to the design and conduct of pragmatic trials which seeks to address some of these challenges. In this article, we report our experiences with the first completed randomised controlled trial (RCT) using the cmRCT design. This trial-the Depression in South Yorkshire (DEPSY) trial-involved comparison of treatment as usual (TAU) with TAU plus the offer of an intervention for people with self-reported long-term moderate to severe depression. In the trial, we used an existing large population-based cohort: the Yorkshire Health Study. We discuss our experiences with recruitment, attrition, crossover, data analysis, generalisability of results, and cost. The main challenges in using the cmRCT design were the high crossover to the control group and the lower questionnaire response rate among patients who refused the offer of treatment. However, the design did help facilitate efficient and complete recruitment of the trial population as well as analysable data that were generalisable to the population of interest. Attrition rates were also smaller than those reported in other depression trials. This first completed full trial using the cmRCT design testing an intervention for self-reported depression was associated with a number of important benefits. Further research is required to compare the acceptability and cost effectiveness of standard pragmatic RCT design with the cmRCT design. ISRCTN registry: ISRCTN02484593 . Registered on 7 Jan 2013.

Psychosocial development in racially and ethnically diverse youth: conceptual and methodological challenges in the 21st century.

PubMed

Swanson, Dena Phillips; Spencer, Margaret Beale; Harpalani, Vinay; Dupree, Davido; Noll, Elizabeth; Ginzburg, Sofia; Seaton, Gregory

2003-01-01

As the US population becomes more diverse in the 21st century, researchers face many conceptual and methodological challenges in working with diverse populations. We discuss these issues for racially and ethnically diverse youth, using Spencer's phenomenological variant of ecological systems theory (PVEST) as a guiding framework. We present a brief historical background and discuss recurring conceptual flaws in research on diverse youth, presenting PVEST as a corrective to these flaws. We highlight the interaction of race, culture, socioeconomic status, and various contexts of development with identity formation and other salient developmental processes. Challenges in research design and interpretation of data are also covered with regard to both assessment of contexts and developmental processes. We draw upon examples from neighborhood assessments, ethnic identity development, and attachment research to illustrate conceptual and methodological challenges, and we discuss strategies to address these challenges. The policy implications of our analysis are also considered.

Setting up a clinical trial for a novel disease: a case study of the Doxycycline for the Treatment of Nodding Syndrome Trial – challenges, enablers and lessons learned

PubMed Central

Anguzu, Ronald; Akun, Pamela R; Ogwang, Rodney; Shour, Abdul Rahman; Sekibira, Rogers; Ningwa, Albert; Nakamya, Phellister; Abbo, Catherine; Mwaka, Amos D; Opar, Bernard; Idro, Richard

2018-01-01

ABSTRACT A large amount of preparation goes into setting up trials. Different challenges and lessons are experienced. Our trial, testing a treatment for nodding syndrome, an acquired neurological disorder of unknown cause affecting thousands of children in Eastern Africa, provides a unique case study. As part of a study to determine the aetiology, understand pathogenesis and develop specific treatment, we set up a clinical trial in a remote district hospital in Uganda. This paper describes our experiences and documents supportive structures (enablers), challenges faced and lessons learned during set-up of the trial. Protocol development started in September 2015 with phased recruitment of a critical study team. The team spent 12 months preparing trial documents, procurement and training on procedures. Potential recruitment sites were pre-visited, and district and local leaders met as key stakeholders. Key enablers were supportive local leadership and investment by the district and Ministry of Health. The main challenges were community fears about nodding syndrome, adverse experiences of the community during previous research and political involvement. Other challenges included the number and delays in protocol approvals and lengthy procurement processes. This hard-to-reach area has frequent power and Internet fluctuations, which may affect cold chains for study samples, communication and data management. These concerns decreased with a pilot community engagement programme. Experiences and lessons learnt can reduce the duration of processes involved in trial-site set-up. A programme of community engagement and local leader involvement may be key to the success of a trial and in reducing community opposition towards participation in research. PMID:29382251

Setting up a clinical trial for a novel disease: a case study of the Doxycycline for the Treatment of Nodding Syndrome Trial - challenges, enablers and lessons learned.

PubMed

Anguzu, Ronald; Akun, Pamela R; Ogwang, Rodney; Shour, Abdul Rahman; Sekibira, Rogers; Ningwa, Albert; Nakamya, Phellister; Abbo, Catherine; Mwaka, Amos D; Opar, Bernard; Idro, Richard

2018-01-01

A large amount of preparation goes into setting up trials. Different challenges and lessons are experienced. Our trial, testing a treatment for nodding syndrome, an acquired neurological disorder of unknown cause affecting thousands of children in Eastern Africa, provides a unique case study. As part of a study to determine the aetiology, understand pathogenesis and develop specific treatment, we set up a clinical trial in a remote district hospital in Uganda. This paper describes our experiences and documents supportive structures (enablers), challenges faced and lessons learned during set-up of the trial. Protocol development started in September 2015 with phased recruitment of a critical study team. The team spent 12 months preparing trial documents, procurement and training on procedures. Potential recruitment sites were pre-visited, and district and local leaders met as key stakeholders. Key enablers were supportive local leadership and investment by the district and Ministry of Health. The main challenges were community fears about nodding syndrome, adverse experiences of the community during previous research and political involvement. Other challenges included the number and delays in protocol approvals and lengthy procurement processes. This hard-to-reach area has frequent power and Internet fluctuations, which may affect cold chains for study samples, communication and data management. These concerns decreased with a pilot community engagement programme. Experiences and lessons learnt can reduce the duration of processes involved in trial-site set-up. A programme of community engagement and local leader involvement may be key to the success of a trial and in reducing community opposition towards participation in research.

Multiattribute selection of acute stroke imaging software platform for Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) clinical trial.

PubMed

Churilov, Leonid; Liu, Daniel; Ma, Henry; Christensen, Soren; Nagakane, Yoshinari; Campbell, Bruce; Parsons, Mark W; Levi, Christopher R; Davis, Stephen M; Donnan, Geoffrey A

2013-04-01

The appropriateness of a software platform for rapid MRI assessment of the amount of salvageable brain tissue after stroke is critical for both the validity of the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) Clinical Trial of stroke thrombolysis beyond 4.5 hours and for stroke patient care outcomes. The objective of this research is to develop and implement a methodology for selecting the acute stroke imaging software platform most appropriate for the setting of a multi-centre clinical trial. A multi-disciplinary decision making panel formulated the set of preferentially independent evaluation attributes. Alternative Multi-Attribute Value Measurement methods were used to identify the best imaging software platform followed by sensitivity analysis to ensure the validity and robustness of the proposed solution. Four alternative imaging software platforms were identified. RApid processing of PerfusIon and Diffusion (RAPID) software was selected as the most appropriate for the needs of the EXTEND trial. A theoretically grounded generic multi-attribute selection methodology for imaging software was developed and implemented. The developed methodology assured both a high quality decision outcome and a rational and transparent decision process. This development contributes to stroke literature in the area of comprehensive evaluation of MRI clinical software. At the time of evaluation, RAPID software presented the most appropriate imaging software platform for use in the EXTEND clinical trial. The proposed multi-attribute imaging software evaluation methodology is based on sound theoretical foundations of multiple criteria decision analysis and can be successfully used for choosing the most appropriate imaging software while ensuring both robust decision process and outcomes. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.

Defining Precision Medicine Approaches to Autism Spectrum Disorders: Concepts and Challenges.

PubMed

Loth, Eva; Murphy, Declan G; Spooren, Will

2016-01-01

The tremendous clinical and etiological variability between individuals with autism spectrum disorder (ASD) has made precision medicine the most promising treatment approach. It aims to combine new pathophysiologically based treatments with objective tests (stratification biomarkers) to predict which treatment may be beneficial for a particular person. Here we discuss significant advances and current challenges for this approach: rare monogenic forms of ASD have provided a major breakthrough for the identification of treatment targets by providing a means to trace causal links from a gene to specific molecular alterations and biological pathways. To estimate whether treatment targets thus identified may be useful for larger patient groups we need a better understanding of whether different etiologies (i.e., genetic and environmental risk factors acting at different critical time points) lead to convergent or divergent molecular mechanisms, and how they map onto differences in circuit-level brain and cognitive development, and behavioral symptom profiles. Several recently failed clinical trials with syndromic forms of ASD provide valuable insights into conceptual and methodological issues linked to limitations in the translatability from animal models to humans, placebo effects, and a need for mechanistically plausible, objective outcome measures. To identify stratification biomarkers that enrich participant selection in clinical trials, large-scale multi-modal longitudinal observational studies are underway. Addressing these different factors in the next generation of research studies requires a translatable developmental perspective and multidisciplinary, collaborative efforts, with a commitment to sharing protocols and data, to increase transparency and reproducibility.

NIAID, NIEHS, NHLBI, and MCAN Workshop Report: The indoor environment and childhood asthma-implications for home environmental intervention in asthma prevention and management.

PubMed

Gold, Diane R; Adamkiewicz, Gary; Arshad, Syed Hasan; Celedón, Juan C; Chapman, Martin D; Chew, Ginger L; Cook, Donald N; Custovic, Adnan; Gehring, Ulrike; Gern, James E; Johnson, Christine C; Kennedy, Suzanne; Koutrakis, Petros; Leaderer, Brian; Mitchell, Herman; Litonjua, Augusto A; Mueller, Geoffrey A; O'Connor, George T; Ownby, Dennis; Phipatanakul, Wanda; Persky, Victoria; Perzanowski, Matthew S; Ramsey, Clare D; Salo, Päivi M; Schwaninger, Julie M; Sordillo, Joanne E; Spira, Avrum; Suglia, Shakira F; Togias, Alkis; Zeldin, Darryl C; Matsui, Elizabeth C

2017-10-01

Environmental exposures have been recognized as critical in the initiation and exacerbation of asthma, one of the most common chronic childhood diseases. The National Institute of Allergy and Infectious Diseases; National Institute of Environmental Health Sciences; National Heart, Lung, and Blood Institute; and Merck Childhood Asthma Network sponsored a joint workshop to discuss the current state of science with respect to the indoor environment and its effects on the development and morbidity of childhood asthma. The workshop included US and international experts with backgrounds in allergy/allergens, immunology, asthma, environmental health, environmental exposures and pollutants, epidemiology, public health, and bioinformatics. Workshop participants provided new insights into the biologic properties of indoor exposures, indoor exposure assessment, and exposure reduction techniques. This informed a primary focus of the workshop: to critically review trials and research relevant to the prevention or control of asthma through environmental intervention. The participants identified important limitations and gaps in scientific methodologies and knowledge and proposed and prioritized areas for future research. The group reviewed socioeconomic and structural challenges to changing environmental exposure and offered recommendations for creative study design to overcome these challenges in trials to improve asthma management. The recommendations of this workshop can serve as guidance for future research in the study of the indoor environment and on environmental interventions as they pertain to the prevention and management of asthma and airway allergies. Published by Elsevier Inc.

Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research

PubMed Central

Oberman, Lindsay M.; Enticott, Peter G.; Casanova, Manuel F.; Rotenberg, Alexander; Pascual-Leone, Alvaro; McCracken, James T.

2016-01-01

Autism Spectrum Disorder (ASD) is a behaviorally defined complex neurodevelopmental syndrome characterized by impairments in social communication, by the presence of restricted and repetitive behaviors, interests and activities, and by abnormalities in sensory reactivity. Transcranial magnetic stimulation (TMS) is a promising, emerging tool for the study and potential treatment of ASD. Recent studies suggest that TMS measures provide rapid and noninvasive pathophysiological ASD biomarkers. Furthermore, repetitive TMS (rTMS) may represent a novel treatment strategy for reducing some of the core and associated ASD symptoms. However, the available literature on the TMS use in ASD is preliminary, composed of studies with methodological limitations. Thus, off-label clinical rTMS use for therapeutic interventions in ASD without an investigational device exemption and outside of an IRB approved research trial is premature pending further, adequately powered and controlled trials. Leaders in this field have gathered annually for a two-day conference (prior to the 2014 and 2015 International Meeting for Autism Research, IMFAR) to share recent progress, promote collaboration across laboratories, and establish consensus on protocols. Here we review the literature in the use of TMS in ASD in the context of the unique challenges required for the study and exploration of treatment strategies in this population. We also suggest future directions for this field of investigations. While its true potential in ASD has yet to be delineated, TMS represents an innovative research tool and a novel, possibly transformative approach to the treatment of neurodevelopmental disorders. PMID:26536383

Methodological strategies in using home sleep apnea testing in research and practice.

PubMed

Miller, Jennifer N; Schulz, Paula; Pozehl, Bunny; Fiedler, Douglas; Fial, Alissa; Berger, Ann M

2017-11-14

Home sleep apnea testing (HSAT) has increased due to improvements in technology, accessibility, and changes in third party reimbursement requirements. Research studies using HSAT have not consistently reported procedures and methodological challenges. This paper had two objectives: (1) summarize the literature on use of HSAT in research of adults and (2) identify methodological strategies to use in research and practice to standardize HSAT procedures and information. Search strategy included studies of participants undergoing sleep testing for OSA using HSAT. MEDLINE via PubMed, CINAHL, and Embase with the following search terms: "polysomnography," "home," "level III," "obstructive sleep apnea," and "out of center testing." Research articles that met inclusion criteria (n = 34) inconsistently reported methods and methodological challenges in terms of: (a) participant sampling; (b) instrumentation issues; (c) clinical variables; (d) data processing; and (e) patient acceptability. Ten methodological strategies were identified for adoption when using HSAT in research and practice. Future studies need to address the methodological challenges summarized in this paper as well as identify and report consistent HSAT procedures and information.

Methodological and ethical challenges in studying patients' perceptions of coercion: a systematic mixed studies review.

PubMed

Soininen, Päivi; Putkonen, Hanna; Joffe, Grigori; Korkeila, Jyrki; Välimäki, Maritta

2014-06-04

Despite improvements in psychiatric inpatient care, patient restrictions in psychiatric hospitals are still in use. Studying perceptions among patients who have been secluded or physically restrained during their hospital stay is challenging. We sought to review the methodological and ethical challenges in qualitative and quantitative studies aiming to describe patients' perceptions of coercive measures, especially seclusion and physical restraints during their hospital stay. Systematic mixed studies review was the study method. Studies reporting patients' perceptions of coercive measures, especially seclusion and physical restraints during hospital stay were included. Methodological issues such as study design, data collection and recruitment process, participants, sampling, patient refusal or non-participation, and ethical issues such as informed consent process, and approval were synthesized systematically. Electronic searches of CINALH, MEDLINE, PsychINFO and The Cochrane Library (1976-2012) were carried out. Out of 846 initial citations, 32 studies were included, 14 qualitative and 18 quantitative studies. A variety of methodological approaches were used, although descriptive and explorative designs were used in most cases. Data were mainly collected in qualitative studies by interviews (n = 13) or in quantitative studies by self-report questionnaires (n = 12). The recruitment process was explained in 59% (n = 19) of the studies. In most cases convenience sampling was used, yet five studies used randomization. Patient's refusal or non-participation was reported in 37% (n = 11) of studies. Of all studies, 56% (n = 18) had reported undergone an ethical review process in an official board or committee. Respondents were informed and consent was requested in 69% studies (n = 22). The use of different study designs made comparison methodologically challenging. The timing of data collection (considering bias and confounding factors) and the reasons for non-participation of eligible participants are likewise methodological challenges, e.g. recommended flow charts could aid the information. Other challenges identified were the recruitment of large and representative samples. Ethical challenges included requesting participants' informed consent and respecting ethical procedures.

A Coorientational Analysis of Trial Lawyer and News Reporter Relationships.

ERIC Educational Resources Information Center

Lipschultz, Jeremy Harris

A study considered the relationships of trial lawyers and news reporters, using the coorientation measurement model and Q-methodology, and adapting an analysis of variance experimental design. Sixty statements were constructed and administered to 24 subjects (12 trial lawyers and 12 news reporters) in two large midwestern cities. It was found…

The Technical Report of NAEP's 1990 Trial State Assessment Program.

