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Sample records for michniak-kohn fda tdds

  1. Evaluating elevated release liner adhesion of a transdermal drug delivery system (TDDS): a study of Daytrana™ methylphenidate transdermal system.

    PubMed

    Wokovich, Anna M; Shen, Meiyu; Doub, William H; Machado, Stella G; Buhse, Lucinda F

    2011-10-01

    Complaints from healthcare providers that the adhesive on the Daytrana™ methylphenidate transdermal drug delivery system (TDDS) adhered to the release liner to such an extent that the release liner could not be removed prompted this study. Daytrana™ has a packaging system consisting of a moisture-permeable pouch contained within a sealed tray containing a desiccant; the tray is impermeable to ambient moisture. The objective of this project was to determine if the Daytrana™ packaging system influenced the difficulty in removing the release liner. Both a sealed tray and an open tray containing sealed pouches were placed into an environmental chamber at 25°C and 60% relative humidity for 30 days; afterwards, release liner removal testing using a peel angle of 90° and a peel speed of 300 mm/min was performed. TDDS from open chamber trays required less force to remove the release liner than did TDDS from closed chamber trays. For the 10 mg/9 h TDDS and the 15 mg/9 h TDDS (the dosages examined), there were substantial differences in release liner removal force between an old lot and a new lot for closed chamber trays but not for open chamber trays. The results demonstrate that for this particular TDDS, storage conditions such as humidity influence release liner adhesion. This project also demonstrates that, to ensure adequate product quality, adhesion needs to become an important design parameter, and the design of a TDDS should consider the ability to remove the release liner under anticipated storage conditions.

  2. Critical attributes of transdermal drug delivery system (TDDS)--a generic product development review.

    PubMed

    Ruby, P K; Pathak, Shriram M; Aggarwal, Deepika

    2014-11-01

    Bioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two products. These current regulatory procedures demand a complete characterization of the generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of products and also outlines their valuable applications in generic product success. Understanding these critical in vitro parameters can probably help to decode the complex bioequivalence outcomes, directing the generic companies to optimize the formulation design in reduced time intervals. It is difficult to summarize a common platform which covers all possible transdermal products; hence few case studies based on this approach has been presented in this review.

  3. Drugs@FDA: FDA Approved Drug Products

    MedlinePlus

    ... Cosmetics Tobacco Products Home Drug Databases Drugs@FDA Drugs@FDA: FDA Approved Drug Products Share Tweet Linkedin Pin it More sharing options Linkedin Pin it Email Print Search by Drug Name, Active Ingredient, or Application Number Enter at ...

  4. Time-dependent Data System (TDDS); an interactive program to assemble, manage, and appraise input data and numerical output of flow/transport simulation models

    USGS Publications Warehouse

    Regan, R.S.; Schaffranek, R.W.; Baltzer, R.A.

    1996-01-01

    A system of functional utilities and computer routines, collectively identified as the Time-Dependent Data System CI DDS), has been developed and documented by the U.S. Geological Survey. The TDDS is designed for processing time sequences of discrete, fixed-interval, time-varying geophysical data--in particular, hydrologic data. Such data include various, dependent variables and related parameters typically needed as input for execution of one-, two-, and three-dimensional hydrodynamic/transport and associated water-quality simulation models. Such data can also include time sequences of results generated by numerical simulation models. Specifically, TDDS provides the functional capabilities to process, store, retrieve, and compile data in a Time-Dependent Data Base (TDDB) in response to interactive user commands or pre-programmed directives. Thus, the TDDS, in conjunction with a companion TDDB, provides a ready means for processing, preparation, and assembly of time sequences of data for input to models; collection, categorization, and storage of simulation results from models; and intercomparison of field data and simulation results. The TDDS can be used to edit and verify prototype, time-dependent data to affirm that selected sequences of data are accurate, contiguous, and appropriate for numerical simulation modeling. It can be used to prepare time-varying data in a variety of formats, such as tabular lists, sequential files, arrays, graphical displays, as well as line-printer plots of single or multiparameter data sets. The TDDB is organized and maintained as a direct-access data base by the TDDS, thus providing simple, yet efficient, data management and access. A single, easily used, program interface that provides all access to and from a particular TDDB is available for use directly within models, other user-provided programs, and other data systems. This interface, together with each major functional utility of the TDDS, is described and documented in this

  5. Drugs@FDA: FDA Approved Drug Products

    MedlinePlus

    ... by Month Approvals, tentative approvals, and supplements Original New Drug Approvals (NDAs and BLAs) by Month All applications ... FDA. Does not include tentative approvals. Original Abbreviated New Drug Approvals (ANDAs) by Month Generic Drug Approvals. Does ...

  6. FDA Certified Mammography Facilities

    MedlinePlus

    ... Products Radiation-Emitting Products Home Radiation-Emitting Products Mammography Quality Standards Act and Program Consumer Information (MQSA) ... it Email Print This list of FDA Certified Mammography Facilities is updated weekly. If you click on ...

  7. FDA Certified Mammography Facilities

    MedlinePlus

    ... Program Consumer Information (MQSA) Search for a Certified Facility Share Tweet Linkedin Pin it More sharing options ... Email Print This list of FDA Certified Mammography Facilities is updated weekly. If you click on Search ...

  8. Pressure-sensitive adhesive properties of poly(N-vinyl pyrrolidone)/D,L-lactic acid oligomer/glycerol/water blends for TDDS.

    PubMed

    Zhang, Jianhua; Deng, Liandong; Zhao, Hujia; Liu, Mei; Jin, Hongjian; Li, Jingqing; Dong, Anjie

    2010-01-01

    In order to develop a new type of pressure-sensitive adhesive (PSA) for a transdermal drug-delivery system (TDDS), a quaternary blend (PDGW) composed of poly(N-vinyl pyrrolidone) (PVP), D,L-lactic acid oligomer (DLLAO), glycerol and water was prepared, in which glycerol and water were used as plasticizer. The effects of the number-average molecular weight (M(n)) of DLLAO and the contents of DLLAO and plasticizer on the PSA properties were studied. The results suggest that PDGW exhibits excellent PSA properties when M(n) of DLLAO is in the range of about 200-400 and the contents of DLLAO, glycerol and water are in the range of 5-20, 15-25 and 20-35 wt%, respectively. The miscibility between PVP and DLLAO was investigated via DSC, TGA and FT-IR, and all results indicate that PVP has good miscibility with DLLAO due to strong hydrogen-bond interaction. The storage stability of PDGW also was studied and the results show that the PDGW matrix possesses stable properties over time. In addition, in vivo skin irritation of PDGW was investigated using rabbit as model animal, and the results show that the PDGW does not cause irritation to skin after topical application for 120 h. Therefore, the PDGW possesses excellent PSA properties and presents potential application in TDDS.

  9. FDA Approval for Imiquimod

    Cancer.gov

    On July 15, 2004, the U.S. Food and Drug Administration (FDA) announced the approval of a new indication for Aldara® (imiquimod) topical cream for the treatment of superficial basal cell carcinoma (sBCC), a type of skin cancer.

  10. Final FDA inspection manual.

    PubMed

    Donawa, M

    2001-04-01

    For some time now, the only publicly available compliance programme guidance manual on medical device inspections and administrative and enforcement activities has been a draft document. On 7 February 2001, a final guidance document was issued. This article discusses this document and its importance to non-US medical device manufacturers preparing for FDA facility inspections.

  11. FDA 101: Regulating Biological Products

    MedlinePlus

    ... Home For Consumers Consumer Updates FDA 101: Regulating Biological Products Share Tweet Linkedin Pin it More sharing ... and highly important field. back to top What biological products does FDA regulate? The Center for Biologics ...

  12. FDA pharmaceutical quality oversight.

    PubMed

    Yu, Lawrence X; Woodcock, Janet

    2015-08-01

    The launch of the Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ) is a milestone in FDA's efforts to assure that quality medicines are available to the American public. As a new super-office within CDER, OPQ is strategically organized to streamline regulatory processes, advance regulatory standards, align areas of expertise, and originate surveillance of drug quality. Supporting these objectives will be an innovative and systematic approach to product quality knowledge management and informatics. Concerted strategies will bring parity to the oversight of innovator and generic drugs as well as domestic and international facilities. OPQ will promote and encourage the adoption of emerging pharmaceutical technology to enhance pharmaceutical quality and potentially reinvigorate the pharmaceutical manufacturing sector in the United States. With a motto of "One Quality Voice," OPQ embodies the closer integration of review, inspection, surveillance, policy, and research for the purpose of strengthening pharmaceutical quality on a global scale.

  13. FDA's evolving approach to nanotechnology.

    PubMed

    Monica, John C

    2012-01-01

    Nanotechnology has emerged as an industry with the potential to change many products regulated by the FDA. While the FDA has been regulating products containing nanoscale materials for several years, questions concerning the effectiveness of existing regulations have emerged. After a period of study and analysis, the FDA has issued three (3) draft guidance documents over the last eighteen (18) months pertaining to the use of nanoscale materials and nanotechnology in certain FDA-regulated products. As these are likely to become the "de facto" standards they merit further analysis. This article examines these draft guidance documents and provides modest commentary for those practicing in the area.

  14. A Guide to the FDA.

    ERIC Educational Resources Information Center

    Miller, Annetta K.

    The United States Food and Drug Administration (FDA) collects information in seven areas: foods, cosmetics, human drugs, animal drugs and feeds, medical devices, biologics, and electronic radiological products. By using procedures outlined in the Freedom of Information Act, the public may get specific information from such FDA files as inspection…

  15. A Guide to the FDA.

    ERIC Educational Resources Information Center

    Miller, Annetta K.

    The United States Food and Drug Administration (FDA) collects information in seven areas: foods, cosmetics, human drugs, animal drugs and feeds, medical devices, biologics, and electronic radiological products. By using procedures outlined in the Freedom of Information Act, the public may get specific information from such FDA files as inspection…

  16. Is It Really FDA Approved?

    MedlinePlus

    ... tissue. back to top FDA doesn’t approve tobacco products. There’s no such thing as a safe tobacco product, so FDA’s safe and effective standard for evaluating medical products is not appropriate for tobacco products. Instead, FDA regulates tobacco products based on ...

  17. FDA-Approved HIV Medicines

    MedlinePlus

    HIV Treatment FDA-Approved HIV Medicines (Last updated 2/27/2017; last reviewed 2/27/2017) Treatment with ... 2007 Pharmacokinetic Enhancers Pharmacokinetic enhancers are used in HIV treatment to increase the effectiveness of an HIV medicine ...

  18. FDA regulation of tobacco: blessing or curse for FDA professionals?

    PubMed

    O'Reilly, James T

    2009-01-01

    Upwards of 400,000 Americans will die that year from the effects of cigarettes, which FDA will now "regulate" very gently, with its hands tied by a slick statutory protection for the largest existing tobacco marketers. Career FDA professionals will be criticized as enablers of mega-marketers' continued sales, working at the margins, arranging the paperwork for protection of megafirms' market share, and sitting by as the deaths and addictive behaviors continue. "Join the Public Health Service, inspired by a public health mission," they were told, and yet they will be unable to do much regulating of the addictive and fatal products for which they now have titular responsibility. This essay observes that these fine FDA professionals are handed the sticky remains of a messy bargain, negotiated in a distracted Congress by expensive lawyers with clients who were potent contributors to political action committees. The only formula that is not secret about the 2009 law is the way in which industry purchased sufficient allegiance to gather the votes for its adoption. The remaining mystery is how FDA could be expected to do these tasks without losing its best and brightest professionals to other fields.

  19. FDA Warns About Stem Cell Claims

    MedlinePlus

    ... Home For Consumers Consumer Updates FDA Warns About Stem Cell Claims Share Tweet Linkedin Pin it More sharing ... blood-forming system. back to top Regulation of Stem Cells FDA regulates stem cells in the U.S. to ...

  20. Internet Database Review: The FDA BBS.

    ERIC Educational Resources Information Center

    Tomaiuolo, Nicholas G.

    1993-01-01

    Describes the electronic bulletin board system (BBS) of the Food and Drug Administration (FDA) that is accessible through the Internet. Highlights include how to gain access; the menu-driven software; other electronic sources of FDA information; and adding value. Examples of the FDA BBS menu and the help screen are included. (LRW)

  1. Doctors, drugs, and the FDA.

    PubMed

    Shanklin, D R

    1972-11-01

    This communication is directed to obstetricians, to the Food and Drug Administration (FDA), and to those individuals who might want to impose possibly unnecessary external structures on the practice of medicine. It is considered a positive that the patients of today are well informed and are more actively participating in therapeutic design. There is more veto power on the part of the patient and more concern over the trained ability of the physician. In the past physicians frequently made judgements individually, applying isolated and at times random standards for their decisions. Such actions were inevitable in an era when neither pathogenesis nor treatment was well understood. Now there is no excuse for such actions. Communication is easy, journals are widely circulated, and there are numerous refresher seminars. Increased specialization of knowledge has meant more corporate or group decisions for therapy. Current trends will continue to offer both opportunities and responsibilities. The opportunities are for better diffusion of knowledge, and the responsibility is to be informed. There can be a high level national standard for medical practice. As a beginning, the medical practice laws could use some uniform decisions. The FDA needs to show more responsiveness to changing knowledge and increased willingness to reconsider indications and contraindications in the light of newer experience. There is sufficient information available now to support the revocation of the approval of the use of diuretics in the management of human pregnancy. Another role of the FDA is the approval of new substances or new uses of old substances. The prostaglandins appear in this category, and the December 1972 issue will include the recent Brook Lodge Symposium on prostaglandins. The individual physician requires journal articles, individual experience, and designed trials in order to make judgements on patients who may have some factors not accounted for by groupthink or regulations.

  2. FDA Issues Final Guidance Clarifying FDA and EPA Jurisdiction over Mosquito-Related Products

    EPA Pesticide Factsheets

    FDA finalized guidance to provide information on FDA and EPA jurisdiction over the regulation of mosquito-related products intended to function as pesticides, including those products intended to function as pesticides

  3. Access to F.D.A. Information.

    ERIC Educational Resources Information Center

    Sinovic, Dianna

    Prior to the enactment of the Freedom of Information Act (FOIA), little of the data collected by the Food and Drug Administration (FDA) was made public or could be obtained from the agency. Although the FDA files are now open, information is considered exempt from public disclosure when it involves regulatory procedures, program guidelines, work…

  4. The new FDA combination products programme.

    PubMed

    Donawa, Maria

    2002-10-01

    The United States (US) Food and Drug Administration (FDA) has established a Combination Products Programme and developed a new internal procedure to increase its effectiveness in regulating products consisting of combinations of drugs, devices and biological products. This article provides a brief overview of the FDA regulation of combination products and discusses the new Programme.

  5. FDA final guidance on software validation.

    PubMed

    Donawa, Maria

    2002-04-01

    The United States Food and Drug Administration (FDA) places considerable importance on the validation of software contained in and used to design, develop, or manufacture medical devices. This article discusses a recently published final FDA guidance document on software validation and the reasons for its importance.

  6. Access to F.D.A. Information.

    ERIC Educational Resources Information Center

    Sinovic, Dianna

    Prior to the enactment of the Freedom of Information Act (FOIA), little of the data collected by the Food and Drug Administration (FDA) was made public or could be obtained from the agency. Although the FDA files are now open, information is considered exempt from public disclosure when it involves regulatory procedures, program guidelines, work…

  7. FDA Approval Summary: TAS-102.

    PubMed

    Marcus, Leigh; Lemery, Steven J; Khasar, Sachia; Wearne, Emily; Helms, Whitney S; Yuan, Weishi; He, Kun; Cao, Xianhua; Yu, Jingyu; Zhao, Hong; Wang, Yaning; Stephens, Olen; Englund, Erika; Agarwal, Rajiv; Keegan, Patricia; Pazdur, Richard

    2017-06-15

    The FDA approved TAS-102 (Lonsurf; Taiho Oncology, Inc.) for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF biological therapy; and if RAS wild type, an anti-EGFR therapy. In an international, multicenter, double-blinded, placebo-controlled trial (TPU-TAS-102-301, herein referred to as RECOURSE), 800 patients with previously treated mCRC were randomly allocated (2:1) to receive either TAS-102 35 mg/m(2) orally twice daily after meals on days 1 through 5 and 8 through 12 of each 28-day cycle (n = 534) or matching placebo (n = 266). The trial demonstrated a statistically significant improvement in overall survival for those randomized to receive TAS-102, with a median survival of 7.1 months in the TAS-102 arm [confidence interval (CI), 6.5-7.8] and 5.3 months in the placebo arm [CI, 4.6-6.0; hazard ratio (HR), 0.68; 95% CI, 0.58-0.81; P < 0.001, stratified log-rank test]. The trial also demonstrated a statistically significant prolongation of progression-free survival (HR, 0.47; 95% CI, 0.40-0.55; P < 0.001). The most common adverse reactions, in order of decreasing frequency, observed in the patients who received TAS-102 were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. Adverse events led to discontinuation of TAS-102 in 3.6% of patients, and 13.7% required a dose reduction. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea. Clin Cancer Res; 23(12); 2924-7. ©2017 AACR. ©2017 American Association for Cancer Research.

  8. Planning for effective interaction with FDA.

    PubMed

    Spurgin, Elizabeth A

    2004-12-01

    Manufacturers of diabetes devices can facilitate the formal regulatory approval process through early interaction with the U.S. Food and Drug Administration (FDA). Effective planning can help manage commonly perceived risks of interaction with the Agency, introduce new technologies to regulatory reviewers, and inform the manufacturer's product development strategy. This article reviews key aspects of the FDA evaluation process and suggests strategies that may facilitate effective communication with the Agency. Integrating early communication with FDA into broader product commercialization planning can streamline regulatory review and lead to early product launch into reimbursed markets.

  9. Beyond biotechnology: FDA regulation of nanomedicine.

    PubMed

    Miller, John

    2003-01-01

    Nanotechnology, which involves investigating and manipulating matter at the atomic and molecular levels, may radically transform industry and society. Because nanotechnology could introduce whole new classes of materials and products, it could present an array of novel challenges to regulatory agencies. In this note, John Miller explores the regulatory challenges facing the Food and Drug Administration in regulating nanomedical products. First, the FDA will have trouble fitting the products into the agency's classification scheme. Second, it will be difficult for the FDA to maintain adequate scientific expertise in the field. He concludes that the FDA should consider implementing several reforms now to ensure that it is adequately prepared to regulate nanomedicine.

  10. New Eczema Drug Gets FDA's Blessing

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_164327.html New Eczema Drug Gets FDA's Blessing Injections may ease ... News) -- Adults plagued by eczema may have a new treatment option, with a new drug approved Tuesday ...

  11. FDA Approves First Immunotherapy for Lymphoma

    Cancer.gov

    The FDA has approved nivolumab (Opdivo®) for the treatment of patients with classical Hodgkin lymphoma whose disease has relapsed or worsened after receiving an autologous hematopoietic stem cell transplantation followed by brentuximab vedotin (Adcetris®)

  12. FDA Suggests Limits on Lead in Cosmetics

    MedlinePlus

    ... 162726.html FDA Suggests Limits on Lead in Cosmetics Agency notes most products already below recommended level ... limit on how much lead can be in cosmetics ranging from lipstick and eye shadow to blush ...

  13. 21 CFR 60.34 - FDA action on petitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FDA action on petitions. 60.34 Section 60.34 Food... RESTORATION Due Diligence Petitions § 60.34 FDA action on petitions. (a) Within 90 days after FDA receives a... during the regulatory review period. FDA will publish its due diligence determination in the...

  14. 42 CFR 405.203 - FDA categorization of investigational devices.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 2 2010-10-01 2010-10-01 false FDA categorization of investigational devices. 405... Coverage Decisions That Relate to Health Care Technology § 405.203 FDA categorization of investigational devices. (a) The FDA assigns a device with an FDA-approved IDE to one of two categories: (1)...

  15. 78 FR 19715 - Implementation of the FDA Food Safety Modernization Act Provision Requiring FDA To Establish...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-02

    ... HUMAN SERVICES Food and Drug Administration Implementation of the FDA Food Safety Modernization Act... comment period for the notice entitled ``Implementation of the FDA Food Safety Modernization Act Provision... Food Safety Modernization Act (FSMA), and as it implements the FSMA provisions relating to the tracking...

  16. Epidural steroid warning controversy still dogging FDA.

    PubMed

    Manchikanti, Laxmaiah; Candido, Kenneth D; Singh, Vijay; Gharibo, Christopher G; Boswell, Mark V; Benyamin, Ramsin M; Falco, Frank J E; Grider, Jay S; Diwan, Sudhir; Hirsch, Joshua A

    2014-01-01

    On April 23, 2014, the Food and Drug Administration (FDA) issued a letter of warning that injection of corticosteroids into the epidural space of the spine may result in rare, but serious adverse events, including "loss of vision, stroke, paralysis, and death." The advisory also advocated that patients should discuss the benefits and risks of epidural corticosteroid injections with their health care professionals, along with the benefits and risks associated with other possible treatments. In addition, the FDA stated that the effectiveness and safety of the corticosteroids for epidural use have not been established, and the FDA has not approved corticosteroids for such use. To raise awareness of the risks of epidural corticosteroid injections in the medical community, the FDA's Safe Use Initiative convened a panel of experts including pain management experts to help define the techniques for such injections with the aim of reducing preventable harm. The panel was unable to reach an agreement on 20 proposed items related to technical aspects of performing epidural injections. Subsequently, the FDA issued the above referenced warning and a notice that a panel will be convened in November 2014. This review assesses the inaccuracies of the warning and critically analyzes the available literature. The literature has been assessed in reference to alternate techniques and an understanding of the risk factors when performing transforaminal epidural injections in the cervical, thoracic, and lumbar regions, ultimately resulting in improved safety. The results of this review show the efficacy of epidural injections, with or without steroids, in a multitude of spinal ailments utilizing caudal, cervical, thoracic, and lumbar interlaminar approaches as well as lumbar transforaminal epidural injections . The evidence also shows the superiority of steroids in managing lumbar disc herniation utilizing caudal and lumbar interlaminar approaches without any significant difference as

  17. The FDA and the new biology.

    PubMed

    Simari, Robert D; Chen, Horng; Burnett, John C

    2008-12-01

    The translation of basic science discoveries to clinical application is dependent on the demonstrated efficacy in humans of the technology but even as importantly on the therapeutic agent or device conforming to the standards of the US Food and Drug Administration (FDA) leading to approval. In this editorial, we propose that the FDA consider a modified process to support the more rapid development of novel agents while furthering the understanding of the risk and benefits of new therapeutics as they are utilized following approval.

  18. Of poops and parasites: unethical FDA overregulation.

    PubMed

    Young, Kenneth A

    2014-01-01

    Therapies born out of the Hygiene Hypothesis--such as helminthic therapy and fecal bacteriotherapy--provide a compelling example of the FDA's institutional blindness. Unlike the traditional pharmaceutical model of treatment, therapies based in the Hygiene Hypothesis purport to resolve or alleviate conditions by reintroducing organisms once thought to be wholly negative. While questions of negative effects and safety remain in the former, they are largely absent in the latter. Nonetheless, the FDA has chosen to regulate the use of both helminthic therapy and fecal bacteriotherapy. Such restriction of doctor-patient autonomy in the name of efficacy is costly and unethical.

  19. FDA approved drugs as potential Ebola treatments

    PubMed Central

    Ekins, Sean; Coffee, Megan

    2015-01-01

    In the search for treatments for the Ebola Virus, multiple screens of FDA drugs have led to the identification of several with promising in vitro activity. These compounds were not originally developed as antivirals and some have been further tested in mouse in vivo models. We put forward the opinion that some of these drugs could be evaluated further and move into the clinic as they are already FDA approved and in many cases readily available. This may be important if there is a further outbreak in future and no other therapeutic is available. PMID:25789163

  20. Regulating nanomedicine - can the FDA handle it?

    PubMed

    Bawa, Raj

    2011-05-01

    There is enormous excitement and expectation surrounding the multidisciplinary field of nanomedicine - the application of nanotechnology to healthcare - which is already influencing the pharmaceutical industry. This is especially true in the design, formulation and delivery of therapeutics. Currently, nanomedicine is poised at a critical stage. However, regulatory guidance in this area is generally lacking and critically needed to provide clarity and legal certainty to manufacturers, policymakers, healthcare providers as well as public. There are hundreds, if not thousands, of nanoproducts on the market for human use but little is known of their health risks, safety data and toxicity profiles. Less is known of nanoproducts that are released into the environment and that come in contact with humans. These nanoproducts, whether they are a drug, device, biologic or combination of any of these, are creating challenges for the Food and Drug Administration (FDA), as regulators struggle to accumulate data and formulate testing criteria to ensure development of safe and efficacious nanoproducts (products incorporating nanoscale technologies). Evidence continues to mount that many nanoproducts inherently posses novel size-based properties and toxicity profiles. Yet, this scientific fact has been generally ignored by the FDA and the agency continues to adopt a precautionary approach to the issue in hopes of countering future potential negative public opinion. As a result, the FDA has simply maintained the status quo with regard to its regulatory policies pertaining to nanomedicine. Therefore, there are no specific laws or mechanisms in place for oversight of nanomedicine and the FDA continues to treat nanoproducts as substantially equivalent ("bioequivalent") to their bulk counterparts. So, for now nanoproducts submitted for FDA review will continue to be subjected to an uncertain regulatory pathway. Such regulatory uncertainty could negatively impact venture funding, stifle

  1. ADHD medication use following FDA risk warnings.

    PubMed

    Barry, Colleen L; Martin, Andres; Busch, Susan H

    2012-09-01

    In 2006, the U.S. Food and Drug Administration (FDA) investigated cardiac and psychiatric risks associated with attention deficit/hyperactivity disorder (ADHD) medication use. To examine how disclosure of safety risks affected pediatric ADHD use, and to assess news media coverage of the issue to better understand trends in treatment patterns. We used the AHRQ's Medical Expenditure Panel Survey (MEPS), a nationally representative household panel survey, to calculate unadjusted rates of pediatric ADHD use from 2002 to 2008 overall and by parents' education. We examined whether children (ages 0 to 20) filled a prescription for any ADHD medication during the calendar year. Next, we used content analysis methods to analyze news coverage of the issue in 10 high-circulation newspapers, the 3 major television networks and a major cable news network in the U.S. We examined 6 measures capturing information conveyed on risk and benefits of ADHD medication use. No declines in medication use following FDA safety warnings overall or by parental education level were observed. News media coverage was relatively balanced in its portrayal of the risks and benefits of ADHD medication use by children. ADHD risk warnings were not associated with large declines in medication use, and balanced news coverage may have contributed to the treatment patterns observed. Self-reported surveys like the MEPS rely on the recall of respondents and may be subject to reporting bias. However, the validity of these data is supported by their consistency with other data on drug use from other sources. These findings are in direct contrast to the substantial declines in use observed after pediatric antidepressant risk warnings in the context of a news media environment that emphasized risks over benefits. Our findings are relevant to the ongoing discussion about improving the FDA's ability to monitor drug safety. Safety warnings occur amid ongoing concern that the agency has insufficient authority and

  2. Screening, HPV Vaccine Can Prevent Cervical Cancer: FDA

    MedlinePlus

    ... medlineplus.gov/news/fullstory_163464.html Screening, HPV Vaccine Can Prevent Cervical Cancer: FDA Agency recommends getting ... by the human papillomavirus (HPV). An FDA-approved vaccine called Gardasil 9 protects against 9 HPV types ...

  3. Mining FDA drug labels for medical conditions

    PubMed Central

    2013-01-01

    Background Cincinnati Children’s Hospital Medical Center (CCHMC) has built the initial Natural Language Processing (NLP) component to extract medications with their corresponding medical conditions (Indications, Contraindications, Overdosage, and Adverse Reactions) as triples of medication-related information ([(1) drug name]-[(2) medical condition]-[(3) LOINC section header]) for an intelligent database system, in order to improve patient safety and the quality of health care. The Food and Drug Administration’s (FDA) drug labels are used to demonstrate the feasibility of building the triples as an intelligent database system task. Methods This paper discusses a hybrid NLP system, called AutoMCExtractor, to collect medical conditions (including disease/disorder and sign/symptom) from drug labels published by the FDA. Altogether, 6,611 medical conditions in a manually-annotated gold standard were used for the system evaluation. The pre-processing step extracted the plain text from XML file and detected eight related LOINC sections (e.g. Adverse Reactions, Warnings and Precautions) for medical condition extraction. Conditional Random Fields (CRF) classifiers, trained on token, linguistic, and semantic features, were then used for medical condition extraction. Lastly, dictionary-based post-processing corrected boundary-detection errors of the CRF step. We evaluated the AutoMCExtractor on manually-annotated FDA drug labels and report the results on both token and span levels. Results Precision, recall, and F-measure were 0.90, 0.81, and 0.85, respectively, for the span level exact match; for the token-level evaluation, precision, recall, and F-measure were 0.92, 0.73, and 0.82, respectively. Conclusions The results demonstrate that (1) medical conditions can be extracted from FDA drug labels with high performance; and (2) it is feasible to develop a framework for an intelligent database system. PMID:23617267

  4. Agenda: EDRN FDA Education Workshop — EDRN Public Portal

    Cancer.gov

    The purpose of this workshop was to open dialogue between FDA staff that provide oversight for review of in vitro diagnostic applications and EDRN scientists currently performing clinical validation studies on cancer biomarkers. Issues related to FDA review of diagnostic tests were presented by FDA personnel. Representatives from EDRN provided details on supporting data of their validation studies and the resources developed within EDRN to facilitate such research for FDA compliance. The agenda provided here provides links to the presentations by each speaker.

  5. 21 CFR 312.86 - Focused FDA regulatory research.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

  6. 21 CFR 312.86 - Focused FDA regulatory research.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

  7. 21 CFR 312.86 - Focused FDA regulatory research.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

  8. 21 CFR 312.86 - Focused FDA regulatory research.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Focused FDA regulatory research. 312.86 Section... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical...

  9. 21 CFR 312.86 - Focused FDA regulatory research.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Severely-debilitating Illnesses § 312.86 Focused FDA regulatory research. At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Focused FDA regulatory research. 312.86...

  10. 21 CFR 316.34 - FDA recognition of exclusive approval.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false FDA recognition of exclusive approval. 316.34... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Orphan-drug Exclusive Approval § 316.34 FDA recognition of exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable)...

  11. 21 CFR 812.30 - FDA action on applications.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA action on applications. 812.30 Section 812.30...) MEDICAL DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Application and Administrative Action § 812.30 FDA action on applications. (a) Approval or disapproval. FDA will notify the sponsor in writing of the...

  12. 21 CFR 806.30 - FDA access to records.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA access to records. 806.30 Section 806.30 Food... DEVICES MEDICAL DEVICES; REPORTS OF CORRECTIONS AND REMOVALS Reports and Records § 806.30 FDA access to... designated by FDA and under section 704(e) of the act, permit such officer or employee at all...

  13. 21 CFR 812.42 - FDA and IRB approval.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA and IRB approval. 812.42 Section 812.42 Food... DEVICES INVESTIGATIONAL DEVICE EXEMPTIONS Responsibilities of Sponsors § 812.42 FDA and IRB approval. A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have...

  14. 77 FR 14404 - Guidance for the Public, Food and Drug Administration (FDA) Advisory Committee Members, and FDA...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-09

    ... HUMAN SERVICES Food and Drug Administration Guidance for the Public, Food and Drug Administration (FDA) Advisory Committee Members, and FDA Staff: Public Availability of Advisory Committee Members' Financial.... SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of a guidance for...

  15. Fisher, Neyman, and Bayes at FDA.

    PubMed

    Rubin, Donald B

    2016-01-01

    The wise use of statistical ideas in practice essentially requires some Bayesian thinking, in contrast to the classical rigid frequentist dogma. This dogma too often has seemed to influence the applications of statistics, even at agencies like the FDA. Greg Campbell was one of the most important advocates there for more nuanced modes of thought, especially Bayesian statistics. Because two brilliant statisticians, Ronald Fisher and Jerzy Neyman, are often credited with instilling the traditional frequentist approach in current practice, I argue that both men were actually seeking very Bayesian answers, and neither would have endorsed the rigid application of their ideas.

  16. 78 FR 14309 - Implementation of the FDA Food Safety Modernization Act Provision Requiring FDA To Establish...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-05

    ... appropriate technologies that enhance the tracking and tracing of foods along the supply chain from source to... ingredients (minimum of two ingredients) and (b) a selected fruit and/or vegetable along the supply chain; 7... along the Food Supply System.'' FDA is announcing the opening of a docket to provide stakeholders and...

  17. The FDA's program for monitoring radionuclides in food

    SciTech Connect

    Baratta, E.J. )

    1992-01-01

    The US Food and Drug Administration (FDA) modified its food-monitoring program in 1973 to include radioactive isotopes. There was concern at this time about the possibility of food contamination by effluents from nuclear power plants, some above-ground weapons testing by nonsignatory powers, and increased use of medical and commercial radioactive materials. The FDA decided, therefore, that a radioanalytical capability must be maintained to detect any upward trend of radioactive contamination in food. This capability would also allow the FDA to respond to any incidents that might occur in order to protect the US food supply. This program is located at the FDA's Winchester Engineering and Analytical Center, Winchester, Massachusetts.

  18. From off-label prescribing towards a new FDA.

    PubMed

    Tabarrok, Alex

    2009-01-01

    Once a drug has been FDA-permitted for some use it can be prescribed for any use. New uses for old drugs are often discovered so a significant fraction of all prescriptions are for uses which were not tested in the FDA permitting process. The prevalence of 'off-label' prescribing has generated concern that prescribing is not scientifically sound or in the patient interest. A better understanding and appreciation of the off-label system suggests that additional FDA regulation is not warranted but that reform of the FDA towards a Consumer Reports model may substantially benefit patients.

  19. Draft guidance for industry; exports and imports under the FDA Export Reform and Enhancement Act of 1996--FDA. Notice.

    PubMed

    1998-06-12

    The Food and Drug Administration (FDA) is announcing the availability of a draft guidance document entitled, "FDA Draft Guidance for Industry on: Exports and Imports Under the FDA Export Reform and Enhancement Act of 1996." The draft guidance document addresses issues pertaining to the exportation of human drugs, animal drugs, biologics, food additives, and devices as well as the importation of components, parts, accessories, or other articles for incorporation or further processing into articles intended for export.

  20. FDA Warns Diabetics Against Use of Secondhand Test Strips

    MedlinePlus

    ... not have been cleared by the FDA for sale in the United States. Signs of unsafe strips include instructions that aren't in English or strips that look different than other strips of the same brand. The FDA recommends buying new, unopened vials of glucose test strips designed specifically ...

  1. 36 CFR 13.980 - Other FDA closures and restrictions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 36 Parks, Forests, and Public Property 1 2014-07-01 2014-07-01 false Other FDA closures and restrictions. 13.980 Section 13.980 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF... center and on the park Web site. Violating FDA closures or restrictions is prohibited. ...

  2. 36 CFR 13.980 - Other FDA closures and restrictions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Other FDA closures and restrictions. 13.980 Section 13.980 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF... center and on the park Web site. Violating FDA closures or restrictions is prohibited. ...

  3. 36 CFR 13.980 - Other FDA closures and restrictions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 36 Parks, Forests, and Public Property 1 2012-07-01 2012-07-01 false Other FDA closures and restrictions. 13.980 Section 13.980 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF... center and on the park Web site. Violating FDA closures or restrictions is prohibited. ...

  4. 36 CFR 13.980 - Other FDA closures and restrictions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 1 2011-07-01 2011-07-01 false Other FDA closures and restrictions. 13.980 Section 13.980 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF... center and on the park Web site. Violating FDA closures or restrictions is prohibited. ...

  5. FDA Drug Approval: Review Time Has Decreased in Recent Years.

    DTIC Science & Technology

    1995-10-01

    New drugs marketed in the United States must be approved first by the Food and Drug Administration (FDA). Approval comes after FDA has determined...reform argue that shortening the time it takes to get new drugs approved will contribute both to public health, by making effective therapies

  6. 21 CFR 5.1110 - FDA public information offices.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FDA public information offices. 5.1110 Section 5.1110 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ORGANIZATION Organization § 5.1110 FDA public information offices. (a) Division of Dockets Management....