ERIC Educational Resources Information Center

Koffler, Stephen L.; And Others

This report documents the design and data analysis procedures of the Trial State Assessment Program of the National Assessment of Educational Progress (NAEP). Today the NAEP is the only survey using advanced plausible values methodology that uses a multiple imputation procedure in a psychometric context. The 1990 Trial State Assessment collected…

A Patient Focused Solution for Enrolling Clinical Trials in Rare and Selective Cancer Indications: A Landscape of Haystacks and Needles

PubMed Central

Lynam, Eric B.; Leaw, Jiin; Wiener, Matthew B.

2013-01-01

Participation of adult cancer patients in US based clinical trials has remained near 3% for decades. Traditional research methodology reaches a small fraction of the target population with a fixed number of predetermined sites. Solutions are needed to ethically increase patient participation and accelerate cancer trial completion. We compared enrollment outcomes of traditional and patient focused research methodologies. A patient prioritized method (Just-In-Time, JIT) was implemented in parallel with traditionally managed sites in three cancer trials. JIT research sites were initiated after candidate patients presented, while traditional sites were initiated in advance. JIT sites enrolled with mean rates no less than, and up to 2.75 fold greater than, traditional sites. Mean patients enrolled per site was comparable (JIT-1.82, traditional-1.78). There were fewer non-enrolling JIT sites (2/28, 7%) compared to traditional sites 19/52, 37%). This retrospective analysis supports JIT as a prospective solution to increase cancer clinical trial enrollment and the efficiency of clinical trial administrative activities. PMID:23990689

Physical activity interventions for people with mental illness: a systematic review and meta-analysis.

PubMed

Rosenbaum, Simon; Tiedemann, Anne; Sherrington, Catherine; Curtis, Jackie; Ward, Philip B

2014-09-01

To determine effects of physical activity on depressive symptoms (primary objective), symptoms of schizophrenia, anthropometric measures, aerobic capacity, and quality of life (secondary objectives) in people with mental illness and explore between-study heterogeneity. MEDLINE, Cochrane Controlled Trials Register, PsycINFO, CINAHL, Embase, and the Physiotherapy Evidence Database (PEDro) were searched from earliest record to 2013. Randomized controlled trials of adults with a DSM-IV-TR, ICD-10, or clinician-confirmed diagnosis of a mental illness other than dysthymia or eating disorders were selected. Interventions included exercise programs, exercise counseling, lifestyle interventions, tai chi, or physical yoga. Study methodological quality and intervention compliance with American College of Sports Medicine (ACSM) guidelines were also assessed. Two investigators extracted data. Data were pooled using random-effects meta-analysis. Meta-regression was used to examine sources of between-study heterogeneity. Thirty-nine eligible trials were identified. The primary meta-analysis found a large effect of physical activity on depressive symptoms (n = 20; standardized mean difference (SMD) = 0.80). The effect size in trial interventions that met ACSM guidelines for aerobic exercise did not differ significantly from those that did not meet these guidelines. The effect for trials with higher methodological quality was smaller than that observed for trials with lower methodological quality (SMD = 0.39 vs 1.35); however, the difference was not statistically significant. A large effect was found for schizophrenia symptoms (SMD = 1.0), a small effect was found for anthropometry (SMD = 0.24), and moderate effects were found for aerobic capacity (SMD = 0.63) and quality of life (SMD = 0.64). Physical activity reduced depressive symptoms in people with mental illness. Larger effects were seen in studies of poorer methodological quality. Physical activity reduced symptoms of schizophrenia and improved anthropometric measures, aerobic capacity, and quality of life among people with mental illness. PROSPERO registration #CRD42012002012. © Copyright 2014 Physicians Postgraduate Press, Inc.

Systematic review finds major deficiencies in sample size methodology and reporting for stepped-wedge cluster randomised trials

PubMed Central

Martin, James; Taljaard, Monica; Girling, Alan; Hemming, Karla

2016-01-01

Background Stepped-wedge cluster randomised trials (SW-CRT) are increasingly being used in health policy and services research, but unless they are conducted and reported to the highest methodological standards, they are unlikely to be useful to decision-makers. Sample size calculations for these designs require allowance for clustering, time effects and repeated measures. Methods We carried out a methodological review of SW-CRTs up to October 2014. We assessed adherence to reporting each of the 9 sample size calculation items recommended in the 2012 extension of the CONSORT statement to cluster trials. Results We identified 32 completed trials and 28 independent protocols published between 1987 and 2014. Of these, 45 (75%) reported a sample size calculation, with a median of 5.0 (IQR 2.5–6.0) of the 9 CONSORT items reported. Of those that reported a sample size calculation, the majority, 33 (73%), allowed for clustering, but just 15 (33%) allowed for time effects. There was a small increase in the proportions reporting a sample size calculation (from 64% before to 84% after publication of the CONSORT extension, p=0.07). The type of design (cohort or cross-sectional) was not reported clearly in the majority of studies, but cohort designs seemed to be most prevalent. Sample size calculations in cohort designs were particularly poor with only 3 out of 24 (13%) of these studies allowing for repeated measures. Discussion The quality of reporting of sample size items in stepped-wedge trials is suboptimal. There is an urgent need for dissemination of the appropriate guidelines for reporting and methodological development to match the proliferation of the use of this design in practice. Time effects and repeated measures should be considered in all SW-CRT power calculations, and there should be clarity in reporting trials as cohort or cross-sectional designs. PMID:26846897

Methodology and lessons-learned from the efficacy clinical trial of the pentavalent rotavirus vaccine in Bangladesh.

PubMed

Zaman, K; Yunus, M; El Arifeen, Shams; Azim, Tasnim; Faruque, A S G; Huq, Ehsanul; Hossain, Ilias; Luby, Stephen P; Victor, John C; Dallas, Michael J; Lewis, Kristen D C; Rivers, Stephen B; Steele, A Duncan; Neuzil, Kathleen M; Ciarlet, Max; Sack, David A

2012-04-27

An efficacy clinical trial with pentavalent rotavirus vaccine (PRV), RotaTeq(®), was conducted at Matlab field site of ICDDR,B, Bangladesh from March 2007 to March 2009. The methodology, including operation logistics, and lessons-learned are described in this report. Vaccination was organized at 41 fixed-site clinics twice/month. A total of 1136 infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age with routine vaccines of the Expanded Programme on Immunization (EPI) schedule. Twelve field-workers routinely visited study participants for safety and efficacy follow-up. The study was conducted following good clinical practices and maintaining cold-chain requirements. There were no temperature deviations of clinical vaccine supplies. Data entry was done using the source documents to a central database developed by the sponsor which was linked to web. Among enrolled infants, 1128 (99.3%) received 3 doses of PRV/placebo and efficacy follow-up was conducted for a median of 554 days. For the evaluation of immunogenicity, blood samples were collected from 150 participants predose 1 and from 147 (98%) of the same participants post dose 3. Stool samples were collected from 778 (99.9%) acute gastroenteritis episodes among children who reported to diarrhoea treatment centres. Thirty-nine serious adverse events, including 6 deaths, occurred among study participants. The efficacy of PRV against severe rotavirus gastroenteritis was 42.7% through the entire follow-up period; serum anti-rotavirus IgA response was 78.1%. Inclement weather, difficult transportation, and movement of study participants were some of the challenges identified. This is the first vaccine trial in rural Bangladesh with online data entry. The study was well accepted in the community and was completed successfully. Copyright © 2011 Elsevier Ltd. All rights reserved.

Wordless intervention for epilepsy in learning disabilities (WIELD): study protocol for a randomized controlled feasibility trial.

PubMed

Durand, Marie-Anne; Gates, Bob; Parkes, Georgina; Zia, Asif; Friedli, Karin; Barton, Garry; Ring, Howard; Oostendorp, Linda; Wellsted, David

2014-11-20

Epilepsy is the most common neurological problem that affects people with learning disabilities. The high seizure frequency, resistance to treatments, associated skills deficit and co-morbidities make the management of epilepsy particularly challenging for people with learning disabilities. The Books Beyond Words booklet for epilepsy uses images to help people with learning disabilities manage their condition and improve quality of life. Our aim is to conduct a randomized controlled feasibility trial exploring key methodological, design and acceptability issues, in order to subsequently undertake a large-scale randomized controlled trial of the Books Beyond Words booklet for epilepsy. We will use a two-arm, single-centre randomized controlled feasibility design, over a 20-month period, across five epilepsy clinics in Hertfordshire, United Kingdom. We will recruit 40 eligible adults with learning disabilities and a confirmed diagnosis of epilepsy and will randomize them to use either the Books Beyond Words booklet plus usual care (intervention group) or to receive routine information and services (control group). We will collect quantitative data about the number of eligible participants, number of recruited participants, demographic data, discontinuation rates, variability of the primary outcome measure (quality of life: Epilepsy and Learning Disabilities Quality of Life scale), seizure severity, seizure control, intervention's patterns of use, use of other epilepsy-related information, resource use and the EQ-5D-5L health questionnaire. We will also gather qualitative data about the feasibility and acceptability of the study procedures and the Books Beyond Words booklet. Ethical approval for this study was granted on 28 April 2014, by the Wales Research Ethics Committee 5. Recruitment began on 1 July 2014. The outcomes of this feasibility study will be used to inform the design and methodology of a definitive study, adequately powered to determine the impact of the Books Beyond Words intervention to improve the management of epilepsy in people with learning disabilities. http://ISRCTN80067039 (Date of ISRCTN assignation: 23 April 2014).

Current-reported outcome domains in studies of adults with a focus on the treatment of tinnitus: protocol for a systematic review.

PubMed

Hall, Deborah A; Szczepek, Agnieszka J; Kennedy, Veronica; Haider, Haúla

2015-11-11

In Europe alone, over 70 million people experience tinnitus. Despite its considerable socioeconomic relevance, progress in developing successful treatments has been limited. Clinical effectiveness is judged according to change in primary outcome measures, but because tinnitus is a subjective condition, the definition of outcomes is challenging and it remains unclear which distinct aspects of tinnitus (ie, 'domains') are most relevant for assessment. The development of a minimum outcome reporting standard would go a long way towards addressing these problems. In 2006, a consensus meeting recommended using 1 of 4 questionnaires for tinnitus severity as an outcome in clinical trials, in part because of availability in different language translations. Our initiative takes an approach motivated by clinimetrics, first by determining what to measure before seeking to determine how to measure it. Agreeing on the domains that contribute to tinnitus severity (ie, 'what') is the first step towards achieving a minimum outcome reporting standard for tinnitus that has been reached via a methodologically rigorous and transparent process. Deciding what should be the core set of outcomes requires a great deal of discussion and so lends itself well to international effort. This protocol lays out the first-step methodology in defining a Core Domain Set for clinical trials of tinnitus by establishing existing knowledge and practice with respect to which outcome domains have been measured and which instruments used in recent registered and published clinical trials. No ethical issues are foreseen. Findings will be reported at national and international ear, nose and throat (ENT) and audiology conferences and in a peer-reviewed journal, using PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analysis) guidelines. The systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Rating the methodological quality of single-subject designs and n-of-1 trials: introducing the Single-Case Experimental Design (SCED) Scale.

PubMed

Tate, Robyn L; McDonald, Skye; Perdices, Michael; Togher, Leanne; Schultz, Regina; Savage, Sharon

2008-08-01

Rating scales that assess methodological quality of clinical trials provide a means to critically appraise the literature. Scales are currently available to rate randomised and non-randomised controlled trials, but there are none that assess single-subject designs. The Single-Case Experimental Design (SCED) Scale was developed for this purpose and evaluated for reliability. Six clinical researchers who were trained and experienced in rating methodological quality of clinical trials developed the scale and participated in reliability studies. The SCED Scale is an 11-item rating scale for single-subject designs, of which 10 items are used to assess methodological quality and use of statistical analysis. The scale was developed and refined over a 3-year period. Content validity was addressed by identifying items to reduce the main sources of bias in single-case methodology as stipulated by authorities in the field, which were empirically tested against 85 published reports. Inter-rater reliability was assessed using a random sample of 20/312 single-subject reports archived in the Psychological Database of Brain Impairment Treatment Efficacy (PsycBITE). Inter-rater reliability for the total score was excellent, both for individual raters (overall ICC = 0.84; 95% confidence interval 0.73-0.92) and for consensus ratings between pairs of raters (overall ICC = 0.88; 95% confidence interval 0.78-0.95). Item reliability was fair to excellent for consensus ratings between pairs of raters (range k = 0.48 to 1.00). The results were replicated with two independent novice raters who were trained in the use of the scale (ICC = 0.88, 95% confidence interval 0.73-0.95). The SCED Scale thus provides a brief and valid evaluation of methodological quality of single-subject designs, with the total score demonstrating excellent inter-rater reliability using both individual and consensus ratings. Items from the scale can also be used as a checklist in the design, reporting and critical appraisal of single-subject designs, thereby assisting to improve standards of single-case methodology.

A systematic review of etiological and risk factors associated with bruxism.

PubMed

Feu, Daniela; Catharino, Fernanda; Quintão, Catia Cardoso Abdo; Almeida, Marco Antonio de Oliveira

2013-06-01

The aim of the present work was to systematically review the literature and identify all peer-reviewed papers dealing with etiological and risk factors associated with bruxism. Data extraction was carried out according to the standard Cochrane systematic review methodology. The following databases were searched for randomized clinical trials (RCT), controlled clinical trials (CCT) or cohort studies: Cochrane Library, Medline, and Embase from 1980 to 2011. Unpublished literature was searched electronically using ClinicalTrials.gov. The primary outcome was bruxism etiology. Studies should have a standardized method to assess bruxism. Screening of eligible studies, assessment of the methodological quality and data extraction were conducted independently and in duplicate. Two reviewers inspected the references using the same search strategy and then applied the same inclusion criteria to the selected studies. They used criteria for methodological quality that was previously described in the Cochrane Handbook. Among the 1247 related articles that were critically assessed, one randomized clinical trial, one controlled clinical trial and seven longitudinal studies were included in the critical appraisal. Of these studies, five were selected, but reported different outcomes. There is convincing evidence that (sleep-related) bruxism can be induced by esophageal acidification and also that it has an important relationship with smoking in a dose-dependent manner. Disturbances in the central dopaminergic system are also implicated in the etiology of bruxism.

Renewable Energy Assessment Methodology for Japanese OCONUS Army Installations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Solana, Amy E.; Horner, Jacob A.; Russo, Bryan J.

2010-08-30

Since 2005, Pacific Northwest National Laboratory (PNNL) has been asked by Installation Management Command (IMCOM) to conduct strategic assessments at selected US Army installations of the potential use of renewable energy resources, including solar, wind, geothermal, biomass, waste, and ground source heat pumps (GSHPs). IMCOM has the same economic, security, and legal drivers to develop alternative, renewable energy resources overseas as it has for installations located in the US. The approach for continental US (CONUS) studies has been to use known, US-based renewable resource characterizations and information sources coupled with local, site-specific sources and interviews. However, the extent to whichmore » this sort of data might be available for outside the continental US (OCONUS) sites was unknown. An assessment at Camp Zama, Japan was completed as a trial to test the applicability of the CONUS methodology at OCONUS installations. It was found that, with some help from Camp Zama personnel in translating and locating a few Japanese sources, there was relatively little difficulty in finding sources that should provide a solid basis for conducting an assessment of comparable depth to those conducted for US installations. Project implementation will likely be more of a challenge, but the feasibility analysis will be able to use the same basic steps, with some adjusted inputs, as PNNL’s established renewable resource assessment methodology.« less

Zhen gan xi feng decoction, a traditional chinese herbal formula, for the treatment of essential hypertension: a systematic review of randomized controlled trials.

PubMed

Xiong, Xingjiang; Yang, Xiaochen; Feng, Bo; Liu, Wei; Duan, Lian; Gao, Ao; Li, Haixia; Ma, Jizheng; Du, Xinliang; Li, Nan; Wang, Pengqian; Su, Kelei; Chu, Fuyong; Zhang, Guohao; Li, Xiaoke; Wang, Jie

2013-01-01

Objectives. To assess the clinical effectiveness and adverse effects of Zhen Gan Xi Feng Decoction (ZGXFD) for essential hypertension (EH). Methods. Five major electronic databases were searched up to August 2012 to retrieve any potential randomized controlled trials designed to evaluate the clinical effectiveness of ZGXFD for EH reported in any language, with main outcome measure as blood pressure (BP). Results. Six randomized trials were included. Methodological quality of the trials was evaluated as generally low. Four trials compared prescriptions based on ZGXFD with antihypertensive drugs. Meta-analysis showed that ZGXFD was more effective in BP control and TCM syndrome and symptom differentiation (TCM-SSD) scores than antihypertensive drugs. Two trials compared the combination of modified ZGXFD plus antihypertensive drugs with antihypertensive drugs. Meta-analysis showed that there is significant beneficial effect on TCM-SSD scores. However, no significant effect on BP was found. The safety of ZGXFD is still uncertain. Conclusions. ZGXFD appears to be effective in improving blood pressure and hypertension-related symptoms for EH. However, the evidence remains weak due to poor methodological quality of the included studies. More rigorous trials are warranted to support their clinical use.

Conducting non-commercial international clinical trials: the ICR-CTSU experience.

PubMed

Fox, Lisa; Toms, Christy; Kernaghan, Sarah; Snowdon, Claire; Bliss, Judith M

2017-09-26

Academic clinical trials play a fundamental role in the development of new treatments, the repurposing of existing treatments and in addressing areas of unmet clinical need. With cancer treatments increasingly targeted at molecular subtypes, and with priority placed on developing new treatments for rare tumour types, the need for international trial participation to access sufficient patient numbers for successful trial conduct is growing. However, lack of harmonisation of international legal, ethical and financial systems can make this challenging and the cost and effort of conducting trials internationally can be considered prohibitive, particularly where the sample size is comparatively small. The Institute of Cancer Research - Clinical Trials and Statistics Unit (ICR-CTSU) is a UK-based academic clinical trials unit that specialises in the design, conduct and analysis of clinical trials of cancer treatments with an expanding portfolio of trials in molecular subtypes of breast and urological cancers and in other rare cancer types. Implementing appropriate mechanisms to enable international participation has therefore been imperative. In this article, we explain how we have approached the challenges involved and describe examples of successful international trial conduct, achieved through robust collaborations with academic and industry partners. Conducting academic trials internationally is challenging but can and should be achieved through appropriate governance mechanisms and strong collaborations.

The Benefits and Challenges of Preconsent in a Multisite, Pediatric Sickle Cell Intervention Trial.

PubMed

Nimmer, Mark; Czachor, Jason; Turner, Laura; Thomas, Bobbe; Woodford, Ashley L; Carpenter, Karli; Gonzalez, Victor; Liem, Robert I; Ellison, Angela; Casper, T Charles; Brousseau, David C

2016-09-01

Enrollment of patients in sickle cell intervention trials has been challenging due to difficulty in obtaining consent from a legal guardian and lack of collaboration between emergency medicine and hematology. We utilized education and preconsent in a pediatric multisite sickle cell intervention trial to overcome these challenges. Overall, 48 patients were enrolled after being preconsented. Variable Institutional Review Board policies related to preconsent validity and its allowable duration decreased the advantages of preconsent at some sites. The utility of preconsent for future intervention trials largely depends on local Institutional Review Board policies. Preeducation may also benefit the consent process, regardless of site differences. © 2016 Wiley Periodicals, Inc.

A study to assess whether fixed-width beam walking provides sufficient challenge to assess balance ability across lower limb prosthesis users.

PubMed

Sawers, Andrew; Hafner, Brian J

2018-04-01

To evaluate the feasibility of fixed-width beam walking for assessing balance in lower limb prosthesis users. Cross-sectional. Laboratory. Lower limb prosthesis users. Participants attempted 10 walking trials on three fixed-width beams (18.6, 8.60, and 4.01 wide; 5.5 m long; 3.8 cm high). Beam-walking performance was quantified using the distance walked to balance failure. Heuristic rules applied to each participant's beam-walking distance to classify each beam as "too easy," "too hard," or "appropriately challenging" and determine whether any single beam provided an appropriate challenge to all participants. The number of trials needed to achieve stable beam-walking performance was quantified for appropriately challenging beams by identifying the last inflection point in the slope of each participant's trial-by-trial cumulative performance record. In all, 30 unilateral lower limb prosthesis users participated in the study. Each of the fixed-width beams was either too easy or too hard for at least 33% of the sample. Thus, no single beam was appropriately challenging for all participants. Beam-walking performance was stable by trial 8 for all participants and by trial 6 for 90% of participants. There was no significant difference in the number of trials needed to achieve stable performance among beams ( P = 0.74). Results suggest that a clinical beam-walking test would require multiple beams to evaluate balance across a range of lower limb prosthesis users, emphasizing the need for adaptive or progressively challenging balance tests. While the administrative burden of a multiple-beam balance test may limit clinical feasibility, alternatives to ease this administrative burden are proposed.

Stakeholders' views on the ethical challenges of pragmatic trials investigating pharmaceutical drugs.

PubMed

Kalkman, Shona; van Thiel, Ghislaine J M W; Grobbee, Diederick E; Meinecke, Anna-Katharina; Zuidgeest, Mira G P; van Delden, Johannes J M

2016-08-22

We explored the views of key stakeholders to identify the ethical challenges of pragmatic trials investigating pharmaceutical drugs. A secondary aim was to capture stakeholders' attitudes towards the implementation of pragmatic trials in the drug development process. We conducted semistructured, in-depth interviews among individuals from different key stakeholder groups (academia and independent research institutions, the pharmaceutical industry, regulators, Health Technology Assessment (HTA) agencies and patients' organizations) through telephone or face-to-face sessions. Interviews were structured around the question "what challenges were experienced or perceived during the design, conduct and/or review of pragmatic trials." Respondents were additionally asked about their views on implementation of pragmatic trials in the drug development process. Thematic analysis was used to identify the ethically relevant features across data sets. We interviewed 34 stakeholders in 25 individual sessions and four group sessions. The four perceived challenges of ethical relevance were: (1) less controlled conditions creating safety concerns, (2) comparison with usual care potentially compromising clinical equipoise, (3) tailored or waivers of informed consent affecting patient autonomy, and (4) minimal interference with "real-world" practice reducing the knowledge value of trial results. We identified stakeholder concerns regarding risk assessment, use of suboptimal usual care as a comparator, tailoring of informed consent procedures and ensuring the social value of pragmatic trials. These concerns increased when respondents were asked about pragmatic trials conducted before market authorization.

Challenges to recruitment and retention of African Americans in the gene-environment trial of response to dietary interventions (GET READI) for heart health

PubMed Central

Kennedy, Betty M.; Harsha, David W.; Bookman, Ebony B.; Hill, Yolanda R.; Rankinen, Tuomo; Rodarte, Ruben Q.; Murla, Connie D.

2011-01-01

In this paper, challenges to recruiting African Americans specifically for a dietary feeding trial are examined, learning experiences gained and suggestions to overcome these challenges in future trials are discussed. A total of 333 individuals were randomized in the trial and 234 (167 sibling pairs and 67 parents/siblings) completed the dietary intervention and required DNA blood sampling for genetic analysis. The trial used multiple strategies for recruitment. Hand distributed letters and flyers through mass distribution at various churches resulted in the largest number (n = 153, 46%) of African Americans in the trial. Word of mouth accounted for the second largest number (n = 120, 36%) and included prior study participants. These two recruitment sources represented 82% (n = 273) of the total number of individuals randomized in GET READI. The remaining 18% (n = 60) consisted of a combination of sources including printed message on check stubs, newspaper articles, radio and TV appearances, screening events and presentations. Though challenging, the recruitment efforts for GET READI produced a significant number of African American participants despite the inability to complete the trial as planned because of low recruitment yields. Nevertheless, the recruitment process produced substantial numbers that successfully completed all study requirements. PMID:21865154

A systematic review of the use of an expertise-based randomised controlled trial design.

PubMed

Cook, Jonathan A; Elders, Andrew; Boachie, Charles; Bassinga, Ted; Fraser, Cynthia; Altman, Doug G; Boutron, Isabelle; Ramsay, Craig R; MacLennan, Graeme S

2015-05-30

Under a conventional two-arm randomised trial design, participants are allocated to an intervention and participating health professionals are expected to deliver both interventions. However, health professionals often have differing levels of expertise in a skill-based interventions such as surgery or psychotherapy. An expertise-based approach to trial design, where health professionals only deliver an intervention in which they have expertise, has been proposed as an alternative. The aim of this project was to systematically review the use of an expertise-based trial design in the medical literature. We carried out a comprehensive search of nine databases--AMED, BIOSIS, CENTRAL, CINAHL, Cochrane Methodology Register, EMBASE, MEDLINE, Science Citation Index, and PsycINFO--from 1966 to 2012 and performed citation searches using the ISI Citation Indexes and Scopus. Studies that used an expertise-based trial design were included. Two review authors independently screened the titles and abstracts and assessed full-text reports. Data were extracted and summarised on the study characteristics, general and expertise-specific study methodology, and conduct. In total, 7476 titles and abstracts were identified, leading to 43 included studies (54 articles). The vast majority (88%) used a pure expertise-based design; three (7%) adopted a hybrid design, and two (5%) used a design that was unclear. Most studies compared substantially different interventions (79%). In many cases, key information relating to the expertise-based design was absent; only 12 (28%) reported criteria for delivering both interventions. Most studies recruited the target sample size or very close to it (median of 101, interquartile range of 94 to 118), although the target was reported for only 40% of studies. The proportion of participants who received the allocated intervention was high (92%, interquartile range of 82 to 99%). While use of an expertise-based trial design is growing, it remains uncommon. Reporting of study methodology and, particularly, expertise-related methodology was poor. Empirical evidence provided some support for purported benefits such as high levels of recruitment and compliance with allocation. An expertise-based trial design should be considered but its value seems context-specific, particularly when interventions differ substantially or interventions are typically delivered by different health professionals.

Bridging semantics and syntax with graph algorithms—state-of-the-art of extracting biomedical relations

PubMed Central

Uzuner, Özlem; Szolovits, Peter

2017-01-01

Research on extracting biomedical relations has received growing attention recently, with numerous biological and clinical applications including those in pharmacogenomics, clinical trial screening and adverse drug reaction detection. The ability to accurately capture both semantic and syntactic structures in text expressing these relations becomes increasingly critical to enable deep understanding of scientific papers and clinical narratives. Shared task challenges have been organized by both bioinformatics and clinical informatics communities to assess and advance the state-of-the-art research. Significant progress has been made in algorithm development and resource construction. In particular, graph-based approaches bridge semantics and syntax, often achieving the best performance in shared tasks. However, a number of problems at the frontiers of biomedical relation extraction continue to pose interesting challenges and present opportunities for great improvement and fruitful research. In this article, we place biomedical relation extraction against the backdrop of its versatile applications, present a gentle introduction to its general pipeline and shared resources, review the current state-of-the-art in methodology advancement, discuss limitations and point out several promising future directions. PMID:26851224

Two Methodological Challenges for Teacher-Researchers: Reflexivity and Trustworthiness

ERIC Educational Resources Information Center

Xerri, Daniel

2018-01-01

Teacher research is lauded as a beneficial enterprise both for practitioners and for learners. However, teachers are sometimes accused of not possessing the necessary knowledge and skills to conduct research effectively. This article focuses on the need for teacher-researchers to find means of addressing the methodological challenges of engaging…

Counseling Psychology Research on Sexual (Orientation) Minority Issues: Conceptual and Methodological Challenges and Opportunities

ERIC Educational Resources Information Center

Moradi, Bonnie; Mohr, Jonathan J.; Worthington, Roger L.; Fassinger, Ruth E.

2009-01-01

This lead article of the special issue discusses conceptual and methodological considerations in studying sexual minority issues, particularly in research conducted by counseling psychologists (including the work represented in this special issue). First, the overarching challenge of conceptualizing and defining sexual minority populations is…

Theoretical Borderlands: Using Multiple Theoretical Perspectives to Challenge Inequitable Power Structures in Student Development Theory

ERIC Educational Resources Information Center

Abes, Elisa S.

2009-01-01

This article is an exploration of possibilities and methodological considerations for using multiple theoretical perspectives in research that challenges inequitable power structures in student development theory. Specifically, I explore methodological considerations when partnering queer theory and constructivism in research on lesbian identity…

Development of an objective gene expression panel as an alternative to self-reported symptom scores in human influenza challenge trials.

PubMed

Muller, Julius; Parizotto, Eneida; Antrobus, Richard; Francis, James; Bunce, Campbell; Stranks, Amanda; Nichols, Marshall; McClain, Micah; Hill, Adrian V S; Ramasamy, Adaikalavan; Gilbert, Sarah C

2017-06-08

Influenza challenge trials are important for vaccine efficacy testing. Currently, disease severity is determined by self-reported scores to a list of symptoms which can be highly subjective. A more objective measure would allow for improved data analysis. Twenty-one volunteers participated in an influenza challenge trial. We calculated the daily sum of scores (DSS) for a list of 16 influenza symptoms. Whole blood collected at baseline and 24, 48, 72 and 96 h post challenge was profiled on Illumina HT12v4 microarrays. Changes in gene expression most strongly correlated with DSS were selected to train a Random Forest model and tested on two independent test sets consisting of 41 individuals profiled on a different microarray platform and 33 volunteers assayed by qRT-PCR. 1456 probes are significantly associated with DSS at 1% false discovery rate. We selected 19 genes with the largest fold change to train a random forest model. We observed good concordance between predicted and actual scores in the first test set (r = 0.57; RMSE = -16.1%) with the greatest agreement achieved on samples collected approximately 72 h post challenge. Therefore, we assayed samples collected at baseline and 72 h post challenge in the second test set by qRT-PCR and observed good concordance (r = 0.81; RMSE = -36.1%). We developed a 19-gene qRT-PCR panel to predict DSS, validated on two independent datasets. A transcriptomics based panel could provide a more objective measure of symptom scoring in future influenza challenge studies. Trial registration Samples were obtained from a clinical trial with the ClinicalTrials.gov Identifier: NCT02014870, first registered on December 5, 2013.

Maximizing Effectiveness Trials in PTSD and SUD Through Secondary Analysis: Benefits and Limitations Using the National Institute on Drug Abuse Clinical Trials Network "Women and Trauma" Study as a Case Example.

PubMed

Hien, Denise A; Campbell, Aimee N C; Ruglass, Lesia M; Saavedra, Lissette; Mathews, Abigail G; Kiriakos, Grace; Morgan-Lopez, Antonio

2015-09-01

Recent federal legislation and a renewed focus on integrative care models underscore the need for economical, effective, and science-based behavioral health care treatment. As such, maximizing the impact and reach of treatment research is of great concern. Behavioral health issues, including the frequent co-occurrence of substance use disorders (SUD) and posttraumatic stress disorder (PTSD), are often complex, with a myriad of factors contributing to the success of interventions. Although treatment guides for comorbid SUD/PTSD exist, most patients continue to suffer symptoms following the prescribed treatment course. Further, the study of efficacious treatments has been hampered by methodological challenges (e.g., overreliance on "superiority" designs (i.e., designs structured to test whether or not one treatment statistically surpasses another in terms of effect sizes) and short term interventions). Secondary analyses of randomized controlled clinical trials offer potential benefits to enhance understanding of findings and increase the personalization of treatment. This paper offers a description of the limits of randomized controlled trials as related to SUD/PTSD populations, highlights the benefits and potential pitfalls of secondary analytic techniques, and uses a case example of one of the largest effectiveness trials of behavioral treatment for co-occurring SUD/PTSD conducted within the National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) and producing 19 publications. The paper concludes with implications of this secondary analytic approach to improve addiction researchers' ability to identify best practices for community-based treatment of these disorders. Innovative methods are needed to maximize the benefits of clinical studies and better support SUD/PTSD treatment options for both specialty and non-specialty healthcare settings. Moving forward, planning for and description of secondary analyses in randomized trials should be given equal consideration and care to the primary outcome analysis. Copyright © 2015 Elsevier Inc. All rights reserved.