  7. Current FDA-approved treatments for Helicobacter pylori and the FDA approval process.

    PubMed

    Hopkins, R J

    1997-12-01

    U.S. Food and Drug Administration (FDA) approval of new drugs expands treatment options and serves as a "safety net" of well-documented efficacy and safety. The information provided in the package insert facilitates physician education and provides some assurance that marketing information is accurate. As of February 1997, three Helicobacter pylori regimes have been FDA-approved for eradication of H. pylori in infected patients with active duodenal ulcers. Regimen 1, omeprazole + clarithromycin (O/C), was supported by two multicenter, controlled studies with a 6-month follow-up. Eradication rates were 74% (n = 53; 95% confidence interval [CI], 62-85) and 64% (n = 61; 95% CI, 52-76). Twenty-five of 26 patients with failed eradication therapy who were taking O/C with clarithromycin-susceptible strains before treatment and who had pretreatment and posttreatment susceptibility tests performed developed clarithromycin resistance after treatment. Regimen 2, ranitidine-bismuth-citrate + clarithromycin, was supported by two multicenter, placebo-controlled studies with a 6-month follow-up. Eradication rates were 84% (n = 19; 95% CI, 60-96) and 73% (n = 22; 95% CI, 50-88). Insufficient pretreatment and posttreatment susceptibility data were collected to assess antimicrobial resistance. Regimen 3, bismuth subsalicylate + metronidazole + tetracycline + an H2-receptor antagonist, was supported by two pivotal literature-based studies. Eradication rates in patients with duodenal ulcer were 82% (n = 51; 95% CI, 70-92) and 77% (n = 39; 95% CI, 61-89), respectively. When extrapolating the results of these three FDA-approved regimens to the clinical setting, particular aspects of the clinical trial should be kept in mind. These include the type of controls, primary end points used, population studied, and number and type of dropouts.

  8. Examining the FDA's oversight of direct-to-consumer advertising.

    PubMed

    Gahart, Martin T; Duhamel, Louise M; Dievler, Anne; Price, Roseanne

    2003-01-01

    Our analysis examined the effects of the Food and Drug Administration's (FDA's) 1997 draft guidance regarding advertisements for prescription drugs broadcast directly to consumers. We found that although direct-to-consumer (DTC) advertising spending by pharmaceutical companies has increased, more than 80 percent of their promotional spending is directed to physicians. DTC advertising appears to increase the use of prescription drugs among consumers. The FDA's oversight has not prevented companies from making misleading claims in subsequent advertisements, and a recent policy change has lengthened the FDA's review process, raising the possibility that some misleading campaigns could run their course before review.

  9. FDA perspective: enrolment of elderly transplant recipients in clinical trials.

    PubMed

    Meyer, Joette M; Archdeacon, Patrick; Albrecht, Renata

    2013-04-15

    Since 1989, the U.S. Food and Drug Administration (FDA) has encouraged the study of new drug and therapeutic products in elderly patients. However, despite the aging population in the United States, elderly patients continue to be underrepresented in clinical trials across a variety of therapeutic areas, including transplantation. The currently available tools for the FDA to encourage and require the evaluation and reporting of safety and efficacy information in elderly patients are summarized. Clinicians, sponsors, and investigators are encouraged to work with the FDA to expand the enrolment of elderly patients in clinical trials of transplantation.

  10. FDA Approves New Drug for Sickle Cell Disease

    MedlinePlus

    ... medlineplus.gov/news/fullstory_167075.html FDA Approves New Drug for Sickle Cell Disease Helps reduce painful, ... and Drug Administration on Friday approved the first new drug for sickle cell disease in nearly two ...

  11. FDA Bacteriological Analytical Manual, Chapter 10, 2003: Listeria monocytogenes

    EPA Pesticide Factsheets

    FDA Bacteriological Analytical Manual, Chapter 10 describes procedures for analysis of food samples and may be adapted for assessment of solid, particulate, aerosol, liquid and water samples containing Listeria monocytogenes.

  12. What FDA Learned About Dark Chocolate and Milk Allergies

    MedlinePlus

    ... For Consumers Consumer Updates What FDA Learned About Dark Chocolate and Milk Allergies Share Tweet Linkedin Pin it ... firm. back to top Milk Detected in Individual Dark Chocolate Products Label/Package Statement Total number of dark ...

  13. FDA Throws Cold Water on Whole Body Cryotherapy

    MedlinePlus

    ... fullstory_163907.html FDA Throws Cold Water on Whole Body Cryotherapy Exposure to ultra-low temperatures shows no benefits ... There's no evidence that a growing trend called whole body cryotherapy is effective, but it does pose a number ...

  14. FDA Issues Anesthesia Warning for Pregnant Women, Kids Under 3

    MedlinePlus

    ... gov/news/fullstory_162543.html FDA Issues Anesthesia Warning for Pregnant Women, Kids Under 3 A long ... latest published studies, the agency announced that these warnings need to be added to the labels of ...

  15. FDA Encourages More Participation, Diversity in Clinical Trials

    MedlinePlus

    ... or older and people from certain racial and ethnic groups. That’s why the FDA is encouraging more ... clinical trials, especially people of different ages, races, ethnic groups, and genders. Read on to learn more ...

  16. America's Porky Pets Face Health Woes, Too, FDA Says

    MedlinePlus

    ... Woes, Too, FDA Says More than half of dogs, cats in the Land of Plenty weigh too ... its pets, with a majority of cats and dogs dangerously overweight, a federal government veterinarian warns. "Just ...

  17. FDA to Weigh Dangers of Exploding E-Cigarettes

    MedlinePlus

    ... FDA had identified 66 instances of e-cigarette explosions in 2015 and early 2016. The batteries overheated, ... that e-cigarettes pose no more fire or explosion risk than other devices that rely on lithium- ...

  18. FDA Approves New Treatment for Dust Mite Allergies

    MedlinePlus

    ... 163882.html FDA Approves New Treatment for Dust Mite Allergies Odactra is a year-round treatment for ... 2017 (HealthDay News) -- A new treatment for dust mite allergies has won approval from the U.S. Food ...

  19. 21 CFR 316.34 - FDA recognition of exclusive approval.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... exclusive approval. (a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely... section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) for a designated orphan drug that...

  20. PREFACE: Fractional Differentiation and its Applications (FDA08) Fractional Differentiation and its Applications (FDA08)

    NASA Astrophysics Data System (ADS)

    Baleanu, Dumitru; Tenreiro Machado, J. A.

    2009-10-01

    The international workshop, Fractional Differentiation and its Applications (FDA08), held at Cankaya University, Ankara, Turkey on 5-7 November 2008, was the third in an ongoing series of conferences dedicated to exploring applications of fractional calculus in science, engineering, economics and finance. Fractional calculus, which deals with derivatives and integrals of any order, is now recognized as playing an important role in modeling multi-scale problems that span a wide range of time or length scales. Fractional calculus provides a natural link to the intermediate-order dynamics that often reflects the complexity of micro- and nanostructures through fractional-order differential equations. Unlike the more established techniques of mathematical physics, the methods of fractional differentiation are still under development; while it is true that the ideas of fractional calculus are as old as the classical integer-order differential operators, modern work is proceeding by both expanding the capabilities of this mathematical tool and by widening its range of applications. Hence, the interested reader will find papers here that focus on the underlying mathematics of fractional calculus, that extend fractional-order operators into new domains, and that apply well established methods to experimental and theoretical problems. The organizing committee invited presentations from experts representing the international community of scholars in fractional calculus and welcomed contributions from the growing number of researchers who are applying fractional differentiation to complex technical problems. The selection of papers in this topical issue of Physica Scripta reflects the success of the FDA08 workshop, with the emergence of a variety of novel areas of application. With these ideas in mind, the guest editors would like to honor the many distinguished scientists that have promoted the development of fractional calculus and, in particular, Professor George M

  1. Subarray-based FDA radar to counteract deceptive ECM signals

    NASA Astrophysics Data System (ADS)

    Abdalla, Ahmed; Wang, Wen-Qin; Yuan, Zhao; Mohamed, Suhad; Bin, Tang

    2016-12-01

    In recent years, the frequency diverse array (FDA) radar concept has attracted extensive attention, as it may benefit from a small frequency increment, compared to the carrier frequency across the array elements and thereby achieve an array factor that is a function of the angle, the time, and the range which is superior to the conventional phase array radar (PAR). However, limited effort on the subject of FDA in electronic countermeasure scenarios, especially in the presence of mainbeam deceptive jamming, has been published. Basic FDA is not desirable for anti-jamming applications, due to the range-angle coupling response of targets. In this paper, a novel method based on subarrayed FDA signal processing is proposed to counteract deceptive ECM signals. We divide the FDA array into multiple subarrays, each of which employs a distinct frequency increment. As a result, in the subarray-based FDA, the desired target can be distinguished at subarray level in joint range-angle-Doppler domain by utilizing the fact that the jammer generates false targets with the same ranges to each subarray without reparations. The performance assessment shows that the proposed solution is effective for deceptive ECM targets suppression. The effectiveness is verified by simulation results.

  2. A hard look at FDA's review of GRAS notices.

    PubMed

    Roberts, Ashley; Haighton, Lois A

    2016-08-01

    Generally Recognized as Safe (GRAS) substances are exempt from premarket approval; however, the standard of "reasonable certainty of no harm" is the same. In 1997, the voluntary GRAS affirmation process was replaced with the voluntary U.S. Food and Drug Administration (FDA) GRAS notice process. Under the GRAS notice process, pivotal safety data are required to be in the public domain, and consensus of safety among experts is required. FDA issues responses of "FDA has no questions", "Notice does not provide a basis for a GRAS determination", or, "At Notifier's request, FDA ceased to evaluate the notice." Of 528 notices reviewed, there were 393 "no questions letters", 17 "insufficient basis letters", and 84 "cease to evaluate letters". Of those deemed to be insufficient, most failed to meet the general recognition criteria. Only four raised questions about potential safety, of which three received a no questions letter upon providing more data. Of the 84 withdrawn notices, 22 received a no questions letter upon resubmission. In spite of criticisms, the FDA GRAS notice process is clearly defined, efficient, and cost-effective, and there have been no known public health issues following its implementation.

  3. US FDA perspective on regulatory issues affecting circulatory assist devices.

    PubMed

    Sapirstein, Wolf; Chen, Eric; Swain, Julie; Zuckerman, Bram

    2006-11-01

    There has been a rapid development in mechanical circulatory support systems in the decade since the US FDA first approved a mechanical device to provide the circulatory support lacking from a failing heart. Devices are presently approved for marketing by the FDA to replace a failing ventricle, the Ventricular Assist Device or the entire heart, Total Artificial Heart. Contemporaneous with, and permitted by, improvement in technology and design, devices have evolved from units located extracorporeally to paracorporeal systems and totally implanted devices. Clinical studies have demonstrated a parallel improvement in the homeostatic adequacy of the circulatory support provided. Thus, while the circulatory support was initially tolerated for short periods to permit recovery of cardiac function, this technology eventually provided effective circulatory support for increasing periods that permitted the FDA to approve devices for bridging patients in end-stage cardiac failure awaiting transplant and eventually a device for destination therapy where patients in end-stage heart failure are not cardiac transplant candidates. The approved devices have relied on displacement pumps that mimic the pulsatility of the physiological system. Accelerated development of more compact devices that rely on alternative pump mechanisms have challenged both the FDA and device manufacturers to assure that the regulatory requirements for safety and effectiveness are met for use of mechanical circulatory support systems in expanded target populations. An FDA regulatory perspective is reviewed of what can be a potentially critical healthcare issue.

  4. Pharmaceutical trademarks: navigating through the FDA's pilot program.

    PubMed

    Ferrer, Elisa

    2010-06-01

    Creation and clearance of pharmaceutical trademarks continues to be one of the most difficult and challenging areas of trademark law. The Food and Drug Administration (FDA) recently initiated a 2-year Pilot Program under Prescription Drug User Fee Act (PDUFA) IV. The intent of the program is to enable participating pharmaceutical firms to evaluate proposed pharmaceutical marks and submit the data generated from those evaluations to the FDA for review. Submitting a trademark to the FDA warrants questions: What supporting data is needed and accepted when proposing a mark? What issues might arise, and how can they be averted? In a recent Thomson Reuters on-demand webinar (http://science.thomsonreuters.com/news/2010-02/8580404/), a group of renowned experts in the field of trademark development review the FDA pilot program, outline the requirements for submission and discuss what the changes will mean in clearing new pharmaceutical marks. They also present various approaches to trademark development and evaluation in light of the FDA's views.

  5. 21 CFR 1.379 - How long may FDA detain an article of food?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false How long may FDA detain an article of food? 1.379... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for a... institute a seizure or injunction action. The authorized FDA representative may approve the additional...

  6. 21 CFR 1.393 - What information must FDA include in the detention order?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false What information must FDA include in the detention... Consumption How Does Fda Order A Detention? § 1.393 What information must FDA include in the detention order? (a) FDA must issue the detention order in writing, in the form of a detention notice, signed...

  7. FDA reform signed into law. Food and Drug Administration.

    PubMed

    James, J S

    1997-12-05

    The laws under which the Food and Drug Administration (FDA) operates have been changed by bipartisan Congressional efforts. The FDA Modernization Act of 1997, signed into law on November 21, 1997 modifies the mission of the FDA to include a goal of speeding research, innovation and access to care. The legislation allows fast track review for the most important drugs. It also allows drug companies to promote off label use of already-approved pharmaceuticals for other purposes. The controversial issue allows drug companies to provide physicians with documentation on the effectiveness of their drugs in treating other conditions. The industry supports the change since the revenue growth for off label use of drugs is especially important for smaller biotechnical companies, while consumer groups fear that it is a loophole for selling unproven drugs. The bill also renews the Prescription Drug User Fee Act (PDUFA), regulating the current practice of compounding, and monitoring medical devices and health care claims for foods.

  8. The FDA and designing clinical trials for chronic cutaneous ulcers.

    PubMed

    Maderal, Andrea D; Vivas, Alejandra C; Eaglstein, William H; Kirsner, Robert S

    2012-12-01

    Treatment of chronic wounds can present a challenge, with many patients remaining refractory to available advanced therapies. As such, there is a strong need for the development of new products. Unfortunately, despite this demand, few new wound-related drugs have been approved over the past decade. This is in part due to unsuccessful clinical trials and subsequent lack of Food and Drug Administration (FDA) approval. In this article, we discuss the FDA approval process, how it relates to chronic wound trials, common issues that arise, and how best to manage them. Additionally, problems encountered specific to diabetic foot ulcers (DFU) and venous leg ulcers (VLU) are addressed. Careful construction of a clinical trial is necessary in order to achieve the best possible efficacy outcomes and thereby, gain FDA approval. How to design an optimal trial is outlined.

  9. Characteristics of pivotal trials and FDA review of innovative devices.

    PubMed

    Rising, Joshua P; Moscovitch, Ben

    2015-01-01

    When patients lack sufficient treatment options for serious medical conditions, they rely on the prompt approval and development of new therapeutic alternatives, such as medical devices. Understanding the development of innovative medical devices, including the characteristics of premarket clinical trials and length of Food and Drug Administration (FDA) review, can help identify ways to expedite patient access to novel technologies and inform recent efforts by FDA to more quickly get these products to patients and physicians. We analyzed publicly available information on clinical trials and premarket FDA review for innovative medical devices that fill an unmet medical need. In this first-of-its-kind study focusing on these products, we extracted data on the length of the pivotal trials, primary study endpoint and FDA review; number of patients enrolled in trials; and in what country the device was available first. We identified 27 approved priority review devices from January 2006 through August 2013. The median duration of pivotal clinical trials was 3 years, ranging from 3 months to approximately 7 years. Trials had a median primary outcome measure evaluation time of one year and a median enrollment of 297 patients. The median FDA review time was 1 year and 3 months. Most priority review devices were available abroad before they were approved in the United States. Our study indicates that addressing the length of clinical studies--and contributing factors, such as primary outcome measures and enrollment--could expedite patient access to innovative medical devices. FDA, manufacturers, Congress and other stakeholders should identify the contributing factors to the length of clinical development, and implement appropriate reforms to address those issues.

  10. Characteristics of Pivotal Trials and FDA Review of Innovative Devices

    PubMed Central

    Rising, Joshua P.; Moscovitch, Ben

    2015-01-01

    When patients lack sufficient treatment options for serious medical conditions, they rely on the prompt approval and development of new therapeutic alternatives, such as medical devices. Understanding the development of innovative medical devices, including the characteristics of premarket clinical trials and length of Food and Drug Administration (FDA) review, can help identify ways to expedite patient access to novel technologies and inform recent efforts by FDA to more quickly get these products to patients and physicians. We analyzed publicly available information on clinical trials and premarket FDA review for innovative medical devices that fill an unmet medical need. In this first-of-its-kind study focusing on these products, we extracted data on the length of the pivotal trials, primary study endpoint and FDA review; number of patients enrolled in trials; and in what country the device was available first. We identified 27 approved priority review devices from January 2006 through August 2013. The median duration of pivotal clinical trials was 3 years, ranging from 3 months to approximately 7 years. Trials had a median primary outcome measure evaluation time of one year and a median enrollment of 297 patients. The median FDA review time was 1 year and 3 months. Most priority review devices were available abroad before they were approved in the United States. Our study indicates that addressing the length of clinical studies—and contributing factors, such as primary outcome measures and enrollment—could expedite patient access to innovative medical devices. FDA, manufacturers, Congress and other stakeholders should identify the contributing factors to the length of clinical development, and implement appropriate reforms to address those issues. PMID:25651420

  11. Characteristics of FDA drug recalls: A 30-month analysis.

    PubMed

    Hall, Kelsey; Stewart, Tyler; Chang, Jongwha; Freeman, Maisha Kelly

    2016-02-15

    The characteristics of drug recalls issued over 30 months by the Food and Drug Administration (FDA) were analyzed. All FDA-issued recalls for drugs (prescription and nonprescription, including dietary supplements) and biological products issued from June 20, 2012, to December 31, 2014, were included in this retrospective analysis. Data for all drug recalls were downloaded and sorted by the inclusion criteria from weekly FDA enforcement reports. The following data were analyzed: product type, recall firm, type of recall firm (compounding or noncompounding), country, voluntary or involuntary recall, method of communication of recall, recall number, FDA recall classification (class I, II, or III), product availability (prescription or nonprescription), reason for recall, recall initiation date, and recall report date. A total of 21,120 products were recalled during the 30-month study period. Of these, 3,045 drug products (14.4%) met the inclusion criteria and were analyzed. A total of 348 total manufacturers were associated with recalled drug products. The 5 firms most frequently involved in recalls accounted for 299, 273, 212, 118, and 112 recalls. The most common reasons for recalls were contamination, mislabeling, adverse reaction, defective product, and incorrect potency. There was a significant association between FDA recall classification and the following outcomes: reasons for recall, product availability, type of recall firm, and form of communication. An investigation of FDA drug recalls revealed that the five most common recall reasons were contamination, mislabeling, adverse reaction, defective product, and incorrect potency. Compounding firms were associated more frequently with contamination than were noncompounding firms. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  12. Bayesian statistics in medical devices: innovation sparked by the FDA.

    PubMed

    Campbell, Gregory

    2011-09-01

    Bayesian statistical methodology has been used for more than 10 years in medical device premarket submissions to the U.S. Food and Drug Administration (FDA). A complete list of the publicly available information associated with these FDA applications is presented. In addition to the increasing number of Bayesian methodological papers in the statistical journals, a number of successful Bayesian clinical trials in the biomedical journals have been recently reported. Some challenges that require more methodological development are discussed. The promise of using Bayesian methods for incorporation of prior information as well as for conducting adaptive trials is great.