Telling our stories: heroin-assisted treatment and SNAP activism in the Downtown Eastside of Vancouver.

PubMed

Boyd, Susan; Murray, Dave; MacPherson, Donald

2017-05-18

This article highlights the experiences of a peer-run group, SALOME/NAOMI Association of Patients (SNAP), that meets weekly in the Downtown Eastside of Vancouver, British Columbia, Canada. SNAP is a unique independent peer- run drug user group that formed in 2011 following Canada's first heroin-assisted treatment trial (HAT), North America Opiate Medication Initiative (NAOMI). SNAP's members are now made up of former research participants who participated in two heroin-assisted trials in Vancouver. This article highlights SNAP members' experiences as research subjects in Canada's second clinical trial conducted in Vancouver, Study to Assess Longer-term Opioid Medication Effectiveness (SALOME), that began recruitment of research participants in 2011. This paper draws on one brainstorming session, three focus groups, and field notes, with the SALOME/NAOMI Association of Patients (SNAP) in late 2013 about their experiences as research subjects in Canada's second clinical trial, SALOME in the DTES of Vancouver, and fieldwork from a 6-year period (March 2011 to February 2017) with SNAP members. SNAP's research draws on research principles developed by drug user groups and critical methodological frameworks on community-based research for social justice. The results illuminate how participating in the SALOME clinical trial impacted the lives of SNAP members. In addition, the findings reveal how SNAP member's advocacy for HAT impacts the group in positive ways. Seven major themes emerged from the analysis of the brainstorming and focus groups: life prior to SALOME, the clinic setting and routine, stability, 6-month transition, support, exiting the trial and ethics, and collective action, including their participation in a constitutional challenge in the Supreme Court of BC to continue receiving HAT once the SALOME trial ended. HAT benefits SNAP members. They argue that permanent HAT programs should be established in Canada because they are an effective harm reduction initiative, one that also reduces opioid overdose deaths.

Effects of virtual reality for stroke individuals based on the International Classification of Functioning and Health: a systematic review.

PubMed

Palma, Gisele Carla Dos Santos; Freitas, Tatiana Beline; Bonuzzi, Giordano Márcio Gatinho; Soares, Marcos Antonio Arlindo; Leite, Paulo Henrique Wong; Mazzini, Natália Araújo; Almeida, Murilo Ruas Groschitz; Pompeu, José Eduardo; Torriani-Pasin, Camila

2017-05-01

This review determines the effects of virtual reality interventions for stroke subjects based on the International Classification of Functioning, Disability,and Health (ICF) framework. Virtual reality is a promising tool for therapy for stroke rehabilitation, but the effects of virtual reality interventions on post-stroke patients based on the specific ICF domains (Body Structures, Body Functions, Activity, and Participation) have not been investigated. A systematic review was conducted, including trials with adults with a clinical diagnosis of a chronic, subacute, or acute stroke. Eligible trials had to include studies with an intervention protocol and follow-up, with a focus on upper limbs and/or lower limbs and/or balance. The Physiotherapy Evidence Database (PEDro) was used to assess the methodological quality of randomized controlled trials. Each trial was separated according to methodological quality into a high-quality trial (PEDro ≥ 6) and a low-quality trial (PEDro ≤ 6). Only high-quality trials were analyzed specifically based on the outcome of these trials. In total, 54 trials involving 1811 participants were included. Of the papers included and considered high quality, 14 trials evaluated areas of the Body Structures component, 20 trials of the Body Functions domain, 17 trials of the Activity component, and 8 trials of the Participation domain. In relation to ICF Part 2, four trials evaluated areas of the Personal Factors component and one trial evaluated domains of the Environmental Factors component. The effects of virtual reality on stroke rehabilitation based on the ICF framework are positive in Body Function and Body Structure. However, the results in the domains Activity and Participation are inconclusive. More high-quality clinical trials are needed to confirm the effectiveness of virtual reality in the domains of Activity and Participation.

Functional Cues for Position Learning Effects in Animals

ERIC Educational Resources Information Center

Burns, Richard A.; Johnson, Kendra S.; Harris, Brian A.; Kinney, Beth A.; Wright, Sarah E.

2004-01-01

Using transfer methodology, several possible factors that could have affected the expression of serial position learning were examined with runway-trained rats. A 3-trial series (SNP) --for which S and P refer to series trials when sucrose (S) and plain (P) Noyes pellets were used as a reward, and N refers to a trial without reward -- was the…

Methodological Considerations in On-Line Contingent Research and Implications for Learning. Technical Report.

ERIC Educational Resources Information Center

Whittington, Marna C.

Methods for the implementation of on-line contingent research are described in this study. In a contingent experimentation procedure, the content of successive experimental trials is a function of a subject's responses to a previous trial or trials (in contrast to traditional experimentation in which the subject is presented a previously…

Grant Izmirlian, PhD | Division of Cancer Prevention

Cancer.gov

Dr. Grant Izmirian has worked on methodology for monitoring clinical trials, conducting formal interim analyses for the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial and the National Lung Screening Trial (NLST). These analyses were nonstandard in nature and required a subject matter expert because of the presumed delay in the effect of screening. He also

Time to be BRAVE: is educating surgeons the key to unlocking the potential of randomised clinical trials in surgery? A qualitative study

PubMed Central

2014-01-01

Background Well-designed randomised clinical trials (RCTs) provide the best evidence to inform decision-making and should be the default option for evaluating surgical procedures. Such trials can be challenging, and surgeons’ preferences may influence whether trials are initiated and successfully conducted and their results accepted. Preferences are particularly problematic when surgeons’ views play a key role in procedure selection and patient eligibility. The bases of such preferences have rarely been explored. Our aim in this qualitative study was to investigate surgeons’ preferences regarding the feasibility of surgical RCTs and their understanding of study design issues using breast reconstruction surgery as a case study. Methods Semistructured qualitative interviews were undertaken with a purposive sample of 35 professionals practicing at 15 centres across the United Kingdom. Interviews were transcribed verbatim and analysed thematically using constant comparative techniques. Sampling, data collection and analysis were conducted concurrently and iteratively until data saturation was achieved. Results Surgeons often struggle with the concept of equipoise. We found that if surgeons did not feel ‘in equipoise’, they did not accept randomisation as a method of treatment allocation. The underlying reasons for limited equipoise were limited appreciation of the methodological weaknesses of data derived from nonrandomised studies and little understanding of pragmatic trial design. Their belief in the value of RCTs for generating high-quality data to change or inform practice was not widely held. Conclusion There is a need to help surgeons understand evidence, equipoise and bias. Current National Institute of Health Research/Medical Research Council investment into education and infrastructure for RCTs, combined with strong leadership, may begin to address these issues or more specific interventions may be required. PMID:24628821

Effect of training and lifting equipment for preventing back pain in lifting and handling: systematic review

PubMed Central

2008-01-01

Objectives To determine whether advice and training on working techniques and lifting equipment prevent back pain in jobs that involve heavy lifting. Data sources Medline, Embase, CENTRAL, Cochrane Back Group’s specialised register, CINAHL, Nioshtic, CISdoc, Science Citation Index, and PsychLIT were searched up to September-November 2005. Review methods The primary search focused on randomised controlled trials and the secondary search on cohort studies with a concurrent control group. Interventions aimed to modify techniques for lifting and handling heavy objects or patients and including measurements for back pain, consequent disability, or sick leave as the main outcome were considered for the review. Two authors independently assessed eligibility of the studies and methodological quality of those included. For data synthesis, we summarised the results of studies comparing similar interventions. We used odds ratios and effect sizes to combine the results in a meta-analysis. Finally, we compared the conclusions of the primary and secondary analyses. Results Six randomised trials and five cohort studies met the inclusion criteria. Two randomised trials and all cohort studies were labelled as high quality. Eight studies looked at lifting and moving patients, and three studies were conducted among baggage handlers or postal workers. Those in control groups received no intervention or minimal training, physical exercise, or use of back belts. None of the comparisons in randomised trials (17 720 participants) yielded significant differences. In the secondary analysis, none of the cohort studies (772 participants) had significant results, which supports the results of the randomised trials. Conclusions There is no evidence to support use of advice or training in working techniques with or without lifting equipment for preventing back pain or consequent disability. The findings challenge current widespread practice of advising workers on correct lifting technique. PMID:18244957

Accelerating the Development and Validation of New Value-Based Diagnostics by Leveraging Biobanks.

PubMed

Schneider, Daniel; Riegman, Peter H J; Cronin, Maureen; Negrouk, Anastassia; Moch, Holger; Balling, Rudi; Penault-Llorca, Frederiques; Zatloukal, Kurt; Horgan, Denis

The challenges faced in developing value-based diagnostics has resulted in few of these tests reaching the clinic, leaving many treatment modalities without matching diagnostics to select patients for particular therapies. Many patients receive therapies from which they are unlikely to benefit, resulting in worse outcomes and wasted health care resources. The paucity of value-based diagnostics is a result of the scientific challenges in developing predictive markers, specifically: (1) complex biology, (2) a limited research infrastructure supporting diagnostic development, and (3) the lack of incentives for diagnostic developers to invest the necessary resources. Better access to biospecimens can address some of these challenges. Methodologies developed to evaluate biomarkers from biospecimens archived from patients enrolled in randomized clinical trials offer the greatest opportunity to develop and validate high-value molecular diagnostics. An alternative opportunity is to access high-quality biospecimens collected from large public and private longitudinal observational cohorts such as the UK Biobank, the US Million Veteran Program, the UK 100,000 Genomes Project, or the French E3N cohort. Value-based diagnostics can be developed to work in a range of samples including blood, serum, plasma, urine, and tumour tissue, and better access to these high-quality biospecimens with clinical data can facilitate biomarker research. © 2016 S. Karger AG, Basel.

Promoting quality and safety in women's health through the use of transdisciplinary clinical simulation educational modules: methodology and a pilot trial.

PubMed

Montgomery, Kymberlee; Morse, Catherine; Smith-Glasgow, Mary Ellen; Posmontier, Bobbie; Follen, Michele

2012-02-01

This manuscript presents the methodology used to assess the impact of a clinical simulation module used for training providers specializing in women's health. The methodology presented here will be used for a quantitative study in the future. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Assessment of Registration Information on Methodological Design of Acupuncture RCTs: A Review of 453 Registration Records Retrieved from WHO International Clinical Trials Registry Platform

PubMed Central

Gu, Jing; Wang, Qi; Wang, Xiaogang; Li, Hailong; Gu, Mei; Ming, Haixia; Dong, Xiaoli; Yang, Kehu; Wu, Hongyan

2014-01-01

Background. This review provides the first methodological information assessment of protocol of acupuncture RCTs registered in WHO International Clinical Trials Registry Platform (ICTRP). Methods. All records of acupuncture RCTs registered in the ICTRP have been collected. The methodological design assessment involved whether the randomization methods, allocation concealment, and blinding were adequate or not based on the information of registration records (protocols of acupuncture RCTs). Results. A total of 453 records, found in 11 registries, were examined. Methodological details were insufficient in registration records; there were 76.4%, 89.0%, and 21.4% records that did not provide information on randomization methods, allocation concealment, and blinding respectively. The proportions of adequate randomization methods, allocation concealment, and blinding were only 107 (23.6%), 48 (10.6%), and 210 (46.4%), respectively. The methodological design improved year by year, especially after 2007. Additionally, methodology of RCTs with ethics approval was clearly superior to those without ethics approval and different among registries. Conclusions. The overall methodological design based on registration records of acupuncture RCTs is not very well but improved year by year. The insufficient information on randomization methods, allocation concealment, and blinding maybe due to the relevant description is not taken seriously in acupuncture RCTs' registration. PMID:24688591

Assessment of Registration Information on Methodological Design of Acupuncture RCTs: A Review of 453 Registration Records Retrieved from WHO International Clinical Trials Registry Platform.

PubMed

Gu, Jing; Wang, Qi; Wang, Xiaogang; Li, Hailong; Gu, Mei; Ming, Haixia; Dong, Xiaoli; Yang, Kehu; Wu, Hongyan

2014-01-01

Background. This review provides the first methodological information assessment of protocol of acupuncture RCTs registered in WHO International Clinical Trials Registry Platform (ICTRP). Methods. All records of acupuncture RCTs registered in the ICTRP have been collected. The methodological design assessment involved whether the randomization methods, allocation concealment, and blinding were adequate or not based on the information of registration records (protocols of acupuncture RCTs). Results. A total of 453 records, found in 11 registries, were examined. Methodological details were insufficient in registration records; there were 76.4%, 89.0%, and 21.4% records that did not provide information on randomization methods, allocation concealment, and blinding respectively. The proportions of adequate randomization methods, allocation concealment, and blinding were only 107 (23.6%), 48 (10.6%), and 210 (46.4%), respectively. The methodological design improved year by year, especially after 2007. Additionally, methodology of RCTs with ethics approval was clearly superior to those without ethics approval and different among registries. Conclusions. The overall methodological design based on registration records of acupuncture RCTs is not very well but improved year by year. The insufficient information on randomization methods, allocation concealment, and blinding maybe due to the relevant description is not taken seriously in acupuncture RCTs' registration.

Population-Level Cost-Effectiveness of Implementing Evidence-Based Practices into Routine Care

PubMed Central

Fortney, John C; Pyne, Jeffrey M; Burgess, James F

2014-01-01

Objective The objective of this research was to apply a new methodology (population-level cost-effectiveness analysis) to determine the value of implementing an evidence-based practice in routine care. Data Sources/Study Setting Data are from sequentially conducted studies: a randomized controlled trial and an implementation trial of collaborative care for depression. Both trials were conducted in the same practice setting and population (primary care patients prescribed antidepressants). Study Design The study combined results from a randomized controlled trial and a pre-post-quasi-experimental implementation trial. Data Collection/Extraction Methods The randomized controlled trial collected quality-adjusted life years (QALYs) from survey and medication possession ratios (MPRs) from administrative data. The implementation trial collected MPRs and intervention costs from administrative data and implementation costs from survey. Principal Findings In the randomized controlled trial, MPRs were significantly correlated with QALYs (p = .03). In the implementation trial, patients at implementation sites had significantly higher MPRs (p = .01) than patients at control sites, and by extrapolation higher QALYs (0.00188). Total costs (implementation, intervention) were nonsignificantly higher ($63.76) at implementation sites. The incremental population-level cost-effectiveness ratio was $33,905.92/QALY (bootstrap interquartile range −$45,343.10/QALY to $99,260.90/QALY). Conclusions The methodology was feasible to operationalize and gave reasonable estimates of implementation value. PMID:25328029

Future role of MR elastography in tissue engineering and regenerative medicine.

PubMed

Othman, Shadi F; Xu, Huihui; Mao, Jeremy J

2015-05-01

Tissue engineering (TE) has been introduced for more than 25 years without a boom in clinical trials. More than 70 TE-related start-up companies spent more than $600 million/year, with only two FDA-approved tissue-engineered products. Given the modest performance in clinically approved organs, TE is a tenaciously promising field. The TE community is advocating the application of clinically driven methodologies in large animal models enabling clinical translation. This challenge is hindered by the scarcity of tissue biopsies and the absence of standardized evaluation tools, but can be negated through non-invasive assessment of growth and integration, with reduced sample size and low cost. Solving this issue will speed the transition to cost-efficient clinical studies. In this paper we: (a) introduce magnetic resonance elastography to the tissue-engineering and regenerative medicine (TERM) community; (b) review recent MRE applications in TERM; and (c) discuss future directions of MRE in TERM. We have used MRE to study engineered tissues both in vitro and in vivo, where the mechanical properties of mesenchymally derived constructs were progressively monitored before and after tissues were implanted in mouse models. This study represents a stepping stone toward the applications of MRE in directing clinical trials with low cost and likely expediting the translation to more relevantly large animal models and clinical trials. Copyright © 2013 John Wiley & Sons, Ltd.

Methodology of clinical trials evaluating the incorporation of new drugs in the first-line treatment of patients with diffuse large B-cell lymphoma (DLBCL): a critical review.

PubMed

Iacoboni, G; Zucca, E; Ghielmini, M; Stathis, A

2018-05-01

The first-line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been carried out over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed. Reports of phase III trials evaluating the addition of molecularly targeted agents or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phases I and II trials which preceded these phase III trials were also reviewed. Among six phase III trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary end point. The other five trials did not show an improved outcome with the addition of the new agent. The preceding phases I and II trials were very heterogeneous in their end points and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase III trials. The standard of care for DLBCL is still R-CHOP. Phase I/II trials failed to predict the results of subsequent phase III trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase II trials evaluating new agents in DLBCL needs to be better defined in the future.

Challenges and perspective of drug repurposing strategies in early phase clinical trials.

PubMed

Kato, Shumei; Moulder, Stacy L; Ueno, Naoto T; Wheler, Jennifer J; Meric-Bernstam, Funda; Kurzrock, Razelle; Janku, Filip

2015-01-01

Despite significant investments in the development of new agents only 5% of cancer drugs entering Phase I clinical trials are ultimately approved for routine clinical cancer care. Drug repurposing strategies using novel combinations of previously tested anticancer agents could reduce the cost and improve treatment outcomes. At MD Anderson Cancer Center, early phase clinical trials with drug repurposing strategies demonstrated promising outcomes in patients with both rare and common treatment refractory advanced cancers. Despite clinical efficacy advancing drug repurposing strategies in the clinical trial trajectory beyond early phase studies has been challenging mainly due to lack of funding and interest from the pharmaceutical industry. In this review, we delineate our experience and challenges with drug repurposing strategies.

Volume and methodological quality of randomized controlled trials in laparoscopic surgery: assessment over a 10-year period.

PubMed

Antoniou, Stavros A; Andreou, Alexandros; Antoniou, George A; Koch, Oliver O; Köhler, Gernot; Luketina, Ruzica-R; Bertsias, Antonios; Pointner, Rudolph; Granderath, Frank-Alexander

2015-11-01

Measures have been taken to improve methodological quality of randomized controlled trials (RCTs). This review systematically assessed the trends in volume and methodological quality of RCTs on minimally invasive surgery within a 10-year period. RCTs on minimally invasive surgery were searched in the 10 most cited general surgical journals and the 5 most cited journals of laparoscopic interest for the years 2002 and 2012. Bibliometric and methodological quality components were abstracted using the Scottish Intercollegiate Guidelines Network. The pooled number of RCTs from low-contribution regions demonstrated an increasing proportion of the total published RCTs, compensating for a concomitant decrease of the respective contributions from Europe and North America. International collaborations were more frequent in 2012. Acceptable or high quality RCTs accounted for 37.9% and 54.4% of RCTs published in 2002 and 2012, respectively. Components of external validity were poorly reported. Both the volume and the reporting quality of laparoscopic RCTs have increased from 2002 to 2012, but there seems to be ample room for improvement of methodological quality. Copyright © 2015 Elsevier Inc. All rights reserved.

Heterogeneous Effects in Education: The Promise and Challenge of Incorporating Intersectionality into Quantitative Methodological Approaches

ERIC Educational Resources Information Center

Schudde, Lauren

2018-01-01

To date, the theory of intersectionality has largely guided qualitative efforts in social science and education research. Translating the construct to new methodological approaches is inherently complex and challenging, but offers the possibility of breaking down silos that keep education researchers with similar interests--but different…

The Challenges to and the Need for International Research in Educational Leadership

ERIC Educational Resources Information Center

Brooks, Melanie Carol; Jean-Marie, Gaetane

2015-01-01

Purpose: The purpose of this paper is twofold: to discuss methodological challenges facing US scholars when conducting international research; and to present personal reflections as educational leadership faculty in the USA conducting and publishing on research undertaken in Haiti and Thailand. Design/Methodology/Approach: This study drew from…

The Challenge of Researching Violent Societies: Navigating Complexities in Ethnography

ERIC Educational Resources Information Center

Tshabangu, Icarbord

2009-01-01

Through use of a recent study researching democratic education and citizenship in Zimbabwe, this paper examines the methodological dilemmas and challenges faced by an ethnographer, particularly by a research student in a violent context. The article posits a bricolage strategy to navigate some of the dangers and methodological dilemmas inherent so…

Queering Methodologies: Challenging Scientific Constraint in the Appreciation of Queer and Trans Subjects

ERIC Educational Resources Information Center

Ferguson, Joshua M.

2013-01-01

Qualitative studies require a queer perspective to challenge stagnant forms of scientific discourse. This paper argues for a deconstruction of hegemonic qualitative practices in order to appreciate and listen to queer and trans subjects when employing qualitative research and methodologies. I focus on qualitative methods from an audiovisual…

Measuring Cognitive and Metacognitive Regulatory Processes during Hypermedia Learning: Issues and Challenges

ERIC Educational Resources Information Center

Azevedo, Roger; Moos, Daniel C.; Johnson, Amy M.; Chauncey, Amber D.

2010-01-01

Self-regulated learning (SRL) with hypermedia environments involves a complex cycle of temporally unfolding cognitive and metacognitive processes that impact students' learning. We present several methodological issues related to treating SRL as an event and strengths and challenges of using online trace methodologies to detect, trace, model, and…

The Psychological Study of Video Game Players: Methodological Challenges and Practical Advice

ERIC Educational Resources Information Center

King, Daniel; Delfabbro, Paul; Griffiths, Mark

2009-01-01

Video game playing has received increased academic interest over the last few decades, particularly with regard to the psychological understanding of addiction. Based on the many studies carried out by the authors, this paper summarises some of the methodological challenges which may arise when studying video game players, including obstacles…

Tough Teens: The Methodological Challenges of Interviewing Teenagers as Research Participants

ERIC Educational Resources Information Center

Bassett, Raewyn; Beagan, Brenda L.; Ristovski-Slijepcevic, Svetlana; Chapman, Gwen E.

2008-01-01

Encouraging a teenager to have a conversation in a semistructured research interview is fraught with difficulties. The authors discuss the methodological challenges encountered when interviewing adolescents of European Canadian, African Canadian, and Punjabi Canadian families who took part in the Family Food Decision-Making Study in two regions of…

Early phase clinical trials with human immunodeficiency virus-1 and malaria vectored vaccines in The Gambia: frontline challenges in study design and implementation.

PubMed

Afolabi, Muhammed O; Adetifa, Jane U; Imoukhuede, Egeruan B; Viebig, Nicola K; Kampmann, Beate; Bojang, Kalifa

2014-05-01

Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and malaria are among the most important infectious diseases in developing countries. Existing control strategies are unlikely to curtail these diseases in the absence of efficacious vaccines. Testing of HIV and malaria vaccines candidates start with early phase trials that are increasingly being conducted in developing countries where the burden of the diseases is high. Unique challenges, which affect planning and implementation of vaccine trials according to internationally accepted standards have thus been identified. In this review, we highlight specific challenges encountered during two early phase trials of novel HIV-1 and malaria vectored vaccine candidates conducted in The Gambia and how some of these issues were pragmatically addressed. We hope our experience will be useful for key study personnel involved in day-to-day running of similar clinical trials. It may also guide future design and implementation of vaccine trials in resource-constrained settings.

Developing dementia prevention trials: baseline report of the Home-Based Assessment study.

PubMed

Sano, Mary; Egelko, Susan; Donohue, Michael; Ferris, Steven; Kaye, Jeffrey; Hayes, Tamara L; Mundt, James C; Sun, Chung-Kai; Paparello, Silvia; Aisen, Paul S

2013-01-01

This report describes the baseline experience of the multicenter, Home-Based Assessment study, designed to develop methods for dementia prevention trials using novel technologies for test administration and data collection. Nondemented individuals of 75 years of age or more were recruited and evaluated in-person using established clinical trial outcomes of cognition and function, and randomized to one of 3 assessment methodologies: (1) mail-in questionnaire/live telephone interviews [mail-in/phone (MIP)]; (2) automated telephone with interactive voice recognition; and (3) internet-based computer Kiosk. Brief versions of cognitive and noncognitive outcomes were adapted to each methodology and administered at baseline and repeatedly over a 4-year period. "Efficiency" measures assessed the time from screening to baseline, and staff time required for each methodology. A total of 713 individuals signed consent and were screened; 640 met eligibility and were randomized to one of 3 assessment arms; and 581 completed baseline. Dropout, time from screening to baseline, and total staff time were highest among those assigned to internet-based computer Kiosk. However, efficiency measures were driven by nonrecurring start-up activities suggesting that differences may be mitigated over a long trial. Performance among Home-Based Assessment instruments collected through different technologies will be compared with established outcomes over this 4-year study.

Developing Dementia Prevention Trials: Baseline Report of the Home-Based Assessment Study

PubMed Central

Sano, Mary; Egelko, Susan; Donohue, Michael; Ferris, Steven; Kaye, Jeffrey; Hayes, Tamara L.; Mundt, James C.; Sun, C.K.; Paparello, Silvia; Aisen, Paul S.

2014-01-01

This report describes the baseline experience of the multi-center, Home Based Assessment (HBA) study, designed to develop methods for dementia prevention trials using novel technologies for test administration and data collection. Non-demented individuals ≥ 75 years old were recruited and evaluated in-person using established clinical trial outcomes of cognition and function, and randomized to one of 3 assessment methodologies: 1) mail-in questionnaire/live telephone interviews (MIP); 2) automated telephone with interactive voice recognition (IVR); and 3) internet-based computer Kiosk (KIO). Brief versions of cognitive and non-cognitive outcomes, were adapted to each methodology and administered at baseline and repeatedly over a 4-year period. “Efficiency” measures assessed the time from screening to baseline, and staff time required for each methodology. 713 individuals signed consent and were screened; 640 met eligibility and were randomized to one of 3 assessment arms and 581 completed baseline. Drop out, time from screening to baseline and total staff time were highest among those assigned to KIO. However efficiency measures were driven by non-recurring start-up activities suggesting that differences may be mitigated over a long trial. Performance among HBA instruments collected via different technologies will be compared to established outcomes over this 4 year study. PMID:23151596

Association between funding source, methodological quality and research outcomes in randomized controlled trials of synbiotics, probiotics and prebiotics added to infant formula: A Systematic Review

PubMed Central

2013-01-01

Background There is little or no information available on the impact of funding by the food industry on trial outcomes and methodological quality of synbiotics, probiotics and prebiotics research in infants. The objective of this study was to compare the methodological quality, outcomes of food industry sponsored trials versus non industry sponsored trials, with regards to supplementation of synbiotics, probiotics and prebiotics in infant formula. Methods A comprehensive search was conducted to identify published and unpublished randomized clinical trials (RCTs). Cochrane methodology was used to assess the risk of bias of included RCTs in the following domains: 1) sequence generation; 2) allocation concealment; 3) blinding; 4) incomplete outcome data; 5) selective outcome reporting; and 6) other bias. Clinical outcomes and authors’ conclusions were reported in frequencies and percentages. The association between source of funding, risk of bias, clinical outcomes and conclusions were assessed using Pearson’s Chi-square test and the Fisher’s exact test. A p-value < 0.05 was statistically significant. Results Sixty seven completed and 3 on-going RCTs were included. Forty (59.7%) were funded by food industry, 11 (16.4%) by non-industry entities and 16 (23.9%) did not specify source of funding. Several risk of bias domains, especially sequence generation, allocation concealment and blinding, were not adequately reported. There was no significant association between the source of funding and sequence generation, allocation concealment, blinding and selective reporting, majority of reported clinical outcomes or authors’ conclusions. On the other hand, source of funding was significantly associated with the domains of incomplete outcome data, free of other bias domains as well as reported antibiotic use and conclusions on weight gain. Conclusion In RCTs on infants fed infant formula containing probiotics, prebiotics or synbiotics, the source of funding did not influence the majority of outcomes in favour of the sponsors’ products. More non-industry funded research is needed to further assess the impact of funding on methodological quality, reported clinical outcomes and authors’ conclusions. PMID:24219082

Regulatory challenges in the review of data from global clinical trials: the PMDA perspective.

PubMed

Asano, K; Tanaka, A; Sato, T; Uyama, Y

2013-08-01

Regulatory agencies face challenges in reviewing data from global clinical trials (GCTs) in the era of globalization of drug development. One major challenge is consideration of ethnic factors in evaluating GCT data so as to extrapolate foreign population data to one's own national population. Here, we present the Pharmaceuticals and Medical Devices Agency (PMDA) perspective in reviewing GCT data in new drug applications (NDAs) and discuss future challenges for new drug approval.

Critical issues in clinical periodontal research.

PubMed

Preshaw, Philip M

2012-06-01

As periodontal researchers and clinicians, we are challenged every day to make decisions relating to the clinical management of our patients and about how best to conduct clinical periodontal research. This volume of Periodontology 2000 addresses some of the critical issues in contemporary clinical periodontics and periodontal research that are of direct relevance to clinicians, researchers, teachers and students. The 11 review articles in this volume of Periodontology 2000 focus on aspects of periodontal research methodology and clinical periodontology. In terms of research methodology, the articles aim to inform the reader on topics relating to randomized controlled trials in periodontal research, evidence-based dentistry, calibration of clinical examiners and statistics relevant to periodontal research. The clinical periodontology articles address issues relating to decisions on retaining periodontally compromised teeth or replacing them with implants, periodontal management in the patient with osteoporosis, surgical approaches for root coverage and the emerging science of advanced regenerative technologies, including the use of stem cells, for periodontal regeneration. It is hoped that these critical reviews will address many of the dilemmas that confront us on a regular basis and provide practical guidance to those engaged in both clinical periodontology and clinical periodontal research. © 2012 John Wiley & Sons A/S.

Occupational therapy and return to work: a systematic literature review

PubMed Central

2011-01-01

Background The primary aim of this review study was to gather evidence on the effectiveness in terms of return to work (RTW) of occupational therapy interventions (OTIs) in rehabilitation patients with non-congenital disorders. A secondary aim was to be able to select the most efficient OTI. Methods A systematic literature review of peer-reviewed papers was conducted using electronic databases (Cinahl, Cochrane Library, Ebsco, Medline (Pubmed), and PsycInfo). The search focussed on randomised controlled trials and cohort studies published in English from 1980 until September 2010. Scientific validity of the studies was assessed. Results Starting from 1532 papers with pertinent titles, six studies met the quality criteria. Results show systematic reviewing of OTIs on RTW was challenging due to varying populations, different outcome measures, and poor descriptions of methodology. There is evidence that OTIs as part of rehabilitation programs, increase RTW rates, although the methodological evidence of most studies is weak. Conclusions Analysis of the selected papers indicated that OTIs positively influence RTW; two studies described precisely what the content of their OTI was. In order to identify the added value of OTIs on RTW, studies with well-defined OT intervention protocols are necessary. PMID:21810228

Cognition in multiple sclerosis

PubMed Central

Benedict, Ralph; Enzinger, Christian; Filippi, Massimo; Geurts, Jeroen J.; Hamalainen, Paivi; Hulst, Hanneke; Inglese, Matilde; Leavitt, Victoria M.; Rocca, Maria A.; Rosti-Otajarvi, Eija M.; Rao, Stephen

2018-01-01

Cognitive decline is recognized as a prevalent and debilitating symptom of multiple sclerosis (MS), especially deficits in episodic memory and processing speed. The field aims to (1) incorporate cognitive assessment into standard clinical care and clinical trials, (2) utilize state-of-the-art neuroimaging to more thoroughly understand neural bases of cognitive deficits, and (3) develop effective, evidence-based, clinically feasible interventions to prevent or treat cognitive dysfunction, which are lacking. There are obstacles to these goals. Our group of MS researchers and clinicians with varied expertise took stock of the current state of the field, and we identify several important practical and theoretical challenges, including key knowledge gaps and methodologic limitations related to (1) understanding and measurement of cognitive deficits, (2) neuroimaging of neural bases and correlates of deficits, and (3) development of effective treatments. This is not a comprehensive review of the extensive literature, but instead a statement of guidelines and priorities for the field. For instance, we provide recommendations for improving the scientific basis and methodologic rigor for cognitive rehabilitation research. Toward this end, we call for multidisciplinary collaborations toward development of biologically based theoretical models of cognition capable of empirical validation and evidence-based refinement, providing the scientific context for effective treatment discovery. PMID:29343470

Evaluations of health promoting schools: a review of nine studies.