  13. Overview of FDA's Expanded Access Program for Investigational Drugs.

    PubMed

    Jarow, Jonathan P; Lurie, Peter; Ikenberry, Sarah Crowley; Lemery, Steven

    2017-03-01

    Expanded access, also called "compassionate use," provides a pathway for patients to gain access to investigational drugs, biologics, and medical devices used to diagnose, monitor, or treat patients with serious diseases or conditions for which there are no comparable or satisfactory therapy options available outside of clinical trials. The US Food and Drug Administration (FDA) facilitates the expanded access process; however, access to investigational treatments requires not only FDA's review and authorization but also the active involvement and cooperation of other parties, including drug companies and health care providers, in order to be successful.

  14. FDA Approvals of Brand-Name Prescription Drugs in 2015

    PubMed Central

    2016-01-01

    The drugs included in this review were approved by the US Food and Drug Administration (FDA) in 2015 and are grouped into the following categories: New Pharmaceuticals: New Molecular Entities and New Biologic License ApplicationsNew Combinations and New IndicationsNew Dosage Forms and New FormulationsNew Biosimilars, Vaccines, Viral Therapies, and Blood Products PMID:27668042

  15. FDA requirements for nonclinical testing of contraceptive steroids.

    PubMed

    Jordan, A

    1992-12-01

    Written guidelines for the preclinical testing of contraceptive steroids have not been revised since 1968 despite the fact that many important changes have been implemented by the FDA's Division of Metabolism and Endocrine Drug Products. This paper describes the new preclinical testing requirements and the rationale for their implementation.

  16. FDA Approvals of Brand-Name Prescription Drugs in 2015.

    PubMed

    2016-03-01

    The drugs included in this review were approved by the US Food and Drug Administration (FDA) in 2015 and are grouped into the following categories: New Pharmaceuticals: New Molecular Entities and New Biologic License ApplicationsNew Combinations and New IndicationsNew Dosage Forms and New FormulationsNew Biosimilars, Vaccines, Viral Therapies, and Blood Products.

  17. 36 CFR 13.980 - Other FDA closures and restrictions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 36 Parks, Forests, and Public Property 1 2013-07-01 2013-07-01 false Other FDA closures and restrictions. 13.980 Section 13.980 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR NATIONAL PARK SYSTEM UNITS IN ALASKA Special Regulations-Denali National Park...

  18. Diabetes Drug Gets FDA Warning Due to Amputation Risk

    MedlinePlus

    ... html Diabetes Drug Gets FDA Warning Due to Amputation Risk Canagliflozin tied to a doubling of amputations of legs, feet, agency says To use the ... to increase the risk of leg and foot amputations, the U.S. Food and Drug Administration says. The ...

  19. Hypnotic Medications and Suicide: Risk, Mechanisms, Mitigation, and the FDA.

    PubMed

    McCall, W Vaughn; Benca, Ruth M; Rosenquist, Peter B; Riley, Mary Anne; McCloud, Laryssa; Newman, Jill C; Case, Doug; Rumble, Meredith; Krystal, Andrew D

    2017-01-01

    Insomnia is associated with increased risk for suicide. The Food and Drug Administration (FDA) has mandated that warnings regarding suicide be included in the prescribing information for hypnotic medications. The authors conducted a review of the evidence for and against the claim that hypnotics increase the risk of suicide. This review focused on modern, FDA-approved hypnotics, beginning with the introduction of benzodiazepines, limiting its findings to adults. PubMed and Web of Science were searched, crossing the terms "suicide" and "suicidal" with each of the modern FDA-approved hypnotics. The FDA web site was searched for postmarketing safety reviews, and the FDA was contacted with requests to provide detailed case reports for hypnotic-related suicide deaths reported through its Adverse Event Reporting System. Epidemiological studies show that hypnotics are associated with an increased risk for suicide. However, none of these studies adequately controlled for depression or other psychiatric disorders that may be linked with insomnia. Suicide deaths have been reported from single-agent hypnotic overdoses. A separate concern is that benzodiazepine receptor agonist hypnotics can cause parasomnias, which in rare cases may lead to suicidal ideation or suicidal behavior in persons who were not known to be suicidal. On the other hand, ongoing research is testing whether treatment of insomnia may reduce suicidality in adults with depression. The review findings indicate that hypnotic medications are associated with suicidal ideation. Future studies should be designed to assess whether increases in suicidality result from CNS impairments from a given hypnotic medication or whether such medication decreases suicidality because of improvements in insomnia.

  20. Revisiting financial conflicts of interest in FDA advisory committees.

    PubMed

    Pham-Kanter, Genevieve

    2014-09-01

    The Food and Drug Administration (FDA) Safety and Innovation Act has recently relaxed conflict-of-interest rules for FDA advisory committee members, but concerns remain about the influence of members' financial relationships on the FDA's drug approval process. Using a large newly available data set, this study carefully examined the relationship between the financial interests of FDA Center for Drug Evaluation and Research (CDER) advisory committee members and whether members voted in a way favorable to these interests. The study used a data set of voting behavior and reported financial interests of 1,379 FDA advisory committee members who voted in CDER committee meetings that were convened during the 15-year period of 1997-2011. Data on 1,168 questions and 15,739 question-votes from 379 meetings were used in the analyses. Multivariable logit models were used to estimate the relationship between committee members' financial interests and their voting behavior. Individuals with financial interests solely in the sponsoring firm were more likely to vote in favor of the sponsor than members with no financial ties (OR = 1.49, p = 0.03). Members with interests in both the sponsoring firm and its competitors were no more likely to vote in favor of the sponsor than those with no financial ties to any potentially affected firm (OR = 1.16, p = 0.48). Members who served on advisory boards solely for the sponsor were significantly more likely to vote in favor of the sponsor (OR = 4.97, p = 0.005). There appears to be a pro-sponsor voting bias among advisory committee members who have exclusive financial relationships with the sponsoring firm but not among members who have nonexclusive financial relationships (ie, those with ties to both the sponsor and its competitors). These findings point to important heterogeneities in financial ties and suggest that policymakers will need to be nuanced in their management of financial relationships of FDA advisory committee members.

  1. Revisiting Financial Conflicts of Interest in FDA Advisory Committees

    PubMed Central

    Pham-Kanter, Genevieve

    2014-01-01

    Context The Food and Drug Administration (FDA) Safety and Innovation Act has recently relaxed conflict-of-interest rules for FDA advisory committee members, but concerns remain about the influence of members’ financial relationships on the FDA's drug approval process. Using a large newly available data set, this study carefully examined the relationship between the financial interests of FDA Center for Drug Evaluation and Research (CDER) advisory committee members and whether members voted in a way favorable to these interests. Methods The study used a data set of voting behavior and reported financial interests of 1,379 FDA advisory committee members who voted in CDER committee meetings that were convened during the 15-year period of 1997–2011. Data on 1,168 questions and 15,739 question-votes from 379 meetings were used in the analyses. Multivariable logit models were used to estimate the relationship between committee members’ financial interests and their voting behavior. Findings Individuals with financial interests solely in the sponsoring firm were more likely to vote in favor of the sponsor than members with no financial ties (OR = 1.49, p = 0.03). Members with interests in both the sponsoring firm and its competitors were no more likely to vote in favor of the sponsor than those with no financial ties to any potentially affected firm (OR = 1.16, p = 0.48). Members who served on advisory boards solely for the sponsor were significantly more likely to vote in favor of the sponsor (OR = 4.97, p = 0.005). Conclusions There appears to be a pro-sponsor voting bias among advisory committee members who have exclusive financial relationships with the sponsoring firm but not among members who have nonexclusive financial relationships (ie, those with ties to both the sponsor and its competitors). These findings point to important heterogeneities in financial ties and suggest that policymakers will need to be nuanced in their management of financial

  2. FDA/CVM's Compliance Policy Guide on compounding of drugs.

    PubMed

    1996-12-15

    As a veterinary practitioner, do you combine drug agents for anesthesia? Create antidotes? Dilute liquids for administration to small, young, or exotic species? Such efforts are examples of compounding. The FDA/CVM's new Compliance Policy Guide (CPG), which regulates the compounding of drugs by veterinarians and pharmacists for use in animals appears here, as originally published in the Compliance Policy Guide Manual. The CPG provides guidance to FDA's field and headquarters staff and serves as a source of useful information to veterinarians. The CPG for Compounding of Drugs for Use in Animals reflects the efforts of a task force made up of a diverse group of veterinarians, pharmacists, and regulators whose conclusions were published in the Symposium of Compounding in JAVMA, July 15, 1994, pp 189-303.

  3. Timelines of translational science: From technology initiation to FDA approval.

    PubMed

    McNamee, Laura M; Walsh, Michael Jay; Ledley, Fred D

    2017-01-01

    While timelines for clinical development have been extensively studied, there is little data on the broader path from initiation of research on novel drug targets, to approval of drugs based on this research. We examined timelines of translational science for 138 drugs and biologicals approved by the FDA from 2010-2014 using an analytical model of technology maturation. Research on targets for 102 products exhibited a characteristic (S-curve) maturation pattern with exponential growth between statistically defined technology initiation and established points. The median initiation was 1974, with a median of 25 years to the established point, 28 years to first clinical trials, and 36 years to FDA approval. No products were approved before the established point, and development timelines were significantly longer when the clinical trials began before this point (11.5 vs 8.5 years, p<0.0005). Technological maturation represents the longest stage of translation, and significantly impacts the efficiency of drug development.

  4. The FDA pesticides program: goals and new approaches.

    PubMed

    Lombardo, P

    1989-01-01

    The U.S. Food and Drug Administration (FDA) has carried out a large-scale monitoring program for pesticide residues in foods since the 1960s. The program has evolved continuously as evidenced by a number of recently incorporated modifications and initiatives. Included are greater emphasis on imports; increased and more specific targeting of pesticide/commodity combinations by geographic area or country; development of individual district sampling plans for domestic and imported foods; expanded use of single residue methods; linkage of information on foreign pesticide usage with food import volumes; development of an analytical methods research plan; and increased cooperative sampling and data exchange with the states. Initiatives to acquire and utilize private sector and other monitoring data are being explored, and aggressive steps are being taken to inform the public of FDA monitoring results in a timely and understandable manner.

  5. 21 CFR 1.279 - When must prior notice be submitted to FDA?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... submitted via Automated Broker Interface/Automated Commercial System (ABI/ACS), you may not submit prior... submitted via the FDA Prior Notice System Interface (FDA PNSI), you may not submit prior notice more than...

  6. 21 CFR 1.279 - When must prior notice be submitted to FDA?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... submitted via Automated Broker Interface/Automated Commercial System (ABI/ACS), you may not submit prior... submitted via the FDA Prior Notice System Interface (FDA PNSI), you may not submit prior notice more than...

  7. 21 CFR 1.279 - When must prior notice be submitted to FDA?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... submitted via Automated Broker Interface/Automated Commercial System (ABI/ACS), you may not submit prior... submitted via the FDA Prior Notice System Interface (FDA PNSI), you may not submit prior notice more than...

  8. 21 CFR 1.279 - When must prior notice be submitted to FDA?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... submitted via Automated Broker Interface/Automated Commercial System (ABI/ACS), you may not submit prior... submitted via the FDA Prior Notice System Interface (FDA PNSI), you may not submit prior notice more than...

  9. 21 CFR 1.279 - When must prior notice be submitted to FDA?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... submitted via Automated Broker Interface/Automated Commercial System (ABI/ACS), you may not submit prior... submitted via the FDA Prior Notice System Interface (FDA PNSI), you may not submit prior notice more than...

  10. 食品药物管理局( FDA

    Center for Drug Evaluation (CDER)

    ... 士应立即与医疗保健专业人员联络咨询。 接触铅会对中央神经系统、肾、和免疫 系统造成严重的 ... 下载并完成表格,然后经传真至 1-800-FDA-0178 提交。 ...

  11. FDA Benchmark Medical Device Flow Models for CFD Validation.

    PubMed

    Malinauskas, Richard A; Hariharan, Prasanna; Day, Steven W; Herbertson, Luke H; Buesen, Martin; Steinseifer, Ulrich; Aycock, Kenneth I; Good, Bryan C; Deutsch, Steven; Manning, Keefe B; Craven, Brent A

    Computational fluid dynamics (CFD) is increasingly being used to develop blood-contacting medical devices. However, the lack of standardized methods for validating CFD simulations and blood damage predictions limits its use in the safety evaluation of devices. Through a U.S. Food and Drug Administration (FDA) initiative, two benchmark models of typical device flow geometries (nozzle and centrifugal blood pump) were tested in multiple laboratories to provide experimental velocities, pressures, and hemolysis data to support CFD validation. In addition, computational simulations were performed by more than 20 independent groups to assess current CFD techniques. The primary goal of this article is to summarize the FDA initiative and to report recent findings from the benchmark blood pump model study. Discrepancies between CFD predicted velocities and those measured using particle image velocimetry most often occurred in regions of flow separation (e.g., downstream of the nozzle throat, and in the pump exit diffuser). For the six pump test conditions, 57% of the CFD predictions of pressure head were within one standard deviation of the mean measured values. Notably, only 37% of all CFD submissions contained hemolysis predictions. This project aided in the development of an FDA Guidance Document on factors to consider when reporting computational studies in medical device regulatory submissions. There is an accompanying podcast available for this article. Please visit the journal's Web site (www.asaiojournal.com) to listen.

  12. The FDA's Final Rule on Expedited Safety Reporting: Statistical Considerations

    PubMed Central

    Wittes, Janet; Crowe, Brenda; Chuang-Stein, Christy; Guettner, Achim; Hall, David; Jiang, Qi; Odenheimer, Daniel; Xia, H. Amy; Kramer, Judith

    2015-01-01

    In March 2011, a Final Rule for expedited reporting of serious adverse events took effect in the United States for studies conducted under an Investigational New Drug (IND) application. In December 2012, the U.S. Food and Drug Administration (FDA) promulgated a final Guidance describing the operationalization of this Final Rule. The Rule and Guidance clarified that a clinical trial sponsor should have evidence suggesting causality before defining an unexpected serious adverse event as a suspected adverse reaction that would require expedited reporting to the FDA. The Rule's emphasis on the need for evidence suggestive of a causal relation should lead to fewer events being reported but, among those reported, a higher percentage actually being caused by the product being tested. This article reviews the practices that were common before the Final Rule was issued and the approach the New Rule specifies. It then discusses methods for operationalizing the Final Rule with particular focus on relevant statistical considerations. It concludes with a set of recommendations addressed to Sponsors and to the FDA in implementing the Final Rule. PMID:26550466

  13. The FDA's sentinel initiative--A comprehensive approach to medical product surveillance.

    PubMed

    Ball, R; Robb, M; Anderson, S A; Dal Pan, G

    2016-03-01

    In May 2008, the Department of Health and Human Services announced the launch of the Sentinel Initiative by the US Food and Drug Administration (FDA) to create the Sentinel System, a national electronic system for medical product safety surveillance. This system complements existing FDA surveillance capabilities that track adverse events reported after the use of FDA regulated products by allowing the FDA to proactively assess the safety of these products.

  14. 21 CFR 1.405 - When does FDA have to issue a decision on an appeal?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false When does FDA have to issue a decision on an... Consumption What Is the Appeal Process for A Detention Order? § 1.405 When does FDA have to issue a decision... final decision within the 5-calendar day period after the appeal is filed. If FDA either fails...

  15. 76 FR 61709 - Agency Information Collection Activities; Proposed Collection; Comment Request; FDA Form 3728...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-05

    ... Collection; Comment Request; FDA Form 3728, Animal Generic Drug User Fee Act Cover Sheet AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing... Drug User Fee Cover Sheet Form FDA 3728 that further implements certain provisions of the...

  16. 21 CFR 1.406 - How will FDA handle classified information in an informal hearing?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false How will FDA handle classified information in an... Animal Consumption What Is the Appeal Process for A Detention Order? § 1.406 How will FDA handle... disclosure in the interest of national security (“classified information”), FDA will not provide you...

  17. 21 CFR 60.20 - FDA action on regulatory review period determinations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the...

  18. 21 CFR 1.378 - What criteria does FDA use to order a detention?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false What criteria does FDA use to order a detention? 1... General Provisions § 1.378 What criteria does FDA use to order a detention? An officer or qualified employee of FDA may order the detention of any article of food that is found during an...

  19. 21 CFR 111.610 - What records must be made available to FDA?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false What records must be made available to FDA? 111... records must be made available to FDA? (a) You must have all records required under this part, or copies of such records, readily available during the retention period for inspection and copying by FDA...

  20. 76 FR 1180 - FDA Transparency Initiative: Improving Transparency to Regulated Industry

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-07

    ... HUMAN SERVICES Food and Drug Administration FDA Transparency Initiative: Improving Transparency to... comments. SUMMARY: As part of the third phase of the Transparency Initiative, the Food and Drug Administration (FDA) is announcing the availability of a report entitled ``FDA Transparency Initiative: Improving...

  1. No sisyphean task: how the FDA can regulate electronic cigarettes.

    PubMed

    Paradise, Jordan

    2013-01-01

    The adverse effects of smoking have fostered a natural market for smoking cessation and smoking reduction products. Smokers attempting to quit or reduce consumption have tried everything: "low" or "light" cigarettes; nicotine-infused chewing gum, lozenges, and lollipops; dermal patches; and even hypnosis. The latest craze in the quest to find a safer source of nicotine is the electronic cigarette. Electronic cigarettes (e-cigarettes) have swept the market, reaching a rapidly expanding international consumer base. Boasting nicotine delivery and the tactile feel of a traditional cigarette without the dozens of other chemical constituents that contribute to carcinogenicity, e-cigarettes are often portrayed as less risky, as a smoking reduction or even a complete smoking cessation product, and perhaps most troubling for its appeal to youth, as a flavorful, trendy, and convenient accessory. The sensationalism associated with e-cigarettes has spurred outcry from health and medical professional groups, as well as the Food and Drug Administration (FDA), because of the unknown effects on public health. Inhabiting a realm of products deemed "tobacco products" under recent 2009 legislation, e-cigarettes pose new challenges to FDA regulation because of their novel method of nicotine delivery, various mechanical and electrical parts, and nearly nonexistent safety data. Consumer use, marketing and promotional claims, and technological characteristics of e-cigarettes have also raised decades old questions of when the FDA can assert authority over products as drugs or medical devices. Recent case law restricting FDA enforcement efforts against e-cigarettes further confounds the distinction among drugs and medical devices, emerging e-cigarette products, and traditional tobacco products such as cigarettes, cigars, and smokeless tobacco. This Article investigates the e-cigarette phenomenon in the wake of the recently enacted Family Smoking Prevention and Tobacco Control Act of 2009

  2. FDA's conduct, review, and evaluation of inspections of clinical investigators.

    PubMed

    Turner, G; Lisook, A B; Delman, D P

    1987-01-01

    This review of the Food and Drug Administration's Bioresearch Monitoring Program focuses on the inspection of clinical investigators who study investigational drugs. The differences between routine, "for-cause," and bioequivalency/bioavailability inspections are examined, with emphasis on the responsibilities of the clinical investigator, reasons for conducting the inspections, and problems found. Important aspects of the inspection report, such as protocol adherence, records maintenance, informed consent, institutional review board approval, and drug accountability, are outlined. The disqualification and consent agreement processes for investigators with serious problems are explained. FDA policies on third-party notification and remote data entry are noted.