PubMed

Mũkoma, Wanjirũ; Flisher, Alan J

2004-09-01

The concept of 'health promoting schools' has been embraced internationally as an effective way of promoting the health of children, adolescents, and the wider school community. It is only recently that attempts have been made to evaluate health promoting schools. This paper reviews evaluations of health promoting schools and draws useful evaluation methodology lessons. The review is confined to school-based interventions that are founded explicitly on the concept of the health promoting school and employ the concept beyond one school domain. We included nine evaluations in this review. Seven of these were published in the peer reviewed scientific literature. Two were unpublished reports. One study was a randomized controlled trial, while a quasi-experimental research design with comparison schools was used in three studies. With three exceptions, combinations of quantitative and qualitative data were collected. There was evidence that the health promoting school has some influence on various domains of health for the school community. It is also possible to integrate health promotion into the school curriculum and policies successfully. However, the evaluation of health promoting schools is complex. We discuss some of the methodological challenges of evaluating health promoting schools and make suggestions for improving future evaluations.

Quality of Reporting of Bioequivalence Trials Comparing Generic to Brand Name Drugs: A Methodological Systematic Review

PubMed Central

van der Meersch, Amélie; Dechartres, Agnès; Ravaud, Philippe

2011-01-01

Background Generic drugs are used by millions of patients for economic reasons, so their evaluation must be highly transparent. Objective To assess the quality of reporting of bioequivalence trials comparing generic to brand-name drugs. Methodology/Principal Findings PubMed was searched for reports of bioequivalence trials comparing generic to brand-name drugs between January 2005 and December 2008. Articles were included if the aim of the study was to assess the bioequivalency of generic and brand-name drugs. We excluded case studies, pharmaco-economic evaluations, and validation dosage assays of drugs. We evaluated whether important information about funding, methodology, location of trials, and participants were reported. We also assessed whether the criteria required by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) to conclude bioequivalence were reported and that the conclusions were in agreement with the results. We identified 134 potentially relevant articles but eliminated 55 because the brand-name or generic drug status of the reference drug was unknown. Thus, we evaluated 79 articles. The funding source and location of the trial were reported in 41% and 56% of articles, respectively. The type of statistical analysis was reported in 94% of articles, but the methods to generate the randomization sequence and to conceal allocation were reported in only 15% and 5%, respectively. In total, 65 articles of single-dose trials (89%) concluded bioequivalence. Of these, 20 (31%) did not report the 3 criteria within the limits required by the FDA and 11 (17%) did not report the 2 criteria within the limits required by the EMA. Conclusions/Significance Important information to judge the validity and relevance of results are frequently missing in published reports of trials assessing generic drugs. The quality of reporting of such trials is in need of improvement. PMID:21858184

A National Strategy to Develop Pragmatic Clinical Trials Infrastructure

PubMed Central

Guise, Jeanne‐Marie; Dolor, Rowena J.; Meissner, Paul; Tunis, Sean; Krishnan, Jerry A.; Pace, Wilson D.; Saltz, Joel; Hersh, William R.; Michener, Lloyd; Carey, Timothy S.

2014-01-01

Abstract An important challenge in comparative effectiveness research is the lack of infrastructure to support pragmatic clinical trials, which compare interventions in usual practice settings and subjects. These trials present challenges that differ from those of classical efficacy trials, which are conducted under ideal circumstances, in patients selected for their suitability, and with highly controlled protocols. In 2012, we launched a 1‐year learning network to identify high‐priority pragmatic clinical trials and to deploy research infrastructure through the NIH Clinical and Translational Science Awards Consortium that could be used to launch and sustain them. The network and infrastructure were initiated as a learning ground and shared resource for investigators and communities interested in developing pragmatic clinical trials. We followed a three‐stage process of developing the network, prioritizing proposed trials, and implementing learning exercises that culminated in a 1‐day network meeting at the end of the year. The year‐long project resulted in five recommendations related to developing the network, enhancing community engagement, addressing regulatory challenges, advancing information technology, and developing research methods. The recommendations can be implemented within 24 months and are designed to lead toward a sustained national infrastructure for pragmatic trials. PMID:24472114

Maximum-likelihood estimation of channel-dependent trial-to-trial variability of auditory evoked brain responses in MEG

PubMed Central

2014-01-01

Background We propose a mathematical model for multichannel assessment of the trial-to-trial variability of auditory evoked brain responses in magnetoencephalography (MEG). Methods Following the work of de Munck et al., our approach is based on the maximum likelihood estimation and involves an approximation of the spatio-temporal covariance of the contaminating background noise by means of the Kronecker product of its spatial and temporal covariance matrices. Extending the work of de Munck et al., where the trial-to-trial variability of the responses was considered identical to all channels, we evaluate it for each individual channel. Results Simulations with two equivalent current dipoles (ECDs) with different trial-to-trial variability, one seeded in each of the auditory cortices, were used to study the applicability of the proposed methodology on the sensor level and revealed spatial selectivity of the trial-to-trial estimates. In addition, we simulated a scenario with neighboring ECDs, to show limitations of the method. We also present an illustrative example of the application of this methodology to real MEG data taken from an auditory experimental paradigm, where we found hemispheric lateralization of the habituation effect to multiple stimulus presentation. Conclusions The proposed algorithm is capable of reconstructing lateralization effects of the trial-to-trial variability of evoked responses, i.e. when an ECD of only one hemisphere habituates, whereas the activity of the other hemisphere is not subject to habituation. Hence, it may be a useful tool in paradigms that assume lateralization effects, like, e.g., those involving language processing. PMID:24939398

Identifying treatment effect heterogeneity in clinical trials using subpopulations of events: STEPP.

PubMed

Lazar, Ann A; Bonetti, Marco; Cole, Bernard F; Yip, Wai-Ki; Gelber, Richard D

2016-04-01

Investigators conducting randomized clinical trials often explore treatment effect heterogeneity to assess whether treatment efficacy varies according to patient characteristics. Identifying heterogeneity is central to making informed personalized healthcare decisions. Treatment effect heterogeneity can be investigated using subpopulation treatment effect pattern plot (STEPP), a non-parametric graphical approach that constructs overlapping patient subpopulations with varying values of a characteristic. Procedures for statistical testing using subpopulation treatment effect pattern plot when the endpoint of interest is survival remain an area of active investigation. A STEPP analysis was used to explore patterns of absolute and relative treatment effects for varying levels of a breast cancer biomarker, Ki-67, in the phase III Breast International Group 1-98 randomized clinical trial, comparing letrozole to tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. Absolute treatment effects were measured by differences in 4-year cumulative incidence of breast cancer recurrence, while relative effects were measured by the subdistribution hazard ratio in the presence of competing risks using O-E (observed-minus-expected) methodology, an intuitive non-parametric method. While estimation of hazard ratio values based on O-E methodology has been shown, a similar development for the subdistribution hazard ratio has not. Furthermore, we observed that the subpopulation treatment effect pattern plot analysis may not produce results, even with 100 patients within each subpopulation. After further investigation through simulation studies, we observed inflation of the type I error rate of the traditional test statistic and sometimes singular variance-covariance matrix estimates that may lead to results not being produced. This is due to the lack of sufficient number of events within the subpopulations, which we refer to as instability of the subpopulation treatment effect pattern plot analysis. We introduce methodology designed to improve stability of the subpopulation treatment effect pattern plot analysis and generalize O-E methodology to the competing risks setting. Simulation studies were designed to assess the type I error rate of the tests for a variety of treatment effect measures, including subdistribution hazard ratio based on O-E estimation. This subpopulation treatment effect pattern plot methodology and standard regression modeling were used to evaluate heterogeneity of Ki-67 in the Breast International Group 1-98 randomized clinical trial. We introduce methodology that generalizes O-E methodology to the competing risks setting and that improves stability of the STEPP analysis by pre-specifying the number of events across subpopulations while controlling the type I error rate. The subpopulation treatment effect pattern plot analysis of the Breast International Group 1-98 randomized clinical trial showed that patients with high Ki-67 percentages may benefit most from letrozole, while heterogeneity was not detected using standard regression modeling. The STEPP methodology can be used to study complex patterns of treatment effect heterogeneity, as illustrated in the Breast International Group 1-98 randomized clinical trial. For the subpopulation treatment effect pattern plot analysis, we recommend a minimum of 20 events within each subpopulation. © The Author(s) 2015.

Efficacy of a modified live Flavobacterium columnare vaccine in fish.

PubMed

Shoemaker, Craig A; Klesius, Phillip H; Drennan, John D; Evans, Joyce J

2011-01-01

Flavobacterium columnare is an aquatic bacterium that is responsible for columnaris disease. This aquatic pathogen has a worldwide distribution and is highly infectious to both warm and cold water fish. A modified live F. columnare vaccine was developed by repeated passage of a virulent strain on increasing concentrations of rifampicin that resulted in attenuation. Here we report vaccination/challenge trials to evaluate efficacy and safety. In separate laboratory trials, immersion vaccination of channel catfish (Ictalurus punctatus) fry between 10 to 48 days post hatch (DPH) with experimental vaccine or licensed product resulted in relative percent survival (RPS) between 57-94% following challenge. Similarly, a vaccination/challenge trial using largemouth bass (Micropterus salmoides) fry at 10 DPH was performed using various doses of licensed product under laboratory conditions. Results demonstrated safety of the vaccine and significant protection following challenge with RPS values between 74-94%, depending on vaccine dose. Together, these trials demonstrate the vaccine administered to early life-stage channel catfish and largemouth bass is safe and reduces mortality following challenge with F. columnare. Published by Elsevier Ltd.

Innovations in design and technology. The story of hip arthroplasty.

PubMed

Amstutz, H C

2000-09-01

The current study reviews the early history of surgeon-initiated trial and error development in hip joint arthroplasty and the subsequent methodological evolution to proper criteria for hypothesis testing using bioengineers and other research scientists. The interplay and relationships to industry, universities, scientific organizations, and the Food and Drug Administration with respect to device development in hip arthroplasty are reviewed. The ethics of and responsibilities to involved parties are outlined, citing the history of many contemporary developments. Examples are provided from the evolution and introduction of unsuccessful innovations, and the problems inherent in the current methodology of the approval process from the Food and Drug Administration using the 5-10K, Investigative Device Exemption, and the Pre-Market Approval protocols. The pros and cons of randomized trials for devices are outlined with the conclusion that they are not appropriate for device introduction. The proper, rational methodology for introduction of new devices is a phased-in clinical trial process after pertinent bench testing. Finally, the ethical dilemmas created by managed care are addressed. Industry involvements of the surgeon-spokesmen are cited.

Trial-Based Economic Evaluations in Occupational Health

PubMed Central

van Wier, Marieke F.; Tompa, Emile; Bongers, Paulien M.; van der Beek, Allard J.; van Tulder, Maurits W.; Bosmans, Judith E.

2014-01-01

To allocate available resources as efficiently as possible, decision makers need information on the relative economic merits of occupational health and safety (OHS) interventions. Economic evaluations can provide this information by comparing the costs and consequences of alternatives. Nevertheless, only a few of the studies that consider the effectiveness of OHS interventions take the extra step of considering their resource implications. Moreover, the methodological quality of those that do is generally poor. Therefore, this study aims to help occupational health researchers conduct high-quality trial-based economic evaluations by discussing the theory and methodology that underlie them, and by providing recommendations for good practice regarding their design, analysis, and reporting. This study also helps consumers of this literature with understanding and critically appraising trial-based economic evaluations of OHS interventions. PMID:24854249

Trial-based economic evaluations in occupational health: principles, methods, and recommendations.

PubMed

van Dongen, Johanna M; van Wier, Marieke F; Tompa, Emile; Bongers, Paulien M; van der Beek, Allard J; van Tulder, Maurits W; Bosmans, Judith E

2014-06-01

To allocate available resources as efficiently as possible, decision makers need information on the relative economic merits of occupational health and safety (OHS) interventions. Economic evaluations can provide this information by comparing the costs and consequences of alternatives. Nevertheless, only a few of the studies that consider the effectiveness of OHS interventions take the extra step of considering their resource implications. Moreover, the methodological quality of those that do is generally poor. Therefore, this study aims to help occupational health researchers conduct high-quality trial-based economic evaluations by discussing the theory and methodology that underlie them, and by providing recommendations for good practice regarding their design, analysis, and reporting. This study also helps consumers of this literature with understanding and critically appraising trial-based economic evaluations of OHS interventions.

A review of the methodological challenges in assessing the cost effectiveness of pharmacist interventions.

PubMed

Elliott, Rachel A; Putman, Koen; Davies, James; Annemans, Lieven

2014-12-01

Pharmacists' roles are shifting away from medicines supply and the provision of patient education involving acute medications towards consultation-type services for chronic medications. Determining the cost effectiveness of pharmacist interventions has been complicated by methodological challenges. A critique of 31 economic evaluations carried out alongside comparative studies of pharmacist interventions published between 2003 and 2013 (12 from the UK, six from the USA) found a range of disease-specific and cross-therapeutic interventions targeting both patients and prescribers in a range of settings evaluated through a variety of study designs. Only ten were full economic evaluations, five of which were based on randomized controlled trials (RCTs). The intervention was usually quite well described, but the comparator was not always clearly described, and some interventions are very context specific due to the variability in pharmacist services available in different countries and practice settings. Complex multidirectional aims of most pharmacist interventions have led to many process, intermediate and longer-term outcomes being included in any one study. Quality of resource use and cost data varied. Most incremental cost-effectiveness ratios (ICERs) were generated from process indicators such as errors and adherence, with only four studies reporting cost per quality-adjusted life-year (QALY). Very few studies examined the effect of uncertainty, and methods used were not very clear in some cases. The principal finding from our critique is that poor RCT study design or analysis precludes many studies from finding pharmacist interventions effective or cost effective. We conclude with a set of recommendations for future study design.

Informative value of Patient Reported Outcomes (PRO) in Health Technology Assessment (HTA)

PubMed Central

Brettschneider, Christian; Lühmann, Dagmar; Raspe, Heiner

2011-01-01

Background “Patient-Reported Outcome” (PRO) is used as an umbrella term for different concepts for measuring subjectively perceived health status e. g. as treatment effects. Their common characteristic is, that the appraisal of the health status is reported by the patient himself. In order to describe the informative value of PRO in Health Technology Assessment (HTA) first an overview of concepts, classifications and methods of measurement is given. The overview is complemented by an empirical analysis of clinical trials and HTA-reports on rheumatoid arthritis and breast cancer in order to report on type, frequency and consequences of PRO used in these documents. Methods For both issues systematic reviews of the literature have been performed. The search for methodological literature covers the publication period from 1990 to 2009, the search for clinical trials of rheumatoid arthritis and breast cancer covers the period 2005 to 2009. Both searches were performed in the medical databases of the German Institute of Medical Documentation and Information (DIMDI). The search for HTA-reports and methodological papers of HTA-agencies was performed in the CRD-Databases (CRD = Centre for Reviews and Dissemination) and by handsearching the websites of INAHTA member agencies (INAHTA = International Network of Agencies for Health Technology Assessment). For all issues specific inclusion and exclusion criteria were defined. The methodological quality of randomized controlled trials (RCT) was assessed by a modified version of the Cochrane Risk of Bias Tool. For the methodological part information extraction from the literature is structured by the report’s chapters, for the empirical part data extraction sheets were constructed. All information is summarized in a qualitative manner. Results Concerning the methodological issues the literature search retrieved 158 documents (87 documents related to definition or classification, 125 documents related to operationalisation of PRO). For the empirical analyses 225 RCT (rheumatoid arthritis: 77; breast cancer: 148) and 40 HTA-reports and method papers were found. The analysis of the methodological literature confirms the role of PRO as an umbrella term for a variety of different concepts. The newest classification system facilitates the description of PRO measures by construct, target population and the method of measurement. Steps of operationalisation involve defining a conceptual framework, instrument development, exploration of measurement properties or, possibly, the modification of existing instruments. Seven out of 59 RCT analysing the effects of antibody therapy for rheumatoid arthritis define PRO as the primary endpoint, 38 trials utilize composite measures (ACR, DAS) and ten trials report clinical or radiological parameters as the primary endpoint. Six out of 123 chemotherapy trials for breast cancer define PRO as the primary endpoint, while 98 trials report clinical endpoints (survival, tumour response, progression) in their primary analyses. Discrepancies in the number of trials result from inaccurate specifications of endpoints in the publications. This distribution is reflected in the HTA-reports: while almost all reports on rheumatoid arthritis refer to PRO, this is only the case in about half of the reports on breast cancer. Conclusions As definition and classification of PRO are concerned, coherent concepts are found in the literature. Their operationalisation and implementation must be guided by scientific principles. The type and frequency of PRO used in clinical trials largely depend on the disease analysed. The HTA-community seems to pursue the utilization of PRO proactively – in case of missing data the need for further research is stated. PMID:21468289

Informative value of Patient Reported Outcomes (PRO) in Health Technology Assessment (HTA).

PubMed

Brettschneider, Christian; Lühmann, Dagmar; Raspe, Heiner

2011-02-02

"Patient-Reported Outcome" (PRO) is used as an umbrella term for different concepts for measuring subjectively perceived health status e. g. as treatment effects. Their common characteristic is, that the appraisal of the health status is reported by the patient himself. In order to describe the informative value of PRO in Health Technology Assessment (HTA) first an overview of concepts, classifications and methods of measurement is given. The overview is complemented by an empirical analysis of clinical trials and HTA-reports on rheumatoid arthritis and breast cancer in order to report on type, frequency and consequences of PRO used in these documents. For both issues systematic reviews of the literature have been performed. The search for methodological literature covers the publication period from 1990 to 2009, the search for clinical trials of rheumatoid arthritis and breast cancer covers the period 2005 to 2009. Both searches were performed in the medical databases of the German Institute of Medical Documentation and Information (DIMDI). The search for HTA-reports and methodological papers of HTA-agencies was performed in the CRD-Databases (CRD = Centre for Reviews and Dissemination) and by handsearching the websites of INAHTA member agencies (INAHTA = International Network of Agencies for Health Technology Assessment). For all issues specific inclusion and exclusion criteria were defined. The methodological quality of randomized controlled trials (RCT) was assessed by a modified version of the Cochrane Risk of Bias Tool. For the methodological part information extraction from the literature is structured by the report's chapters, for the empirical part data extraction sheets were constructed. All information is summarized in a qualitative manner. Concerning the methodological issues the literature search retrieved 158 documents (87 documents related to definition or classification, 125 documents related to operationalisation of PRO). For the empirical analyses 225 RCT (rheumatoid arthritis: 77; breast cancer: 148) and 40 HTA-reports and method papers were found. The analysis of the methodological literature confirms the role of PRO as an umbrella term for a variety of different concepts. The newest classification system facilitates the description of PRO measures by construct, target population and the method of measurement. Steps of operationalisation involve defining a conceptual framework, instrument development, exploration of measurement properties or, possibly, the modification of existing instruments. Seven out of 59 RCT analysing the effects of antibody therapy for rheumatoid arthritis define PRO as the primary endpoint, 38 trials utilize composite measures (ACR, DAS) and ten trials report clinical or radiological parameters as the primary endpoint. Six out of 123 chemotherapy trials for breast cancer define PRO as the primary endpoint, while 98 trials report clinical endpoints (survival, tumour response, progression) in their primary analyses. Discrepancies in the number of trials result from inaccurate specifications of endpoints in the publications. This distribution is reflected in the HTA-reports: while almost all reports on rheumatoid arthritis refer to PRO, this is only the case in about half of the reports on breast cancer. As definition and classification of PRO are concerned, coherent concepts are found in the literature. Their operationalisation and implementation must be guided by scientific principles. The type and frequency of PRO used in clinical trials largely depend on the disease analysed. The HTA-community seems to pursue the utilization of PRO proactively - in case of missing data the need for further research is stated.

Zhen Gan Xi Feng Decoction, a Traditional Chinese Herbal Formula, for the Treatment of Essential Hypertension: A Systematic Review of Randomized Controlled Trials

PubMed Central

Xiong, Xingjiang; Yang, Xiaochen; Feng, Bo; Liu, Wei; Duan, Lian; Gao, Ao; Li, Haixia; Ma, Jizheng; Du, Xinliang; Li, Nan; Wang, Pengqian; Su, Kelei; Chu, Fuyong; Zhang, Guohao; Li, Xiaoke; Wang, Jie

2013-01-01

Objectives. To assess the clinical effectiveness and adverse effects of Zhen Gan Xi Feng Decoction (ZGXFD) for essential hypertension (EH). Methods. Five major electronic databases were searched up to August 2012 to retrieve any potential randomized controlled trials designed to evaluate the clinical effectiveness of ZGXFD for EH reported in any language, with main outcome measure as blood pressure (BP). Results. Six randomized trials were included. Methodological quality of the trials was evaluated as generally low. Four trials compared prescriptions based on ZGXFD with antihypertensive drugs. Meta-analysis showed that ZGXFD was more effective in BP control and TCM syndrome and symptom differentiation (TCM-SSD) scores than antihypertensive drugs. Two trials compared the combination of modified ZGXFD plus antihypertensive drugs with antihypertensive drugs. Meta-analysis showed that there is significant beneficial effect on TCM-SSD scores. However, no significant effect on BP was found. The safety of ZGXFD is still uncertain. Conclusions. ZGXFD appears to be effective in improving blood pressure and hypertension-related symptoms for EH. However, the evidence remains weak due to poor methodological quality of the included studies. More rigorous trials are warranted to support their clinical use. PMID:23573163

The effectiveness of mindfulness-based interventions for supporting people with intellectual disabilities: a narrative review.

PubMed

Harper, Sarah K; Webb, Thomas L; Rayner, Kelly

2013-05-01

A number of studies have used mindfulness-based interventions to influence the behavior of people with intellectual disabilities, to improve their quality of life, and to reduce challenging behavior. The present review critically evaluates 18 studies and assesses the clinical and academic impact of their findings. Strengths identified included replicable methodological approaches, use of multiple baseline designs, strong construct and criterion validity, and consideration of the mechanisms by which mindfulness influences behavior change. Limitations included a lack of randomized controlled trials, inclusion of qualitative data without structured analysis, limited use of statistical analyses, and problems with sampling leading to difficulties generalizing findings. There was also a paucity of research investigating the impact of "Dialectical Behavior Therapy" and "Acceptance and Commitment Therapy" and the role of mindfulness within these approaches. Further research is warranted in this regard.

Advances in the Treatment of Non-small Cell Lung Cancer: Focus on Nivolumab, Pembrolizumab, and Atezolizumab.

PubMed

Leventakos, Konstantinos; Mansfield, Aaron S

2016-10-01

Immunotherapy is revolutionizing the treatment of non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors, including programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) monoclonal antibodies, are being introduced to routine clinical practice. This review summarizes clinical trials of nivolumab, pembrolizumab, and atezolizumab in patients with NSCLC. These agents have efficacy against NSCLC and a unique toxicity profile. The role of PD-L1 as a predictive biomarker is still unclear, partially because of the nuances of PD-L1 testing. These novel therapies also challenge our existing methodologies of radiologic assessment and efficacy analysis. This new era of immunotherapy has ushered in as much hope for patients as questions from physicians that need to be answered to clarify the optimal use of these agents.

Moving from Efficacy to Effectiveness Trials in Prevention Research

PubMed Central

Marchand, Erica; Stice, Eric; Rohde, Paul; Becker, Carolyn Black

2013-01-01

Efficacy trials test whether interventions work under optimal, highly controlled conditions whereas effectiveness trials test whether interventions work with typical clients and providers in real-world settings. Researchers, providers, and funding bodies have called for more effectiveness trials to understand whether interventions produce effects under ecologically valid conditions, which factors predict program effectiveness, and what strategies are needed to successfully implement programs in practice settings. The transition from efficacy to effectiveness with preventive interventions involves unique considerations, some of which are not shared by treatment research. The purpose of this article is to discuss conceptual and methodological issues that arise when making the transition from efficacy to effectiveness research in primary, secondary, and tertiary prevention, drawing on the experiences of two complimentary research groups as well as the existing literature. We address (a) program of research, (b) intervention design and conceptualization, (c) participant selection and characteristics, (d) providers, (e) context, (f) measurement and methodology, (g) outcomes, (h) cost, and (i) sustainability. We present examples of research in eating disorder prevention that demonstrate the progression from efficacy to effectiveness trials. PMID:21092935

Methodological and ethical challenges in studying patients’ perceptions of coercion: a systematic mixed studies review

PubMed Central

2014-01-01

Background Despite improvements in psychiatric inpatient care, patient restrictions in psychiatric hospitals are still in use. Studying perceptions among patients who have been secluded or physically restrained during their hospital stay is challenging. We sought to review the methodological and ethical challenges in qualitative and quantitative studies aiming to describe patients’ perceptions of coercive measures, especially seclusion and physical restraints during their hospital stay. Methods Systematic mixed studies review was the study method. Studies reporting patients’ perceptions of coercive measures, especially seclusion and physical restraints during hospital stay were included. Methodological issues such as study design, data collection and recruitment process, participants, sampling, patient refusal or non-participation, and ethical issues such as informed consent process, and approval were synthesized systematically. Electronic searches of CINALH, MEDLINE, PsychINFO and The Cochrane Library (1976-2012) were carried out. Results Out of 846 initial citations, 32 studies were included, 14 qualitative and 18 quantitative studies. A variety of methodological approaches were used, although descriptive and explorative designs were used in most cases. Data were mainly collected in qualitative studies by interviews (n = 13) or in quantitative studies by self-report questionnaires (n = 12). The recruitment process was explained in 59% (n = 19) of the studies. In most cases convenience sampling was used, yet five studies used randomization. Patient’s refusal or non-participation was reported in 37% (n = 11) of studies. Of all studies, 56% (n = 18) had reported undergone an ethical review process in an official board or committee. Respondents were informed and consent was requested in 69% studies (n = 22). Conclusions The use of different study designs made comparison methodologically challenging. The timing of data collection (considering bias and confounding factors) and the reasons for non-participation of eligible participants are likewise methodological challenges, e.g. recommended flow charts could aid the information. Other challenges identified were the recruitment of large and representative samples. Ethical challenges included requesting participants’ informed consent and respecting ethical procedures. PMID:24894162

Effectiveness of the 'Who's Challenging Who' support staff training intervention to improve attitudes and empathy towards adults with intellectual disability and challenging behaviours: study protocol for a cluster randomised controlled trial.

PubMed

Randell, Elizabeth; Hastings, Richard P; McNamara, Rachel; Knight, Roseanna; Gillespie, David; Taylor, Zachary

2017-10-05

Findings suggest approximately one in six people with intellectual disability engage in 'challenging behaviours', which include aggression towards others/property and self-injurious actions. In residential settings, actions of staff members can make challenging behaviours more likely to occur, or make these behaviours worse. In particular, negative attitudes from members of staff and lack of understanding about the reasons for challenging behaviour are contributory factors. 'Who's Challenging Who?' (WCW) training is designed to emphasise the role of staff in residential settings as a challenge also to people with intellectual disability. The course is delivered jointly by a trainer with intellectual disability who has been labelled as having challenging behaviour, along with a trainer without intellectual disability. This is a cluster randomised two-arm trial of WCW training versus a waiting list control. Overall, 118 residential settings will be recruited and randomised on a 1:1 ratio. Within each setting, two members of staff will be invited to take part in the trial. Participants will complete assessments at baseline and at 6 and 20 weeks. WCW is a half day initial training course with some follow-on coaching to ensure implementation. The primary outcome is changes in staff empathy towards people with challenging behaviour. Secondary outcomes at the staff level include confidence, attitudes and work-related well-being. Secondary outcomes at the residential setting level include recorded incidents of aggressive challenging behaviour, and use of any restrictive practices. If the results of the cluster randomised trial are positive, we will disseminate the findings widely and make all training manuals and materials freely available for anyone in intellectual disability services (and beyond) to use. Our training approach may have wider implications in other areas of social care. It may also provide a generally applicable model for how to train people with intellectual disability to act as co-trainers in intellectual disability social care settings. People with intellectual disability and challenging behaviour have already been involved centrally with the design, development and pilot evaluation of WCW and will also be fully involved throughout this trial. Registered on the International Standard Randomised Controlled Trial Number registry on 8th December 2015: ISRCTN53763600 .

Evaluation of hospital palliative care teams: strengths and weaknesses of the before-after study design and strategies to improve it.

PubMed

Simon, S; Higginson, I J

2009-01-01

Hospital palliative care teams (HPCTs) are well established as multi-professional services to provide palliative care in an acute hospital setting and are increasing in number. However, there is still limited evaluation of them, in terms of efficacy and effectiveness. The gold standard method of evaluation is a randomised control trial, but because of methodological (e.g., randomisation), ethical and practical difficulties such trials are often not possible. HPCT is a complex intervention, and the specific situation in palliative care makes it challenging to evaluate (e.g., distress and cognitive impairment of patients). The quasi-experimental before-after study design has the advantage of enabling an experimental character without randomisation. But this has other weaknesses and is prone to bias, for example, temporal trends and selection bias. As for every study design, avoidance and minimisation of bias is important to improve validity. Therefore, strategies of selecting an appropriate control group or time series and applying valid outcomes and measurement tools help reducing bias and strengthen the methods. Special attention is needed to plan and define the design and applied method.

Clinical Application of Mesenchymal Stem Cells and Novel Supportive Therapies for Oral Bone Regeneration

PubMed Central

O'Valle, Francisco; Lanis, Alejandro; Dohan Ehrenfest, David M.; Wang, Hom-Lay; Galindo-Moreno, Pablo

2015-01-01

Bone regeneration is often needed prior to dental implant treatment due to the lack of adequate quantity and quality of the bone after infectious diseases, trauma, tumor, or congenital conditions. In these situations, cell transplantation technologies may help to overcome the limitations of autografts, xenografts, allografts, and alloplastic materials. A database search was conducted to include human clinical trials (randomized or controlled) and case reports/series describing the clinical use of mesenchymal stem cells (MSCs) in the oral cavity for bone regeneration only specifically excluding periodontal regeneration. Additionally, novel advances in related technologies are also described. 190 records were identified. 51 articles were selected for full-text assessment, and only 28 met the inclusion criteria: 9 case series, 10 case reports, and 9 randomized controlled clinical trials. Collectively, they evaluate the use of MSCs in a total of 290 patients in 342 interventions. The current published literature is very diverse in methodology and measurement of outcomes. Moreover, the clinical significance is limited. Therefore, the use of these techniques should be further studied in more challenging clinical scenarios with well-designed and standardized RCTs, potentially in combination with new scaffolding techniques and bioactive molecules to improve the final outcomes. PMID:26064899

Assessing Health Promotion Interventions: Limitations of Traditional Research Methods in Community-Based Studies.