  3. Statin-associated ocular disorders: the FDA and ADRAC data.

    PubMed

    Mizranita, Vinci; Pratisto, Eko Harry

    2015-10-01

    Statins are a class of medication indicated for atherosclerotic diseases and dyslipidemia. Since their appearance, many adverse events have been associated with their use. Ocular disorders are rare but serious adverse events of statins. To report the association between statins and ocular adverse events (blurred vision, visual impairment, visual field defect, reduced visual acuity, myopia, hypermetropia, presbyopia, and astigmatism) which might be associated with muscle or liver problems by examining the frequency of ocular adverse events among the reported adverse drug reactions from the Food and Drug Administration (FDA) and Adverse Drug Reactions Advisory Committee (ADRAC) data. Setting The FDA USA and ADRAC Australia databases. We conducted a retrospective study of statin-associated ocular adverse events reported to FDA between 1988 and 2013 and ADRAC between 1988 and 2011. The recoded data included: patient's age, gender, suspected drug and dosage, concomitant drug, adverse events, duration of therapy, dechallenge and rechallenge therapy. The differences in the adverse events profiles between each of the statins and atorvastatin were performed using Chi square and multivariate (logistic regression) statistical tests. Percentages of subjects correlated with each Ocular adverse events. Among 131,755 cases of patients taking statins in the FDA, there were 2325 cases reported ocular adverse events after using statins (1.8%). The Chi square statistic showed that the proportions of ocular adverse events varied significantly (p < 0.0001) across the different statin drugs. The most highly reported ocular adverse events associated with statins were blurred vision (48.4%) and visual impairment (25.7%). Results from logistic regression indicated that the ocular problems formed a greater proportion of the adverse events for subjects taking atorvastatin (2.1%). Of the 1.8%, ocular adverse events mostly occurred alone (60.9%), followed by 30.3% where muscle adverse events

  4. 2015 in review: FDA approval of new drugs.

    PubMed

    Kinch, Michael S

    2016-07-01

    The myriad new molecular entities (NMEs) approved by the US Food and Drug Administration (FDA) in 2015 reflected both the opportunities and risks associated with the development of new medicines. On the one hand, the approval of 45 NMEs was among the highest ever recorded. Likewise, the diversity underlying the mechanistic basis of new medicines suggests continued broadening relative to the predominate trends of the past few decades. On the other hand, closer inspection indicates that business model decisions surrounding orphan indications and consolidation could be placing the industry in an ever-more precarious position, with severe implications for the sustainability of the entire enterprise.

  5. Vagus nerve stimulation therapy summary: five years after FDA approval.

    PubMed

    Schachter, Steven C

    2002-09-24

    With more than 16,000 patients implanted with the vagus nerve stimulation (VNS) therapy system (Cyberonics, Inc., Houston, Texas), VNS therapy has assumed an increasingly important role in the treatment of medically refractory seizures since its approval 5 years ago by the United States FDA. This review discusses the clinical trials that provided evidence for the approval, long-term efficacy, efficacy in special populations and co-morbid conditions, and safety and tolerability. Additional studies are suggested to further explore the capabilities of VNS therapy.

  6. Evaluation of genotoxicity testing of FDA approved large molecule therapeutics.

    PubMed

    Sawant, Satin G; Fielden, Mark R; Black, Kurt A

    2014-10-01

    Large molecule therapeutics (MW>1000daltons) are not expected to enter the cell and thus have reduced potential to interact directly with DNA or related physiological processes. Genotoxicity studies are therefore not relevant and typically not required for large molecule therapeutic candidates. Regulatory guidance supports this approach; however there are examples of marketed large molecule therapeutics where sponsors have conducted genotoxicity studies. A retrospective analysis was performed on genotoxicity studies of United States FDA approved large molecule therapeutics since 1998 identified through the Drugs@FDA website. This information was used to provide a data-driven rationale for genotoxicity evaluations of large molecule therapeutics. Fifty-three of the 99 therapeutics identified were tested for genotoxic potential. None of the therapeutics tested showed a positive outcome in any study except the peptide glucagon (GlucaGen®) showing equivocal in vitro results, as stated in the product labeling. Scientific rationale and data from this review indicate that testing of a majority of large molecule modalities do not add value to risk assessment and support current regulatory guidance. Similarly, the data do not support testing of peptides containing only natural amino acids. Peptides containing non-natural amino acids and small molecules in conjugated products may need to be tested.

  7. NIEHS/FDA CLARITY-BPA research program update.

    PubMed

    Heindel, Jerrold J; Newbold, Retha R; Bucher, John R; Camacho, Luísa; Delclos, K Barry; Lewis, Sherry M; Vanlandingham, Michelle; Churchwell, Mona I; Twaddle, Nathan C; McLellen, Michelle; Chidambaram, Mani; Bryant, Matthew; Woodling, Kellie; Gamboa da Costa, Gonçalo; Ferguson, Sherry A; Flaws, Jodi; Howard, Paul C; Walker, Nigel J; Zoeller, R Thomas; Fostel, Jennifer; Favaro, Carolyn; Schug, Thaddeus T

    2015-12-01

    Bisphenol A (BPA) is a chemical used in the production of numerous consumer products resulting in potential daily human exposure to this chemical. The FDA previously evaluated the body of BPA toxicology data and determined that BPA is safe at current exposure levels. Although consistent with the assessment of some other regulatory agencies around the world, this determination of BPA safety continues to be debated in scientific and popular publications, resulting in conflicting messages to the public. Thus, the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), and U.S. Food and Drug Administration (FDA) developed a consortium-based research program to link more effectively a variety of hypothesis-based research investigations and guideline-compliant safety testing with BPA. This collaboration is known as the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA). This paper provides a detailed description of the conduct of the study and a midterm update on progress of the CLARITY-BPA research program.

  8. NIEHS/FDA CLARITY-BPA research program update

    PubMed Central

    Heindel, Jerrold J.; Newbold, Retha R.; Bucher, John R.; Camacho, Luísa; Delclos, K. Barry; Lewis, Sherry M.; Vanlandingham, Michelle; Churchwell, Mona I.; Twaddle, Nathan C.; McLellen, Michelle; Chidambaram, Mani; Bryant, Matthew; Woodling, Kellie; Gamboa da Costa, Gonçalo; Ferguson, Sherry A.; Flaws, Jodi; Howard, Paul C.; Walker, Nigel J.; Zoeller, R. Thomas; Fostel, Jennifer; Favaro, Carolyn; Schug, Thaddeus T.

    2016-01-01

    Bisphenol A (BPA) is a chemical used in the production of numerous consumer products resulting in potential daily human exposure to this chemical. The FDA previously evaluated the body of BPA toxicology data and determined that BPA is safe at current exposure levels. Although consistent with the assessment of some other regulatory agencies around the world, this determination of BPA safety continues to be debated in scientific and popular publications, resulting in conflicting messages to the public. Thus, the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), and U.S Food and Drug Administration (FDA) developed a consortium-based research program to link more effectively a variety of hypothesis-based research investigations and guideline-compliant safety testing with BPA. This collaboration is known as the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA). This paper provides a detailed description of the conduct of the study and a midterm update on progress of the CLARITY-BPA research program. PMID:26232693

  9. Integration of new technology into clinical practice after FDA approval.

    PubMed

    Govil, Ashul; Hao, Steven C

    2016-10-01

    Development of new medical technology is a crucial part of the advancement of medicine and our ability to better treat patients and their diseases. This process of development is long and arduous and requires a significant investment of human, financial and material capital. However, technology development can be rewarded richly by its impact on patient outcomes and successful sale of the product. One of the major regulatory hurdles to technology development is the Food and Drug Administration (FDA) approval process, which is necessary before a technology can be marketed and sold in the USA. Many businesses, medical providers and consumers believe that the FDA approval process is the only hurdle prior to use of the technology in day-to-day care. In order for the technology to be adopted into clinical use, reimbursement for both the device as well as the associated work performed by physicians and medical staff must be in place. Work and coverage decisions require Current Procedural Terminology (CPT) code development and Relative Value Scale Update Committee (RUC) valuation determination. Understanding these processes is crucial to the timely availability of new technology to patients and providers. Continued and better partnerships between physicians, industry, regulatory bodies and payers will facilitate bringing technology to market sooner and ensure appropriate utilization.

  10. FDA critical path initiatives: opportunities for generic drug development.

    PubMed

    Lionberger, Robert A

    2008-01-01

    FDA's critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document "Critical Path Opportunities for Generic Drugs" that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs.

  11. A review of US EPA and FDA requirements for electronic records, electronic signatures, and electronic submissions.

    PubMed

    Keatley, K L

    1999-01-01

    Both the United States Environmental Protection Agency (EPA) and the U.S. Food and Drug Administration (FDA) have issued regulatory documents that address the issues and requirements concerning electronic reporting to the Agencies. EPA has published two comprehensive and useful electronic data interchange (EDI) guidelines: 1) the EPA Electronic Data Interchange (EDI) Implementation Guideline, Draft of September 23, 1994 and October 18, 1994 that is available at the following EPA web site address: www.epa.gov/oppeedi1/guidelines/general.pdf and 2) the Interim Final Notice, Filing of Electronic Reports via Electronic Data Interchange, September 4, 1996, Federal Register Notice [FRL-5601-4, Volume 61, Number 172, page 46684], also available at: www.epa.gov/oppeedi1/edipoli.htm. The FDA has published a guidance document titled, "Guidance for Industry, Computerized Systems Used in Clinical Trials, April 1999" that is available at FDA's web site: www.fda.gov/ora/compliance_ref/bimo/ffinalcct.++ +htm. FDA's guidance document addresses a number of issues for electronic records that are applicable to all areas of GLP compliance. Another FDA document presently under development is titled, "Electronic Standards for the Transmission of Regulatory Information (ESTRI) Gateway." The ESTRI document defines strategic plans for electronic submissions to FDA. FDA has published a guidance document in this area titled, "Guidance for Industry: Providing Regulatory Submissions in Electronic Format--General Considerations, January 1999." This guidance document is available at: www.fda.gov/cder/guidance/index.htm. FDA has also published an important final rule applicable to all electronic records and signatures that is part of the U.S. Title 21 Code of Federal Regulations (CFR), Part 11, titled, "FDA's Final Rule, Electronic Records; Electronic Signatures, effective August 20, 1997." This FDA ruling is discussed below and is available at: www.fda.gov/cder/esig/index.htm.

  12. Drug development in inflammatory bowel disease: the role of the FDA.

    PubMed

    Lahiff, Conor; Kane, Sunanda; Moss, Alan C

    2011-12-01

    All medicinal compounds sold in the United States for inflammatory bowel disease (IBD) are regulated by the Food and Drug Administration (FDA) via a number of regulations dating back to 1906. The primary contemporary role of the FDA is in the assessment of safety and efficacy, and subsequent marketing, of medications based on preclinical and clinical trial data provided by sponsors. This includes pharmacokinetic, toxicology and clinical studies, and postapproval safety monitoring. Mesalamine formulations, budesonide, and biologic therapies have all been assessed for efficacy and safety in IBD by the FDA via large randomized controlled trials (RCTs). There has been considerable evolution in the endpoints used by the FDA to approve medications for IBD, and the mechanisms through which newer agents have been approved. This review examines the methods of drug approval by the FDA, the bench-marks used to approve drugs for IBD, and recent controversies in the FDA's role in drug approval in general.

  13. FDA Should Reduce Expensive Antibiotic Testing and Charge Fees Which More Closely Reflect Cost of Certification.

    DTIC Science & Technology

    1981-10-28

    between 1970 and 1979 were not certified because of potency problems. GAO was told by two FDA officials that, except for nonsterile products , if...been low. Batch certification is an expensive product assurance strategy and other less costly control mecha- A nisms are available. Further, GAO...issuing of certificates for batches that pass the tests. Manufacturers may not market products subject to these tests until FDA certifies them. FDA charges

  14. 21 CFR 1.379 - How long may FDA detain an article of food?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false How long may FDA detain an article of food? 1.379 Section 1.379 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL... Provisions § 1.379 How long may FDA detain an article of food? (a) FDA may detain an article of food for...

  15. Autologous cell therapies: challenges in US FDA regulation.

    PubMed

    McAllister, Todd N; Audley, David; L'Heureux, Nicolas

    2012-11-01

    Cell-based therapies (CBTs) have been hailed for the last two decades as the next pillar of healthcare, yet the clinical and commercial potential of regenerative medicine has yet to live up to the hype. While recent analysis has suggested that regenerative medicine is maturing into a multibillion dollar industry, examples of clinical and commercial success are still relatively rare. With 30 years of laboratory and clinical efforts fueled by countless billions in public and private funding, one must contemplate why CBTs have not made a greater impact. The current regulatory environment, with its zero-risk stance, stymies clinical innovation while fueling a potentially risky medical tourism industry. Here, we highlight the challenges the US FDA faces and present talking points for an improved regulatory framework for autologous CBTs.

  16. FDA, companies test RFID tracking to prevent drug counterfeiting.

    PubMed

    James, John S

    2005-12-01

    The U.S. has an apparently growing problem with fake, counterfeit drugs entering the mainstream drug supply, and being fraudulently sold at full price in regular pharmacies and hospitals; some have no active ingredient, or too little, or substitute a cheap drug for an expensive one. The FDA has asked drug manufacturers to develop technology to track all shipments electronically as they move through the distribution chain; currently, RFID (radio frequency identification) is the preferred method for doing so. This article explains what is happening, and why we do not believe that this use of RFID is a privacy threat--though other privacy issues are among the most important questions we face today.

  17. An analysis of FDA-approved drugs for oncology.

    PubMed

    Kinch, Michael S

    2014-12-01

    Cancer remains the second leading cause of death globally. The number of new medicines targeting cancer has grown impressively since the 1990s. On average, ten new drugs are introduced each year. Such growth has partly been achieved by emphasizing biologics and orphan indications, which account for one-quarter and one-half of new oncology drugs, respectively. The biotechnology industry likewise has become the primary driver of cancer drug development in terms of patents, preclinical and clinical research, although pharmaceutical companies are granted more FDA approvals. Many targeting strategies have been successful but recent trends suggest that kinase targets, although tractable, might be overemphasized. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Repurposing FDA-approved drugs for anti-aging therapies.

    PubMed

    Snell, Terry W; Johnston, Rachel K; Srinivasan, Bharath; Zhou, Hongyi; Gao, Mu; Skolnick, Jeffrey

    2016-11-01

    There is great interest in drugs that are capable of modulating multiple aging pathways, thereby delaying the onset and progression of aging. Effective strategies for drug development include the repurposing of existing drugs already approved by the FDA for human therapy. FDA approved drugs have known mechanisms of action and have been thoroughly screened for safety. Although there has been extensive scientific activity in repurposing drugs for disease therapy, there has been little testing of these drugs for their effects on aging. The pool of FDA approved drugs therefore represents a large reservoir of drug candidates with substantial potential for anti-aging therapy. In this paper we employ FINDSITE(comb), a powerful ligand homology modeling program, to identify binding partners for proteins produced by temperature sensing genes that have been implicated in aging. This list of drugs with potential to modulate aging rates was then tested experimentally for lifespan and healthspan extension using a small invertebrate model. Three protein targets of the rotifer Brachionus manjavacas corresponding to products of the transient receptor potential gene 7, ribosomal protein S6 polypeptide 2 gene, or forkhead box C gene, were screened against a compound library consisting of DrugBank drugs including 1347 FDA approved, non-nutraceutical molecules. Twenty nine drugs ranked in the top 1 % for binding to each target were subsequently included in our experimental analysis. Continuous exposure of rotifers to 1 µM naproxen significantly extended rotifer mean lifespan by 14 %. We used three endpoints to estimate rotifer health: swimming speed (mobility proxy), reproduction (overall vitality), and mitochondria activity (cellular senescence proxy). The natural decline in swimming speed with aging was more gradual when rotifers were exposed to three drugs, so that on day 6, mean swimming speed of females was 1.19 mm/s for naproxen (P = 0.038), 1.20 for fludarabine (P = 0

  19. Large Eddy Simulation of FDA's Idealized Medical Device.

    PubMed

    Delorme, Yann T; Anupindi, Kameswararao; Frankel, Steven H

    2013-12-01

    A hybrid large eddy simulation (LES) and immersed boundary method (IBM) computational approach is used to make quantitative predictions of flow field statistics within the Food and Drug Administration's (FDA) idealized medical device. An in-house code is used, hereafter (W enoHemo(™) ), that combines high-order finite-difference schemes on structured staggered Cartesian grids with an IBM to facilitate flow over or through complex stationary or rotating geometries and employs a subgrid-scale (SGS) turbulence model that more naturally handles transitional flows [2]. Predictions of velocity and wall shear stress statistics are compared with previously published experimental measurements from Hariharan et al. [6] for the four Reynolds numbers considered.

  20. FDA-approved small-molecule kinase inhibitors.

    PubMed

    Wu, Peng; Nielsen, Thomas E; Clausen, Mads H

    2015-07-01

    Kinases have emerged as one of the most intensively pursued targets in current pharmacological research, especially for cancer, due to their critical roles in cellular signaling. To date, the US FDA has approved 28 small-molecule kinase inhibitors, half of which were approved in the past 3 years. While the clinical data of these approved molecules are widely presented and structure-activity relationship (SAR) has been reported for individual molecules, an updated review that analyzes all approved molecules and summarizes current achievements and trends in the field has yet to be found. Here we present all approved small-molecule kinase inhibitors with an emphasis on binding mechanism and structural features, summarize current challenges, and discuss future directions in this field.

  1. FDA toxicity databases and real-time data entry

    SciTech Connect

    Arvidson, Kirk B.