PubMed

Dressel, Anne; Schneider, Robert; DeNomie, Melissa; Kusch, Jennifer; Welch, Whitney; Sosa, Mirtha; Yeldell, Sally; Maida, Tatiana; Wineberg, Jessica; Holt, Keith; Bernstein, Rebecca

2017-09-01

Most low-income Americans fail to meet physical activity recommendations. Inactivity and poor diet contribute to obesity, a risk factor for multiple chronic diseases. Health promotion activities have the potential to improve health outcomes for low-income populations. Measuring the effectiveness of these activities, however, can be challenging in community settings. A "Biking for Health" study tested the impact of a bicycling intervention on overweight or obese low-income Latino and African American adults to reduce barriers to cycling and increase physical activity and fitness. A randomized controlled trial was conducted in Milwaukee, Wisconsin, in summer 2015. A 12-week bicycling intervention was implemented at two sites with low-income, overweight, or obese Latino and African American adults. We found that randomized controlled trial methodology was suboptimal for use in this small pilot study and that it negatively affected participation. More discussion is needed about the effectiveness of using traditional research methods in community settings to assess the effectiveness of health promotion interventions. Modifications or alternative methods may yield better results. The aim of this article is to discuss the effectiveness and feasibility of using traditional research methods to assess health promotion interventions in community-based settings.

Patient-Reported Outcomes in Cancer Drug Development and US Regulatory Review: Perspectives From Industry, the Food and Drug Administration, and the Patient.

PubMed

Basch, Ethan; Geoghegan, Cindy; Coons, Stephen Joel; Gnanasakthy, Ari; Slagle, Ashley F; Papadopoulos, Elektra J; Kluetz, Paul G

2015-06-01

Data reported directly by patients about how they feel and function are rarely included in oncology drug labeling in the United States, in contrast to Europe and to nononcology labeling in the United States, where this practice is more common. Multiple barriers exist, including challenges unique to oncology trials, and industry's concerns regarding cost, logistical complexities, and the Food and Drug Administration's (FDA's) rigorous application of its 2009 guidance on the use of patient-reported outcome (PRO) measures. A panel consisting of representatives of industry, FDA, the PRO Consortium, clinicians, and patients was assembled at a 2014 workshop cosponsored by FDA to identify practical recommendations for overcoming these barriers. Key recommendations included increasing proactive encouragement by FDA to clinical trial sponsors for including PROs in drug development programs; provision of comprehensive PRO plans by sponsors to FDA early in drug development; promotion of an oncology-specific PRO research agenda; development of an approach to existing ("legacy") PRO measures, when appropriate (focused initially on symptoms and functional status); and increased FDA and industry training in PRO methodology. FDA has begun implementing several of these recommendations.

A systematic review of cognitive and/or behavioural therapies for methamphetamine dependence

PubMed Central

Lee, Nicole K; Rawson, Richard A.

2015-01-01

Introduction and aims The use of methamphetamine is widespread and poses significant challenges for treatment providers. Much of the treatment knowledge about this group has been extrapolated from studies of treatment for cocaine dependence. Medications have been shown to be of limited effectiveness for methamphetamine users, making psychological interventions the treatment of choice. Design and methods This paper describes a systematic review of cognitive-behavioural and behavioural interventions for methamphetamine users. A systematic search of published literature was undertaken focusing only on randomised trials. Results There were a relatively small number of intervention studies that compared cognitive-behavioural or behavioural interventions using randomised trial methodology. Most commonly, studies examined cognitive behaviour therapy (CBT) and/or contingency management (CM). Treatment with CBT appears to be associated with reductions in methamphetamine use and other positive changes ,even over very short periods of treatment (2 and 4 sessions). CM studies found a significant reduction of methamphetamine during application of the procedure, but it is not clear if these gains are sustained at post-treatment follow-up. Discussion and conclusion Further research into cognitive behavioural and behavioural treatments for methamphetamine users is required, with a focus on improving longevity of the effect of intervention. PMID:18368613

Using minimal human-computer interfaces for studying the interactive development of social awareness

PubMed Central

Froese, Tom; Iizuka, Hiroyuki; Ikegami, Takashi

2014-01-01

According to the enactive approach to cognitive science, perception is essentially a skillful engagement with the world. Learning how to engage via a human-computer interface (HCI) can therefore be taken as an instance of developing a new mode of experiencing. Similarly, social perception is theorized to be primarily constituted by skillful engagement between people, which implies that it is possible to investigate the origins and development of social awareness using multi-user HCIs. We analyzed the trial-by-trial objective and subjective changes in sociality that took place during a perceptual crossing experiment in which embodied interaction between pairs of adults was mediated over a minimalist haptic HCI. Since that study required participants to implicitly relearn how to mutually engage so as to perceive each other's presence, we hypothesized that there would be indications that the initial developmental stages of social awareness were recapitulated. Preliminary results reveal that, despite the lack of explicit feedback about task performance, there was a trend for the clarity of social awareness to increase over time. We discuss the methodological challenges involved in evaluating whether this trend was characterized by distinct developmental stages of objective behavior and subjective experience. PMID:25309490

Research Methodology in Second Language Studies: Trends, Concerns, and New Directions

ERIC Educational Resources Information Center

King, Kendall A.; Mackey, Alison

2016-01-01

The field of second language studies is using increasingly sophisticated methodological approaches to address a growing number of urgent, real-world problems. These methodological developments bring both new challenges and opportunities. This article briefly reviews recent ontological and methodological debates in the field, then builds on these…

The Challenges of Managing Transnational Education Partnerships: The Views of "Home-Based" Managers vs "In-Country" Managers

ERIC Educational Resources Information Center

Healey, Nigel Martin

2018-01-01

Purpose: The purpose of this paper is to investigate the challenges of managing transnational education (TNE) partnerships from the perspective of the home university managers. Design/methodology/approach: The study adopts a qualitative, "insider researcher" methodology. It uses a sample set of eight mangers who operate from the home…

Small studies may overestimate the effect sizes in critical care meta-analyses: a meta-epidemiological study

PubMed Central

2013-01-01

Introduction Small-study effects refer to the fact that trials with limited sample sizes are more likely to report larger beneficial effects than large trials. However, this has never been investigated in critical care medicine. Thus, the present study aimed to examine the presence and extent of small-study effects in critical care medicine. Methods Critical care meta-analyses involving randomized controlled trials and reported mortality as an outcome measure were considered eligible for the study. Component trials were classified as large (≥100 patients per arm) and small (<100 patients per arm) according to their sample sizes. Ratio of odds ratio (ROR) was calculated for each meta-analysis and then RORs were combined using a meta-analytic approach. ROR<1 indicated larger beneficial effect in small trials. Small and large trials were compared in methodological qualities including sequence generating, blinding, allocation concealment, intention to treat and sample size calculation. Results A total of 27 critical care meta-analyses involving 317 trials were included. Of them, five meta-analyses showed statistically significant RORs <1, and other meta-analyses did not reach a statistical significance. Overall, the pooled ROR was 0.60 (95% CI: 0.53 to 0.68); the heterogeneity was moderate with an I2 of 50.3% (chi-squared = 52.30; P = 0.002). Large trials showed significantly better reporting quality than small trials in terms of sequence generating, allocation concealment, blinding, intention to treat, sample size calculation and incomplete follow-up data. Conclusions Small trials are more likely to report larger beneficial effects than large trials in critical care medicine, which could be partly explained by the lower methodological quality in small trials. Caution should be practiced in the interpretation of meta-analyses involving small trials. PMID:23302257

Mesh fixation in endoscopic inguinal hernia repair: evaluation of methodology based on a systematic review of randomised clinical trials.

PubMed

Lederhuber, Hans; Stiede, Franziska; Axer, Stephan; Dahlstrand, Ursula

2017-11-01

The issue of mesh fixation in endoscopic inguinal hernia repair is frequently debated and still no conclusive data exist on differences between methods regarding long-term outcome and postoperative complications. The quantity of trials and the simultaneous lack of high-quality evidence raise the question how future trials should be planned. PubMed, EMBASE and the Cochrane Library were searched, using the filters "randomised clinical trials" and "humans". Trials that compared one method of mesh fixation with another fixation method or with non-fixation in endoscopic inguinal hernia repair were eligible. To be included, the trial was required to have assessed at least one of the following primary outcome parameters: recurrence; surgical site infection; chronic pain; or quality-of-life. Fourteen trials assessing 2161 patients and 2562 hernia repairs were included. Only two trials were rated as low risk for bias. Eight trials evaluated recurrence or surgical site infection; none of these could show significant differences between methods of fixation. Two of 11 trials assessing chronic pain described significant differences between methods of fixation. One of two trials evaluating quality-of-life showed significant differences between fixation methods in certain functions. High-quality evidence for differences between the assessed mesh fixation techniques is still lacking. From a socioeconomic and ethical point of view, it is necessary that future trials will be properly designed. As small- and medium-sized single-centre trials have proven unable to find answers, register studies or multi-centre studies with an evident focus on methodology and study design are needed in order to answer questions about mesh fixation in inguinal hernia repair.

Integrative treatment for low back pain: An exploratory systematic review and meta-analysis of randomized controlled trials.

PubMed

Hu, Xiao-Yang; Chen, Ni-Ni; Chai, Qian-Yun; Yang, Guo-Yan; Trevelyan, Esmé; Lorenc, Ava; Liu, Jian-Ping; Robinson, Nicola

2015-10-26

Low back pain (LBP) is a common musculoskeletal condition often treated using integrative medicine (IM). Most reviews have focused on a single complementary and alternative medicine (CAM) therapy for LBP rather than evaluating wider integrative approaches. This exploratory systematic review aimed to identify randomized controlled trials (RCTs) and provide evidence on the effectiveness, cost effectiveness and adverse effects of integrative treatment for LBP. A literature search was conducted in 12 English and Chinese databases. RCTs evaluating an integrative treatment for musculoskeletal related LBP were included. Reporting, methodological quality and relevant clinical characteristics were assessed and appraised. Metaanalyses were performed for outcomes where trials were sufficiently homogenous. Fifty-six RCTs were identified evaluating integrative treatment for LBP. Although reporting and methodological qualities were poor, meta-analysis showed a favourable effect for integrative treatment over conventional and CAM treatment for back pain and function at 3 months or less follow-up. Two trials investigated costs, reporting £ 5332 per quality adjusted life years with 6 Alexander technique lessons plus exercise at 12 months follow-up; and an increased total costs of $244 when giving an additional up to 15 sessions of CAM package of care at 12 weeks. Sixteen trials mentioned safety; no severe adverse effects were reported. Integrative treatment that combines CAM with conventional therapies appeared to have beneficial effects on pain and function. However, evidence is limited due to heterogeneity, the relatively small numbers available for subgroup analyses and the low methodological quality of the included trials. Identification of studies of true IM was not possible due to lack of reporting of the intervention details (registration No. CRD42013003916).

[Evaluation of methodological quality in published RCTs on cataract surgery : Pilot study on the degree of adherence to CONSORT statement requirements and their qualitative validity].

PubMed

Baulig, C; Krummenauer, F; Knippschild, S

2018-01-01

The CONSORT statement can be considered as a guideline to ensure transparency in the reporting of randomized clinical trials (RCT), in addition to specific author instructions and requirements of journals. It provides a total of 25 criteria and 12 additional subcriteria on methodological and regulatorical determinants of clinical trials. The availability of the CONSORT recommendations, however, does not necessarily imply adherence to their obligations and correct realisation of the latter from a methodological perspective, so that even in ophthalmology a lack of transparency in trial reporting cannot be excluded. The question was whether a consistent consideration of the CONSORT checklist criteria by authors actually implied transparent reporting of underlying study results. This pilot study was based on a random sample of six published RCTs on cataract surgery extracted from an existing trial publication register. Compliance with each of the 25 CONSORT criteria and its 12 subcriteria and the content accuracy of the latter were independently assessed by two parallel raters for the six trial publications. The median compliance with the 37 CONSORT criteria and subcriteria was 62% [min-max 48-81%]; the median fraction of their correct implementation was 47% [min-max 34-69%]. Promotion of transparent reporting by means of the CONSORT statement appears to be problematic in implementation. There is a discrepancy between information as required by CONSORT and the content accuracy of its actual presentation. Thus, in particular, reviewers of clinical trial publications should not only check for the presence of data to be provided according to CONSORT, but also verify the meaningfulness in the respective context, at least on a random basis.

Music for medical indications in the neonatal period: a systematic review of randomised controlled trials.

PubMed

Hartling, L; Shaik, M S; Tjosvold, L; Leicht, R; Liang, Y; Kumar, M

2009-09-01

To conduct a systematic review of the efficacy of music for medical indications in term or preterm neonates. We searched 17 electronic databases, subject bibliographies, reference lists and trials registries. Two reviewers independently screened studies for inclusion, assessed methodological quality, and extracted data. Meta-analysis was not feasible due to heterogeneity in outcomes so a qualitative analysis is presented. Nine randomised trials were included. The methodological quality was generally poor (median Jadad score = 1). The outcomes most commonly reported were physiological measures (heart rate (HR), respiratory rate, oxygen saturation (SaO2)), behavioural state and pain. Six studies evaluated music for the painful procedures circumcision (three trials) and heel prick (three trials). For circumcisions, one high quality pilot study (n = 23) showed benefits of music for the outcomes of HR, SaO2 and pain, while two low quality studies showed no difference. For heel prick, three low quality studies provided some evidence that music may be beneficial primarily for measures of behaviour and pain. The remaining studies evaluated the use of music in preterm infants to improve physiological and behavioural parameters (n = 31; benefits observed for behavioural parameters), to reinforce non-nutritive sucking via use of a pacifier activated lullaby (n = 32; significant increase in feeding rates), and to influence physiological stability and behaviours in infants with chronic lung disease (n = 22; no significant differences for outcomes assessed). The heterogeneity in study populations, interventions and outcomes precludes definitive conclusions around efficacy. There is preliminary evidence for some therapeutic benefits of music for specific indications; however, these findings need to be confirmed in methodologically rigorous trials.

Exercise and osteoporosis: Methodological and practical considerations

NASA Technical Reports Server (NTRS)

Block, Jon E.; Friedlander, Anne L.; Steiger, Peter; Genant, Harry K.

1994-01-01

Physical activity may have important implications for enhancing bone density prior to the initiation of space flight, for preserving bone density during zero gravity, and for rehabilitating the skeleton upon return to Earth. Nevertheless, the beneficial effects of exercise upon the skeleton have not been proven by controlled trials and no consensus exists regarding the type, duration, and intensity of exercise necessary to make significant alterations to the skeleton. The following sections review our current understanding of exercise and osteoporosis, examine some of the methodological shortcomings of these investigations, and make research recommendations for future clinical trials.

Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4–5 December 2014)

PubMed Central

Manolis, E; Holford, N; Cheung, SYA; Friberg, LE; Ogungbenro, K; Posch, M; Yates, JWT; Berry, S; Thomas, N; Corriol‐Rohou, S; Bornkamp, B; Bretz, F; Hooker, AC; Van der Graaf, PH; Standing, JF; Hay, J; Cole, S; Gigante, V; Karlsson, K; Dumortier, T; Benda, N; Serone, F; Das, S; Brochot, A; Ehmann, F; Hemmings, R; Rusten, I Skottheim

2017-01-01

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late‐stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well‐established and regulatory‐acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4–5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP‐Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)‐based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well‐designed dose‐finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale. PMID:28722322