    2008-11-15

    Structure-searchable electronic databases are valuable new tools that are assisting the FDA in its mission to promptly and efficiently review incoming submissions for regulatory approval of new food additives and food contact substances. The Center for Food Safety and Applied Nutrition's Office of Food Additive Safety (CFSAN/OFAS), in collaboration with Leadscope, Inc., is consolidating genetic toxicity data submitted in food additive petitions from the 1960s to the present day. The Center for Drug Evaluation and Research, Office of Pharmaceutical Science's Informatics and Computational Safety Analysis Staff (CDER/OPS/ICSAS) is separately gathering similar information from their submissions. Presently, these data are distributed in various locations such as paper files, microfiche, and non-standardized toxicology memoranda. The organization of the data into a consistent, searchable format will reduce paperwork, expedite the toxicology review process, and provide valuable information to industry that is currently available only to the FDA. Furthermore, by combining chemical structures with genetic toxicity information, biologically active moieties can be identified and used to develop quantitative structure-activity relationship (QSAR) modeling and testing guidelines. Additionally, chemicals devoid of toxicity data can be compared to known structures, allowing for improved safety review through the identification and analysis of structural analogs. Four database frameworks have been created: bacterial mutagenesis, in vitro chromosome aberration, in vitro mammalian mutagenesis, and in vivo micronucleus. Controlled vocabularies for these databases have been established. The four separate genetic toxicity databases are compiled into a single, structurally-searchable database for easy accessibility of the toxicity information. Beyond the genetic toxicity databases described here, additional databases for subchronic, chronic, and teratogenicity studies have been prepared.

  2. Disparities in Discontinuing Rosiglitazone Following the 2007 FDA Safety Alert

    PubMed Central

    Qato, Danya M.; Trivedi, Amal N.; Mor, Vincent; Dore, David D.

    2016-01-01

    Background Responsiveness to the Food and Drug Administration (FDA) rosiglitazone safety alert, issued on May 21, 2007, has not been examined among vulnerable subpopulations of the elderly. Objective To compare time to discontinuation of rosiglitazone after the safety alert between black and white elderly persons, and across sociodemographic and economic subgroups. Research Design A cohort study. Subjects Medicare fee-for-service enrollees in 2007 who were established users of rosiglitazone identified from a 20% national sample of pharmacy claims. Measures Outcome of interest was time to discontinuation of rosiglitazone after the May alert. We modeled the number of days following the warning to the end of the days’ supply for the last rosiglitazone claim during the study period (May 21, 2007–December 31, 2007) using multivariable proportional hazards models. Results More than 67% of enrollees discontinued rosiglitazone within six months of the advisory. In adjusted analysis, white enrollees (hazard ratio = 0.90; 95% confidence interval, 0.86–0.94) discontinued rosiglitazone later than the comparison group of black enrollees. Enrollees with a history of low personal income also discontinued later than their comparison group (hazard ratio = 0.84; 95% confidence interval, 0.81–0.87). There were no observed differences across quintiles of area-level socioeconomic status. Conclusions White race and a history of low personal income modestly predicted later discontinuation of rosiglitazone after the FDA’s safety advisory in 2007. The impact of FDA advisories can vary among sociodemographic groups. Policymakers should continue to monitor whether risk management policies reach their intended populations. PMID:26978569

  3. The FDA's new advice on fish: it's complicated.

    PubMed

    Wenstrom, Katharine D

    2014-11-01

    The Food and Drug Administration and Environmental Protection Agency recently issued an updated draft of advice on fish consumption for pregnant and breastfeeding women, after survey data indicated that the majority of pregnant women do not eat much fish and thus may have inadequate intake of the omega 3 fatty acids eicosapentaenoic acid [EPA] and ducosahexaenoic acid [DHA]. Omega 3 fatty acids are essential components of membranes in all cells of the body and are vitally important for normal development of the brain and retinal tissues (especially myelin and retinal photoreceptors) and for maintenance of normal neurotransmission and connectivity. They also serve as substrates for the synthesis of a variety of antiinflammatory and inflammation-resolving mediators, favorably alter the production of thromboxane and prostaglandin E2, and improve cardiovascular health by preventing fatal arrhythmias and reducing triglyceride and C-reactive protein levels. Maternal ingestion of adequate quantities of fish (defined in many studies as at least 340 g of oily fish each week) has been associated with better childhood IQ scores, fine motor coordination, and communication and social skills, along with other benefits. Although the FDA did not clarify which fish to eat, it specifically advised against eating fish with the highest mercury levels and implied that fish with high levels of EPA and DHA and low levels of mercury are ideal. The FDA draft did not recommend taking omega 3 fatty acid or fish oil supplements instead of eating fish, which is advice that may reflect the fact that randomized controlled trials of DHA and EPA or fish oil supplementation generally have been disappointing and that the ideal daily dose of DHA and EPA is unknown. It seems safe to conclude that pregnant and nursing women should be advised to eat fish to benefit from naturally occurring omega 3 fatty acids, to avoid fish with high levels of mercury and other contaminants, and, if possible, to choose

  4. Revocation of regulation on positron emission tomography drug products--FDA. Final rule; revocation.

    PubMed

    1997-12-19

    The Food and Drug Administration (FDA) is revoking a regulation on positron emission tomography (PET) radiopharmaceutical drug products. The regulation permits FDA to approve requests from manufacturers of PET drugs for exceptions or alternatives to provisions of the current good manufacturing practice (CGMP) regulations. FDA is taking this action in accordance with provisions of the Food and Drug Administration Modernization Act of 1997 (Modernization Act). Elsewhere in this issue of the Federal Register, FDA is publishing a notice revoking two notices concerning certain guidance documents on PET drugs and the guidance documents to which the notices relate.

  5. 77 FR 14401 - Draft Guidance on Drug Safety Information-FDA's Communication to the Public; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-09

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance on Drug Safety Information--FDA's Communication to the Public; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of a draft guidance...

  6. 21 CFR 830.220 - Termination of FDA service as an issuing agency.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Termination of FDA service as an issuing agency. 830.220 Section 830.220 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... be likely to lead to a return of the conditions that prompted us to act. (b) If FDA has ended...

  7. 21 CFR 14.171 - Utilization of an advisory committee on the initiative of FDA.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Utilization of an advisory committee on the initiative of FDA. 14.171 Section 14.171 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... Human Prescription Drugs § 14.171 Utilization of an advisory committee on the initiative of FDA. (a) Any...

  8. 21 CFR 516.34 - FDA recognition of exclusive marketing rights.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false FDA recognition of exclusive marketing rights. 516... SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive...

  9. 21 CFR 516.34 - FDA recognition of exclusive marketing rights.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false FDA recognition of exclusive marketing rights. 516... SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive...

  10. 21 CFR 516.34 - FDA recognition of exclusive marketing rights.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false FDA recognition of exclusive marketing rights. 516... SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of exclusive...

  11. 76 FR 34715 - Draft Guidance for Industry; Considering Whether an FDA-Regulated Product Involves the...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-14

    ...-Regulated Product Involves the Application of Nanotechnology; Availability AGENCY: Food and Drug... the Application of Nanotechnology''. This guidance is intended to provide industry with FDA's current... nanotechnology. The points to consider are intended to be broadly applicable to all FDA-regulated products, with...

  12. FDA regulation of invasive neural recording electrodes: a daunting task for medical innovators.

    PubMed

    Welle, Cristin; Krauthamer, Victor

    2012-03-01

    The U.S. Food and Drug Administration (FDA) is charged with assuring the safety and effectiveness of medical devices. Before any medical device can be brought to market, it must comply with all federal regulations regarding FDA processes for clearance or approval. Navigating the FDA regulatory process may seem like a daunting task to the innovator of a novel medical device who has little experience with the FDA regulatory process or device commercialization. This review introduces the basics of the FDA regulatory premarket process, with a focus on issues relating to chronically implanted recording devices in the central or peripheral nervous system. Topics of device classification and regulatory pathways, the use of standards and guidance documents, and optimal time lines for interaction with the FDA are discussed. Additionally, this article summarizes the regulatory research on neural implant safety and reliability conducted by the FDA's Office of Science and Engineering Laboratories (OSEL) in collaboration with Defense Advanced Research Projects Agency (DARPA) Reliable Neural Technology (RE-NET) Program. For a more detailed explanation of the medical device regulatory process, please refer to several excellent reviews of the FDA's regulatory pathways for medical devices [1]-[4].

  13. FDA Procedures for Standardization and Certification of Retail Food Inspection/Training Officers, 2000.

    ERIC Educational Resources Information Center

    Food and Drug Administration (DHHS/PHS), Rockville, MD.

    This document provides information, standards, and behavioral objectives for standardization and certification of retail food inspection personnel in the Food and Drug Administration (FDA). The procedures described in the document are based on the FDA Food Code, updated to reflect current Food Code provisions and to include a more refined focus on…

  14. The FDA's failure to address the lack of generalisability of antidepressant efficacy trials in product labelling.

    PubMed

    Zimmerman, Mark

    2016-06-01

    According to the US Food and Drug Administration's (FDA's) regulations, the criteria used to select patients into registration studies should be addressed in a product's label. The FDA's labelling guidelines, which specifically indicate that the routine exclusion of patients of a certain level of severity should be noted in the label, has been uniformly ignored. © The Royal College of Psychiatrists 2016.

  15. 10 CFR 35.7 - FDA, other Federal, and State requirements.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false FDA, other Federal, and State requirements. 35.7 Section 35.7 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL General Information § 35.7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee...

  16. 10 CFR 35.7 - FDA, other Federal, and State requirements.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false FDA, other Federal, and State requirements. 35.7 Section 35.7 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL General Information § 35.7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee...

  17. 10 CFR 35.7 - FDA, other Federal, and State requirements.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false FDA, other Federal, and State requirements. 35.7 Section 35.7 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL General Information § 35.7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee...

  18. 10 CFR 35.7 - FDA, other Federal, and State requirements.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false FDA, other Federal, and State requirements. 35.7 Section 35.7 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL General Information § 35.7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee...

  19. 10 CFR 35.7 - FDA, other Federal, and State requirements.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 1 2014-01-01 2014-01-01 false FDA, other Federal, and State requirements. 35.7 Section 35.7 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL General Information § 35.7 FDA, other Federal, and State requirements. Nothing in this part relieves the licensee...

  20. 21 CFR 4.2 - How does FDA define key terms and phrases in this subpart?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false How does FDA define key terms and phrases in this... Combination Products § 4.2 How does FDA define key terms and phrases in this subpart? The terms listed in this section have the following meanings for purposes of this subpart: Biological product has the meaning set...

  1. 21 CFR 4.2 - How does FDA define key terms and phrases in this subpart?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false How does FDA define key terms and phrases in this... Combination Products § 4.2 How does FDA define key terms and phrases in this subpart? The terms listed in this section have the following meanings for purposes of this subpart: Biological product has the meaning set...

  2. 76 FR 30175 - Draft Guidance for Clinical Investigators, Industry, and FDA Staff: Financial Disclosure by...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-24

    ... regulations governing financial disclosure by clinical investigators, part 54 (21 CFR part 54), and to provide... Investigators, Industry, and FDA Staff: Financial Disclosure by Clinical Investigators; Availability AGENCY... FDA Staff: Financial Disclosure by Clinical Investigators.'' This draft guidance is intended to assist...

  3. 21 CFR 516.34 - FDA recognition of exclusive marketing rights.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false FDA recognition of exclusive marketing rights. 516... SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS NEW ANIMAL DRUGS FOR MINOR USE AND MINOR SPECIES Designation of a Minor Use or Minor Species New Animal Drug § 516.34 FDA recognition of...

  4. EBOLA and FDA: reviewing the response to the 2014 outbreak, to find lessons for the future

    PubMed Central

    Largent, Emily A.

    2016-01-01

    Abstract In 2014, West Africa confronted the most severe outbreak of Ebola virus disease (EVD) in history. At the onset of the outbreak—as now—there were no therapies approved by the U.S. Food and Drug Administration (FDA) for prevention of, post-exposure prophylaxis against, or treatment of EVD. As a result, the outbreak spurred interest in developing novel treatments, sparked calls to use experimental interventions in the field, and highlighted challenges to the standard approach to FDA approval of new drugs. Although the outbreak was geographically centered in West Africa, it showcased FDA's global role in drug development, approval, and access. FDA's response to EVD highlights the panoply of agency powers and demonstrates the flexibility of FDA's regulatory framework. This paper evaluates the strengths and weaknesses of FDA's response and makes policy recommendations regarding how FDA should respond to new and re-emerging public health threats. In particular, it argues that greater emphasis should be placed on drug development in interoutbreak periods and on assuring access to approved products. The current pandemic of Zika virus infection is but one example of an emerging health threat that will require FDA involvement in order to achieve a successful response. PMID:28852537

  5. 76 FR 38666 - Food and Drug Administration (FDA) and Marine Environmental Sciences Consortium/Dauphin Island...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-01

    ... HUMAN SERVICES Food and Drug Administration Food and Drug Administration (FDA) and Marine Environmental Sciences Consortium/Dauphin Island Sea Lab Collaboration (U19) AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of...

  6. Development of a Course of Study in FDA Drug Regulatory Procedures

    ERIC Educational Resources Information Center

    Jacobs, Robin Wills; King, James C.

    1977-01-01

    It is evident that more colleges of pharmacy should establish some major course of study in the area of governmental drug regulatory procedures. This study is aimed at expanding cooperative educational programs through an FDA residency for pharmacy students and preparing a didactic course in FDA procedures. (LBH)

  7. 21 CFR 1271.27 - Will FDA assign me a registration number?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Section 1271.27 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES..., TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Procedures for Registration and Listing § 1271.27 Will FDA assign me a registration number? (a) FDA will assign each location a permanent registration number....

  8. The FDA and genetic testing: improper tools for a difficult problem

    PubMed Central

    Willmarth, Kirk

    2015-01-01

    The US Food and Drug Administration (FDA) has recently issued draft guidance on how it intends to regulate laboratory-developed tests, including genetic tests. This article argues that genetic tests differ from traditional targets of FDA regulation in both product as well as industry landscape, and that the FDA's traditional tools are ill-suited for regulating this space. While existing regulatory gaps do create risks in genetic testing, the regulatory burden of the FDA's proposal introduces new risks for both test providers and patients that may offset the benefits. Incremental expansion of current oversight outside of the FDA can mitigate many of the risks necessitating increased oversight while avoiding the creation of new ones that could undermine this industry. PMID:27774193

  9. The FDA and genetic testing: improper tools for a difficult problem.

    PubMed

    Willmarth, Kirk

    2015-02-01

    The US Food and Drug Administration (FDA) has recently issued draft guidance on how it intends to regulate laboratory-developed tests, including genetic tests. This article argues that genetic tests differ from traditional targets of FDA regulation in both product as well as industry landscape, and that the FDA's traditional tools are ill-suited for regulating this space. While existing regulatory gaps do create risks in genetic testing, the regulatory burden of the FDA's proposal introduces new risks for both test providers and patients that may offset the benefits. Incremental expansion of current oversight outside of the FDA can mitigate many of the risks necessitating increased oversight while avoiding the creation of new ones that could undermine this industry.

  10. FDA-Approved Natural Polymers for Fast Dissolving Tablets

    PubMed Central

    Alam, Md Tausif; Parvez, Nayyar; Sharma, Pramod Kumar

    2014-01-01

    Oral route is the most preferred route for administration of different drugs because it is regarded as safest, most convenient, and economical route. Fast disintegrating tablets are very popular nowadays as they get dissolved or facilely disintegrated in mouth within few seconds of administration without the need of water. The disadvantages of conventional dosage form, especially dysphagia (arduousness in swallowing), in pediatric and geriatric patients have been overcome by fast dissolving tablets. Natural materials have advantages over synthetic ones since they are chemically inert, non-toxic, less expensive, biodegradable and widely available. Natural polymers like locust bean gum, banana powder, mango peel pectin, Mangifera indica gum, and Hibiscus rosa-sinenses mucilage ameliorate the properties of tablet and utilized as binder, diluent, and superdisintegrants increase the solubility of poorly water soluble drug, decrease the disintegration time, and provide nutritional supplement. Natural polymers are obtained from the natural origin and they are cost efficacious, nontoxic, biodegradable, eco-friendly, devoid of any side effect, renewable, and provide nutritional supplement. It is proved from the studies that natural polymers are more safe and efficacious than the synthetic polymers. The aim of the present article is to study the FDA-approved natural polymers utilized in fast dissolving tablets. PMID:26556207

  11. The US FDA and animal cloning: risk and regulatory approach.

    PubMed

    Rudenko, Larisa; Matheson, John C

    2007-01-01

    The Food and Drug Administration's (FDA's) Center for Veterinary Medicine issued a voluntary request to producers of livestock clones not to introduce food from clones or their progeny into commerce until the agency had assessed whether production of cattle, swine, sheep, or goats by somatic cell nuclear transfer (SCNT) posed any unique risks to the animal(s) involved in the process, humans, or other animals by consuming food from those animals, compared with any other assisted reproductive technology (ART) currently in use. Following a comprehensive review, no anomalies were observed in animals produced by cloning that have not also been observed in animals produced by other ARTs and natural mating. Further systematic review on the health of, and composition of meat and milk from, cattle, swine, and goat clones and the progeny of cattle and sheep did not result in the identification of any food-consumption hazards. The agency therefore concluded that food from cattle, swine, and goat clones was as safe to eat as food from animals of those species derived by conventional means. The agency also concluded that food from the progeny of the clone of any species normally consumed for food is as safe to eat as those animals. The article also describes the methodology used by the agency to analyze data and draw these conclusions, the plans the agency has proposed to manage any identified risks, and the risk communication approaches the agency has used.

  12. The FDA role in contact lens development and safety.

    PubMed

    Lippman, R E

    1990-01-01

    The Food and Drug Administration (FDA) exercises a multifaceted role in fulfilling its mission of enforcing the Federal Food, Drug and Cosmetic Act (Act), functioning not only as industry regulator and consumer protector, but also as scientific advisor and consumer educator regarding medical devices, drugs, foods, cosmetics, and veterinary medicine. Medical devices are regulated within the Center for Devices and Radiological Health. Contact lenses are regulated under the authority of the medical device amendments. The Center is responsible for promulgating regulations, publishing guidelines, and developing written guidance in enforcing the Act, and also for guiding manufacturers of medical devices in safe and effective product development. Other components deal with the compliance of manufacturers with the marketing of medical devices within the meaning of the Act, and through labeling requirements of the Act and consumer education and informational activities. As for contact lenses, the process of updating product development regulations and guidelines is an ongoing activity. The most recent version of the Contact Lens Guideline Document, issued in April 1988, contains two major revisions involving preclinical and clinical testing. The first redefines plastics into one materials category, thus reducing testing requirements with respect to animal toxicology studies and other preclinical areas. The second revision restricts clinical testing requirements to allow confirmatory trials in applications for new daily wear lenses. The intention was to maintain the ability of studies to detect major material or design flaws in lenses, thus boosting confidence in their performance while eliminating unnecessary trials.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. FDA-Approved Natural Polymers for Fast Dissolving Tablets.

    PubMed

    Alam, Md Tausif; Parvez, Nayyar; Sharma, Pramod Kumar

    2014-01-01

    Oral route is the most preferred route for administration of different drugs because it is regarded as safest, most convenient, and economical route. Fast disintegrating tablets are very popular nowadays as they get dissolved or facilely disintegrated in mouth within few seconds of administration without the need of water. The disadvantages of conventional dosage form, especially dysphagia (arduousness in swallowing), in pediatric and geriatric patients have been overcome by fast dissolving tablets. Natural materials have advantages over synthetic ones since they are chemically inert, non-toxic, less expensive, biodegradable and widely available. Natural polymers like locust bean gum, banana powder, mango peel pectin, Mangifera indica gum, and Hibiscus rosa-sinenses mucilage ameliorate the properties of tablet and utilized as binder, diluent, and superdisintegrants increase the solubility of poorly water soluble drug, decrease the disintegration time, and provide nutritional supplement. Natural polymers are obtained from the natural origin and they are cost efficacious, nontoxic, biodegradable, eco-friendly, devoid of any side effect, renewable, and provide nutritional supplement. It is proved from the studies that natural polymers are more safe and efficacious than the synthetic polymers. The aim of the present article is to study the FDA-approved natural polymers utilized in fast dissolving tablets.

  14. Dissolution testing for generic drugs: an FDA perspective.

    PubMed

    Anand, Om; Yu, Lawrence X; Conner, Dale P; Davit, Barbara M

    2011-09-01

    In vitro dissolution testing is an important tool used for development and approval of generic dosage forms. The objective of this article is to summarize how dissolution testing is used for the approval of safe and effective generic drug products in the United States (US). Dissolution testing is routinely used for stability and quality control purposes for both oral and non-oral dosage forms. The dissolution method should be developed using an appropriate validated method depending on the dosage form. There are several ways in which dissolution testing plays a pivotal role in regulatory decision-making. It may be used to waive in vivo bioequivalence (BE) study requirements, as BE documentation for Scale Up and Post Approval Changes (SUPAC), and to predict the potential for a modified-release (MR) drug product to dose-dump if co-administered with alcoholic beverages. Thus, in vitro dissolution testing plays a major role in FDA's efforts to reduce the regulatory burden and unnecessary human studies in generic drug development without sacrificing the quality of the drug products.

  15. Adherence of pharmaceutical advertisements in medical journals to FDA guidelines and content for safe prescribing.

    PubMed

    Korenstein, Deborah; Keyhani, Salomeh; Mendelson, Ali; Ross, Joseph S

    2011-01-01

    Physician-directed pharmaceutical advertising is regulated in the United States by the Food and Drug Administration (FDA); adherence to current FDA guidelines is unknown. Our objective was to determine adherence rates of physician-directed print advertisements in biomedical journals to FDA guidelines and describe content important for safe prescribing. Cross-sectional analysis of November 2008 pharmaceutical advertisements within top U.S.-based biomedical journals publishing original research. We excluded advertisements for devices, over the counter medications, and disease awareness. We utilized FDA guideline items identifying unique forms of advertisement bias to categorize advertisements as adherent to FDA guidelines, possibly non-adherent to at least 1 item, or non-adherent to at least 1 item. We also evaluated advertisement content important for safe prescribing, including benefit quantification, risk information and verifiable references. All advertisements were evaluated by 2 or more investigators, with differences resolved by discussion. Twelve journals met inclusion criteria. Nine contained pharmaceutical advertisements, including 192 advertisements for 82 unique products; median 2 per product (range 1-14). Six "teaser" advertisements presented only drug names, leaving 83 full unique advertisements. Fifteen advertisements (18.1%) adhered to all FDA guidelines, 41 (49.4%) were non-adherent with at least one form of FDA-described bias, and 27 (32.5%) were possibly non-adherent due to incomplete information. Content important for safe prescribing was often incomplete; 57.8% of advertisements did not quantify serious risks, 48.2% lacked verifiable references and 28.9% failed to present adequate efficacy quantification. Study limitations included its focus on advertisements from a single month, the subjectivity of FDA guidelines themselves, and the necessary subjectivity of determinations of adherence. Few physician-directed print pharmaceutical advertisements

  16. Rare cancer trial design: lessons from FDA approvals.

    PubMed

    Gaddipati, Himabindu; Liu, Ke; Pariser, Anne; Pazdur, Richard

    2012-10-01

    A systematic analysis of clinical trials supporting rare cancer drug approvals may identify concepts and terms that can inform the effective design of prospective clinical trials for rare cancers. In this article, using annual incidence ≤6 of 100,000 individuals to define "rare cancer," we identified clinical trials for rare cancers, supporting U.S. Food and Drug Administration (FDA) drug approvals for rare cancer indications between December 1987 and May 2011. We characterized each selected trial for study design, sample size, primary efficacy endpoints, and statistical comparisons. We also profiled trials with regard to type of submission, review designation, and approval type. Our results indicated that, of 99 trials that supported the approvals of 45 drugs for 68 rare cancer indications, one third of these trials were randomized; 69% of approvals relied on objective response rate as the primary efficacy endpoint; and 63% were based on a single trial. Drugs granted accelerated approval appeared more likely to be associated with postmarketing safety findings, relative to drugs approved under the regular approval. Data collected across clinical trials were robust: Use of different lower incidence rates in analyzing these trials did not have effects on trial characteristics. The absolute number of drug approvals for rare cancer indications increased markedly over time. We concluded that one third of clinical trials supporting drug approvals for rare cancer indications were randomized, affirming the feasibility and value of randomized trial design to evaluate drugs for rare cancers. Postmarketing safety data may relate to trial design and approval type. An operational definition of "rare cancer" can be useful for the analysis of trial data and for the path toward harmonizing the terminology in the area of clinical research on rare cancers.

  17. Ortho markets first FDA-approved triphasic pill.

    PubMed

    1984-06-01

    Ortho-Novum 7/7/7, the 1st triphasic oral contraceptive to be approved by the FDA (Federal Food and Drug Administration) is now being marketed in the US by the Ortho Pharmaceutical Corporation. The triphasic pill is similar to the biphasic pill as the steriod level is varied during the cycle, but the new triphasic pill more closely follows the normal ovulatory cycle cycle in regard to steriod levels. During days 1-7 of the cycle, the dosage is 0.5 mg of progestogen and 35 mcg of estrogen. Respective doses for days 8-14 are 0.75 mg amd 35 mcg and for days 15-21 they are 1.0 mg and 35 mcg. The total dosage of progestogen for the entire cycle is 15.75 mg. The new pill is associated with less breakthrough bleeding than the biphasic pill and the bleeding pattern is similar to that observed for Ortho 1-35. 2 pregnancies were observed during worldwide clinical trails but only 1 was attributed to product failure. The Pearl Formula failure rate was 0.22 or less. The incidence of side effects was low. The pill is packaged in a 28-day circular dial pack which contains 7 white, 7 light peach, and 7 dark peach pills with an additional 7 placebo pills. Some objectives have been raised concerning the packaging of the product. The pills are very similar in color and patients might find this confusing. Ortho representatives indicated that this should not be a problem if patient are given sufficient counseling.

  18. 76 FR 62073 - Guidance for Industry on Implementation of the Fee Provisions of the FDA Food Safety...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-06

    ... Modernization Act.'' FDA is issuing this guidance to provide answers to common questions that might arise about... to common questions that might arise about the new fee provisions and FDA's plans for...

  19. Reflections on the US FDA's Warning on Direct-to-Consumer Genetic Testing.

    PubMed

    Yim, Seon-Hee; Chung, Yeun-Jun

    2014-12-01

    In November 2013, the US Food and Drug Administration (FDA) sent a warning letter to 23andMe, Inc. and ordered the company to discontinue marketing of the 23andMe Personal Genome Service (PGS) until it receives FDA marketing authorization for the device. The FDA considers the PGS as an unclassified medical device, which requires premarket approval or de novo classification. Opponents of the FDA's action expressed their concerns, saying that the FDA is overcautious and paternalistic, which violates consumers' rights and might stifle the consumer genomics field itself, and insisted that the agency should not restrict direct-to-consumer (DTC) genomic testing without empirical evidence of harm. Proponents support the agency's action as protection of consumers from potentially invalid and almost useless information. This action was also significant, since it reflected the FDA's attitude towards medical application of next-generation sequencing techniques. In this review, we followed up on the FDA-23andMe incident and evaluated the problems and prospects for DTC genetic testing.

  20. What's next after 50 years of psychiatric drug development: an FDA perspective.

    PubMed

    Laughren, Thomas P

    2010-09-01

    This article discusses changes in psychiatric drug development from a US Food and Drug Administration (FDA) standpoint. It first looks back at changes that have been influenced by regulatory process and then looks forward at FDA initiatives that are likely to affect psychiatric drug development in the future. FDA protects the public health by ensuring the safety and efficacy of drug products introduced into the US market. FDA works with drug sponsors during development, and, when applications are submitted, reviews the safety and efficacy data and the proposed labeling. Drug advertising and promotion and postmarketing surveillance also fall within FDA's responsibility. Among the many changes in psychiatric drug development over the past 50 years, several have been particularly influenced by FDA. Populations studied have expanded diagnostically and demographically, and approved psychiatric indications have become more focused on the clinical entities actually studied, including in some cases specific symptom domains of recognized syndromes. Trial designs have become increasingly complex and informative, and approaches to data analysis have evolved to better model the reality of clinical trials. This article addresses 2 general areas of innovation at FDA that will affect psychiatric drug development in years to come. Several programs falling under the general heading of the Critical Path Initiative, ie, biomarkers, adaptive design, end-of-phase 2A meetings, and data standards, are described. In addition, a number of important safety initiatives, including Safety First, the Sentinel Initiative, the Safe Use Initiative, and meta-analysis for safety, are discussed.

  1. How drugs are developed and approved by the FDA: current process and future directions.

    PubMed

    Ciociola, Arthur A; Cohen, Lawrence B; Kulkarni, Prasad

    2014-05-01

    This article provides an overview of FDA's regulatory processes for drug development and approval, and the estimated costs associated with the development of a drug, and also examines the issues and challenges facing the FDA in the near future. A literature search was performed using MEDLINE to summarize the current FDA drug approval processes and future directions. MEDLINE was further utilized to search for all cost analysis studies performed to evaluate the pharmaceutical industry R&D productivity and drug development cost estimates. While the drug approval process remains at high risk and spans over multiple years, the FDA drug review and approval process has improved, with the median approval time for new molecular drugs been reduced from 19 months to 10 months. The overall cost to development of a drug remains quite high and has been estimated to range from $868M to $1,241M USD. Several new laws have been enacted, including the FDA Safety and Innovation Act (FDASIA) of 2013, which is designed to improve the drug approval process and enhance access to new medicines. The FDA's improved processes for drug approval and post-market surveillance have achieved the goal of providing patients with timely access to effective drugs while minimizing the risk of drug-related harm. The FDA drug approval process is not without controversy, as a number of well-known gastroenterology drugs have been withdrawn from the US market over the past few years. With the approval of the new FDASIA law, the FDA will continue to improve their processes and, working together with the ACG through the FDA-Related Matters Committee, continue to develop safe and effective drugs for our patients.

  2. Buckman extended: federal preemption of state fraud-on-the-FDA statutes.

    PubMed

    Gaddis, Christine A

    2014-01-01

    A number of states have enacted statutes that provide protection to drug manufacturers in product liability actions. Additionally, several of these states have enacted "fraud-on-the-FDA" statutory provisions, which remove statutory protection afforded to drug manufacturers in product liability actions if plaintiffs can provide evidence that the drug manufacturer made misrepresentations to the FDA during the process of obtaining marketing approval for the drug. Currently, the federal circuits are in disagreement over whether these state "fraud-on-the-FDA" statutes should be federally preempted. This issue warrants resolution for drug manufacturers, private citizens, and state legislatures. This Comment will discuss the history and role of the FDA's authority in drug and medical device regulation; federal preemption generally and the Supreme Court's decisions that considered whether state law failure to warn claims are federally preempted in the context of drugs and medical devices; the Supreme Court's decision in Buckman v. Plaintiffs' Legal Committee, where the Court held that claims that a medical device manufacturer made fraudulent representations to the FDA were federally preempted because such claims interfered with the relationship between the FDA and the entities it regulated, state fraud-on-the-FDA statutory provisions, and the existing circuit split regarding whether those statutes should be federally preempted; the potential resolutions to the circuit split; and will conclude and advocate that the Supreme Court's Buckman holding be applied to federally preempt state fraud-on-the-FDA statutes because such statutes involve the relationship between a federal agency and the entity it regulates and thus undermine the FDA's authority.

  3. Science, law, and politics in FDA's genetically engineered foods policy: scientific concerns and uncertainties.

    PubMed

    Pelletier, David L

    2005-06-01

    The Food and Drug Administration's (FDA's) 1992 policy statement granted genetically engineered foods presumptive GRAS (generally recognized as safe) status. Since then, divergent views have been expressed concerning the scientific support for this policy. This paper examines four sources to better understand the basis for these claims: 1) internal FDA correspondence; 2) reports from the National Academy of Sciences; 3) research funded by US Department of Agriculture from 1981 to 2002; and 4) FDA's proposed rules issued in 2001. These sources reveal that little research has been conducted on unintended compositional changes from genetic engineering. Profiling techniques now make this feasible, but the new debate centers on the functional meaning of compositional changes.

  4. Turning point or tipping point: new FDA draft guidances and the future of DTC advertising.

    PubMed

    Pitts, Peter J

    2004-01-01

    According to Food and Drug Administration (FDA) research, direct-to-consumer (DTC) drug ads are not as empowering as they were even three years ago. How will the FDA's new draft guidances reverse this trend and affect the future of DTC advertising? Will they be a turning point, resulting in pharmaceutical companies' embracing an educational public health imperative, or a tipping point with politicians and the public zeroing in on aggressively targeted DTC ads as the postimportation pharmaceutical bête noire? The FDA believes that its new guidances strengthen the strategic argument that a better-informed consumer lays the groundwork for a better potential customer.

  5. "Off Label" Use of FDA-Approved Devices and Digital Breast Tomosynthesis.

    PubMed

    Kopans, Daniel B

    2015-11-01

    The purpose of this article is to clarify for radiologists the meaning of U.S. Food and Drug Administration (FDA) approval with respect to Digital Breast Tomosynthesis (DBT). DBT is a major improvement over 2D mammography in the detection of cancers (sensitivity) and the reduction in recalls resulting from screening (specificity). Most imaging systems that have been approved by the FDA are used "off label" for breast imaging. Although the FDA determines which claims a manufacturer can make for a device, physicians may use approved devices, such as DBT, off label to provide better patient care.

  6. The FDA And ABCs: Unintended Consequences Of Antidepressant Warnings On Human Capital*

    PubMed Central

    Busch, Susan H.; Golberstein, Ezra; Meara, Ellen

    2014-01-01

    Using annual cross-sectional data on over 100,000 adolescents aged 12-17, we studied academic and behavioral outcomes among those who were and were not likely affected by FDA warnings regarding the safety of antidepressants. Compared to other adolescents, adolescents with probable depression experienced a relative decline in grade point average of .14 points following the FDA warnings. The FDA warnings also coincided with increased delinquency, use of tobacco and use of illicit drugs. Together, our results stress the importance of mental health and its treatment as an input into cognitive and non-cognitive aspects of human capital. PMID:25284886

  7. Ensuring that consumers receive appropriate information from drug ads: what is the FDA's role?

    PubMed

    Waxman, Henry A

    2004-01-01

    The promise of direct-to-consumer (DTC) prescription drug advertisements lies in their potential to educate consumers about medical conditions and the possibility of treatment. But this promise can only be fulfilled if consumers are given clear and accurate information. The responsibility for ensuring that this occurs falls on the Food and Drug Administration (FDA). Recent congressional investigations have indicated that the agency is failing at this task, as FDA enforcement actions against false and misleading ads have declined precipitously in recent years. Other FDA efforts, such as its recently released guidelines on prescription drugs, do not appear to be helpful, potentially confusing consumers more than helping them.

  8. An analysis of FDA passive surveillance reports of seizures associated with consumption of aspartame.

    PubMed

    Tollefson, L; Barnard, R J

    1992-05-01

    Aspartame, the methyl ester of the dipeptide formed from combining phenylalanine and aspartic acid, was approved by the US Food and Drug Administration (FDA) in July 1981. FDA monitors complaints from consumers and health professionals through the Adverse Reaction Monitoring System, a passive surveillance program FDA has received 251 reports of seizures that have been linked to ingestion of aspartame by consumers. In most cases, information obtained from the complainants' medical records as well as data on consumption patterns, temporal relationships, and challenge tests did not support the claim that the occurrences of the seizures were linked to consumption of aspartame.

  9. Implications of the FDA statement on transvaginal placement of mesh: the aftermath.

    PubMed

    Koski, Michelle E; Rovner, Eric S

    2014-02-01

    The release of the U.S. Food and Drug Administration (FDA) safety communication on the use of transvaginal mesh (TVM) for pelvic organ prolapse (POP) has resulted in changes in the pelvic reconstruction community. This monograph reviews the implications of the FDA statements over the last 18-24 months. Recent findings show that there have been significant developments in the areas of regulatory mandates, media and medico-legal activity, and statements from surgical societies. In summary, well-publicized communications from the FDA and major medical organizations are defining a change in the use of TVM for POP.

  10. 76 FR 41506 - Draft Guidance for Industry and FDA Staff on In Vitro Companion Diagnostic Devices; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-14

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry and FDA Staff on In Vitro.... SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of a draft guidance.... This guidance defines in vitro companion diagnostic devices; explains the need for FDA oversight...

  11. MedWatch, the FDA Safety Information and Adverse Event Reporting Program

    MedlinePlus

    ... Program MedWatch: The FDA Safety Information and Adverse Event Reporting Program Share Tweet Linkedin Pin it More ... information that can help patients avoid serious adverse events. Potential Signals of Serious Risks/New Safety Information ...

  12. Small Area Estimate Maps: Does the FDA Regulate Tobacco? - Small Area Estimates

    Cancer.gov

    This metric is defined as a person 18 years of age or older who must have reported that he/she believes that the United States Food and Drug Administration (FDA) regulates tobacco products in the U.S.

  13. FDA Widens Access to 'Cooling Cap' to Stop Hair Loss in Cancer Patients

    MedlinePlus

    ... FDA Widens Access to 'Cooling Cap' to Stop Hair Loss in Cancer Patients Treatment now OK'd ... cancer patients may be able to ward off hair loss during chemotherapy treatment. A cooling cap approved ...

  14. FDA OKs First Cancer Drug by Genetic Type, Not Organ of Origin

    MedlinePlus

    ... 165908.html FDA OKs First Cancer Drug by Genetic Type, Not Organ of Origin Keytruda is targeted ... 2017 (HealthDay News) -- Many new cancer drugs target genetic "biomarkers" that are specific to tumors -- wherever in ...

  15. Blood donation, deferral, and discrimination: FDA donor deferral policy for men who have sex with men.

    PubMed

    Galarneau, Charlene

    2010-02-01

    U.S. Food and Drug Administration (FDA) policy prohibits blood donation from men who have had sex with men (MSM) even one time since 1977. Growing moral criticism claims that this policy is discriminatory, a claim rejected by the FDA. An overview of U.S. blood donation, recent donor deferral policy, and the conventional ethical debate introduce the need for a different approach to analyzing discrimination claims. I draw on an institutional understanding of injustice to discern and describe five features of the MSM policy and its FDA context that contribute to its discriminatory effect. I note significant similarities in the 1980s policy of deferring Haitians, suggesting an historical pattern of discrimination in FDA deferral policy. Finally, I point to changes needed to move toward a nondiscriminatory deferral policy.

  16. FDA Approves 1st Direct-to-Consumer Genetic Risk Tests

    MedlinePlus

    ... 164507.html FDA Approves 1st Direct-to-Consumer Genetic Risk Tests They screen for gene variants linked ... on Thursday approved the first direct-to-consumer genetic health risk tests. Known as the 23andMe Personal ...

  17. Quality assessment of digital annotated ECG data from clinical trials by the FDA ECG Warehouse.

    PubMed

    Sarapa, Nenad

    2007-09-01

    The FDA mandates that digital electrocardiograms (ECGs) from 'thorough' QTc trials be submitted into the ECG Warehouse in Health Level 7 extended markup language format with annotated onset and offset points of waveforms. The FDA did not disclose the exact Warehouse metrics and minimal acceptable quality standards. The author describes the Warehouse scoring algorithms and metrics used by FDA, points out ways to improve FDA review and suggests Warehouse benefits for pharmaceutical sponsors. The Warehouse ranks individual ECGs according to their score for each quality metric and produces histogram distributions with Warehouse-specific thresholds that identify ECGs of questionable quality. Automatic Warehouse algorithms assess the quality of QT annotation and duration of manual QT measurement by the central ECG laboratory.

  18. Medical devices; exemptions from premarket notification and reserved devices; class I--FDA. Notice.

    PubMed

    1998-02-02

    The Food and Drug Administration (FDA) is publishing a list of class I devices, subject to certain limitations, that will be exempt from premarket notification requirements on February 19, 1998. FDA is also publishing a list of those class I devices that FDA believes will remain subject to premarket notification requirements because they meet the new statutory criteria for premarket notification requirements. These lists do not include class I devices that have been previously exempted by regulation from the premarket notification requirements. FDA is taking this action in order to meet a requirement of the Food and Drug Administration Modernization Act of 1997 (the FDAMA). The agency requests comments on whether the list of class I devices that will remain subject to the premarket notification requirements should be modified.

  19. Commentary: Public outreach by the FDA: evaluating oversight of human drugs and medical devices.

    PubMed

    Frankel, Mark S

    2009-01-01

    As nanotechnology emerges as an important public policy issue, the FDA's relationship with society is about to be tested. Most would agree that fostering public input will be critical to developing effective public policy for nanotechnology. Yet, it will not be easy. Low public confidence in the FDA, the general lack of knowledge about nanotechnology among ordinary Americans, and the way in which the "average" citizen obtains and evaluates knowledge about a public policy issue all pose serious challenges to any public outreach by the FDA. It will be necessary for the FDA to be attentive to not only its own public messages, but also to who is listening and how those messages are being perceived.

  20. FDA Proposes New Safety Measures for Indoor Tanning Devices: The Facts

    MedlinePlus

    ... that they should not be used by people under age 18. We know that the effects of exposure ... 400 of those patients each year were individuals under age 18. “The FDA is particularly concerned about children ...

  1. Erythrityl tetranitrate; drug efficacy study implementation; revocation of exemption; opportunity for a hearing--FDA. Notice.

    PubMed

    1998-06-23

    The Food and Drug Administration (FDA) is revoking the temporary exemption that has allowed single-entity coronary vasodilator drug products containing erythrityl tetranitrate to remain on the market beyond the time limits scheduled for implementation of the Drug Efficacy Study. FDA is announcing that the products lack substantial evidence of effectiveness and is offering an opportunity for a hearing on a proposal to withdraw approval of any applicable new drug applications (NDA's) or abbreviated new drug applications (ANDA's).

  2. How Did Multiple FDA Actions Affect the Utilization and Reimbursed Costs of Thiazolidinediones in US Medicaid?

    PubMed Central

    Hsu, Jason C.; Ross-Degnan, Dennis; Wagner, Anita K.; Zhang, Fang; Lu, Christine Y.

    2016-01-01

    Purpose The US Food and Drug Administration (FDA) communicated the potential cardiovascular risk of thiazolidinediones (rosiglitazone and pioglitazone) in 2007 and required a Risk Evaluation and Mitigation Strategy (REMS) for rosiglitazone in 2010. It also communicated in 2010 the potential risk of bladder cancer with pioglitazone use. This study examined the effects of these multiple FDA actions on utilization and reimbursed costs of thiazolidinediones in state Medicaid programs. Methods State Drug Utilization Data from the Centers for Medicare & Medicaid Services were assessed. An interrupted time series design and segmented linear regression models were used to examine changes in market shares according to both prescription volume and reimbursed costs for rosiglitazone and pioglitazone in the Northeast and Midwest regions of the United States after multiple FDA actions. Findings Compared with expected rates, there were relative reductions of 65.84% (Northeast region) and 55.09% (Midwest region) in the use of rosiglitazone at 1 year after the 2007 FDA actions for thiazolidindiones and cardiac risk. At the same time, relative increases of 7.30% and 9.28% in the use of pioglitazone were observed in the Northeast and Midwest regions, respectively. Changes in both use and costs of rosiglitazone after the 2010 REMS program could not be estimated because of the already low rates (~1%) before REMS was implemented. One year after the 2010 FDA actions for pioglitazone and its possible association with bladder cancer, relative reductions in pioglitazone use of 21.41% (Northeast region) and 18.12% (Midwest region) were detected. Implications The Northeast and Midwest regions reported similar patterns of changes after the FDA actions. Use and costs of rosiglitazone were substantially reduced after the 2007 FDA actions for cardiovascular risk, and this drug was rarely used after the 2010 REMS program. Conversely, use and costs of pioglitazone were substantially reduced after

  3. Access to Investigational Drugs: FDA Expanded Access Programs or “Right‐to‐Try” Legislation?

    PubMed Central

    Berglund, Jelena P.; Weatherwax, Kevin; Gerber, David E.; Adamo, Joan E.

    2015-01-01

    Abstract Purpose The Food and Drug Administration Expanded Access (EA) program and “Right‐to‐Try” legislation aim to provide seriously ill patients who have no other comparable treatment options to gain access to investigational drugs and biological agents. Physicians and institutions need to understand these programs to respond to questions and requests for access. Methods FDA EA programs and state and federal legislative efforts to provide investigational products to patients by circumventing FDA regulations were summarized and compared. Results The FDA EA program includes Single Patient‐Investigational New Drug (SP‐IND), Emergency SP‐IND, Intermediate Sized Population IND, and Treatment IND. Approval rates for all categories exceed 99%. Approval requires FDA and Institutional Review Board (IRB) approval, and cooperation of the pharmaceutical partner is essential. “Right‐to‐Try” legislation bypasses some of these steps, but provides no regulatory or safety oversight. Conclusion The FDA EA program is a reasonable option for patients for whom all other therapeutic interventions have failed. The SP‐IND not only provides patient access to new drugs, but also maintains a balance between immediacy and necessary patient protection. Rather than circumventing existing FDA regulations through proposed legislation, it seems more judicious to provide the knowledge and means to meet the EA requirements. PMID:25588691

  4. Access to Investigational Drugs: FDA Expanded Access Programs or "Right-to-Try" Legislation?

    PubMed

    Holbein, M E Blair; Berglund, Jelena P; Weatherwax, Kevin; Gerber, David E; Adamo, Joan E

    2015-10-01

    The Food and Drug Administration Expanded Access (EA) program and "Right-to-Try" legislation aim to provide seriously ill patients who have no other comparable treatment options to gain access to investigational drugs and biological agents. Physicians and institutions need to understand these programs to respond to questions and requests for access. FDA EA programs and state and federal legislative efforts to provide investigational products to patients by circumventing FDA regulations were summarized and compared. The FDA EA program includes Single Patient-Investigational New Drug (SP-IND), Emergency SP-IND, Intermediate Sized Population IND, and Treatment IND. Approval rates for all categories exceed 99%. Approval requires FDA and Institutional Review Board (IRB) approval, and cooperation of the pharmaceutical partner is essential. "Right-to-Try" legislation bypasses some of these steps, but provides no regulatory or safety oversight. The FDA EA program is a reasonable option for patients for whom all other therapeutic interventions have failed. The SP-IND not only provides patient access to new drugs, but also maintains a balance between immediacy and necessary patient protection. Rather than circumventing existing FDA regulations through proposed legislation, it seems more judicious to provide the knowledge and means to meet the EA requirements. © 2015 Wiley Periodicals, Inc.

  5. Assessment of foetal risk associated with 93 non-US-FDA approved medications during pregnancy

    PubMed Central

    Al-jedai, Ahmed H.; Balhareth, Sakra S.; Algain, Roaa A.

    2012-01-01

    Health care practitioners utilize the United States-Food and Drug Administration (US-FDA) pregnancy categorization (A, B, C, D, X) for making decision on the appropriateness of certain medications during pregnancy. Many non US-FDA approved medications are registered and marketed in Saudi Arabia. However, these medications do not have an assigned pregnancy risk categorization like those approved in the US. The objective of this review is to evaluate, report, and categorize the foetal risk associated with non-US-FDA approved medications registered by the Saudi Food and Drug Authority (S-FDA) according to the US-FDA pregnancy risk categorization system. We identified 109 non-US-FDA approved medications in the Saudi National Formulary (SNF) as of October 2007. We searched for data on functional or anatomical birth defects or embryocidal-associated risk using different databases and references. An algorithm for risk assessment was used to determine a pregnancy risk category for each medication. Out of 93 eligible medications, 73% were assigned category risk C, 10 medications (11%) were assigned category risk D, and 12 medications (13%) were assigned category risk B. Only three medications were judged to be safe during pregnancy based on the available evidence and were assigned category risk A. Inconsistencies in defining and reporting the foetal risk category among different drug regulatory authorities could create confusion and affect prescribing. We believe that standardization and inclusion of this information in the medication package insert is extremely important to all health care practitioners. PMID:23960803

  6. Reform at FDA: faster access to promising drugs? Food and Drug Administration.

    PubMed

    Baker, R

    1995-06-01

    The Food and Drug Administration (FDA), the government agency responsible for ensuring that drugs, vaccines, and medical devices are safe and effective, is under hot debate by Congress, the Clinton administration, and the AIDS community. The Clinton/Gore proposal favors excluding drug and biologic manufacturers from requirements for more environmental assessments and only indirectly addresses drug development. Oregon Democratic Congressman Ron Wyden introduced an FDA reform bill which calls for the FDA to use expert panels, independent testing organizations, and institutional review boards (IRB) to help speed new drugs and devices through the approval process. The bill calls for the use of the IRB for the approval (or denial) of applications for Phase I review of new drugs. Not surprisingly, the AIDS community has differing views on the reform at the FDA. The Treatment Action Group (TAG), whose members hold key positions in well-known AIDS groups, supports the status quo at FDA and is lobbying AIDS organizations across the country to sign on to its FDA Reform Principles. Other AIDS treatment activists, such as members of ACT UP, favor local IRB jurisdiction over Phase I research.

  7. FDA's misplaced priorities: premarket review under the Family Smoking Prevention and Tobacco Control Act.

    PubMed

    Jenson, Desmond; Lester, Joelle; Berman, Micah L

    2016-05-01

    Among other key objectives, the 2009 Family Smoking Prevention and Tobacco Control Act was designed to end an era of constant product manipulation by the tobacco industry that had led to more addictive and attractive products. The law requires new tobacco products to undergo premarket review by the US Food and Drug Administration (FDA) before they can be sold. To assess FDA's implementation of its premarket review authorities, we reviewed FDA actions on new product applications, publicly available data on industry applications to market new products, and related FDA guidance documents and public statements. We conclude that FDA has not implemented the premarket review process in a manner that prioritises the protection of public health. In particular, FDA has (1) prioritised the review of premarket applications that allow for the introduction of new tobacco products over the review of potentially non-compliant products that are already on the market; (2) misallocated resources by accommodating the industry's repeated submissions of deficient premarket applications and (3) weakened the premarket review process by allowing the tobacco industry to market new and modified products that have not completed the required review process.

  8. FDA Safety Reviews on Drugs, Biologics, and Vaccines: 2007-2013.

    PubMed

    Cope, Judith U; Rosenthal, Geoffrey L; Weinel, Pamela; Odegaard, Amy; Murphy, Dianne M

    2015-12-01

    In 2002, Congress mandated that the US Food and Drug Administration (FDA) monitor postmarketing pediatric adverse events and present safety reports to the FDA's Pediatric Advisory Committee (PAC). These safety reviews play a critical role in the postmarketing surveillance and identification of pediatric safety issues. This article follows a previous review ending in 2007 and summarizes 6 years of recent pediatric safety reporting, recommendations by the PAC, and actions by the FDA, including labeling changes. An analysis of the FDA's PAC safety reviews performed from November 2007 through September 2013 was conducted. PAC recommendations for subsequent labeling changes, future studies, or other safety issues were reviewed. There were 6930 serious adverse event reports in 181 reviews. These findings resulted in 33 (18%) recommended labeling changes, and 21 (64%) of these changes were adopted. For 10 products, information was added to the Warning and Precautions section of the label. The PAC also discussed or recommended additional studies for certain products. This article highlights the importance of the FDA's ongoing pediatric postmarketing safety reviews of regulated products, advice from the PAC, and FDA actions in the best interest of pediatric patients. This mandated process facilitates detection of safety concerns that may not be identified in prelicensure clinical trials. It continues to identify critical safety concerns, including unlabeled adverse events, frequent off-label use, product misuse, and secondary exposures in children. Copyright © 2015 by the American Academy of Pediatrics.

  9. Adherence of Pharmaceutical Advertisements in Medical Journals to FDA Guidelines and Content for Safe Prescribing

    PubMed Central

    Korenstein, Deborah; Keyhani, Salomeh; Mendelson, Ali; Ross, Joseph S.

    2011-01-01

    Background Physician-directed pharmaceutical advertising is regulated in the United States by the Food and Drug Administration (FDA); adherence to current FDA guidelines is unknown. Our objective was to determine adherence rates of physician-directed print advertisements in biomedical journals to FDA guidelines and describe content important for safe prescribing. Methods and Findings Cross-sectional analysis of November 2008 pharmaceutical advertisements within top U.S.-based biomedical journals publishing original research. We excluded advertisements for devices, over the counter medications, and disease awareness. We utilized FDA guideline items identifying unique forms of advertisement bias to categorize advertisements as adherent to FDA guidelines, possibly non-adherent to at least 1 item, or non-adherent to at least 1 item. We also evaluated advertisement content important for safe prescribing, including benefit quantification, risk information and verifiable references. All advertisements were evaluated by 2 or more investigators, with differences resolved by discussion. Twelve journals met inclusion criteria. Nine contained pharmaceutical advertisements, including 192 advertisements for 82 unique products; median 2 per product (range 1–14). Six “teaser” advertisements presented only drug names, leaving 83 full unique advertisements. Fifteen advertisements (18.1%) adhered to all FDA guidelines, 41 (49.4%) were non-adherent with at least one form of FDA-described bias, and 27 (32.5%) were possibly non-adherent due to incomplete information. Content important for safe prescribing was often incomplete; 57.8% of advertisements did not quantify serious risks, 48.2% lacked verifiable references and 28.9% failed to present adequate efficacy quantification. Study limitations included its focus on advertisements from a single month, the subjectivity of FDA guidelines themselves, and the necessary subjectivity of determinations of adherence. Conclusions Few

  10. Single Cigarette Sales: State Differences in FDA Advertising and Labeling Violations, 2014, United States.

    PubMed

    Baker, Hannah M; Lee, Joseph G L; Ranney, Leah M; Goldstein, Adam O

    2016-02-01

    Single cigarettes, which are sold without warning labels and often evade taxes, can serve as a gateway for youth smoking. The Family Smoking Prevention and Tobacco Control Act of 2009 gives the US Food and Drug Administration (FDA) authority to regulate the manufacture, distribution, and marketing of tobacco products, including prohibiting the sale of single cigarettes. To enforce these regulations, the FDA conducted over 335,661 inspections between 2010 and September 30, 2014, and allocated over $115 million toward state inspections contracts. To examine differences in single cigarette violations across states and determine if likely correlates of single cigarette sales predict single cigarette violations at the state level. Cross-sectional study of publicly available FDA warning letters from January 1 to July 31, 2014. All 50 states and the District of Columbia. Tobacco retailer inspections conducted by FDA (n = 33 543). State cigarette tax, youth smoking prevalence, poverty, and tobacco production. State proportion of FDA warning letters issued for single cigarette violations. There are striking differences in the number of single cigarette violations found by state, with 38 states producing no warning letters for selling single cigarettes even as state policymakers developed legislation to address retailer sales of single cigarettes. The state proportion of warning letters issued for single cigarettes is not predicted by state cigarette tax, youth smoking, poverty, or tobacco production, P = .12. Substantial, unexplained variation exists in violations of single cigarette sales among states. These data suggest the possibility of differences in implementation of FDA inspections and the need for stronger quality monitoring processes across states implementing FDA inspections. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Analysis of lomustine drug content in FDA-approved and compounded lomustine capsules.

    PubMed

    KuKanich, Butch; Warner, Matt; Hahn, Kevin

    2017-02-01

    OBJECTIVE To determine the lomustine content (potency) in compounded and FDA-approved lomustine capsules. DESIGN Evaluation study. SAMPLE 2 formulations of lomustine capsules (low dose [7 to 11 mg] and high dose [40 to 48 mg]; 5 capsules/dose/source) from 3 compounders and from 1 manufacturer of FDA-approved capsules. PROCEDURES Lomustine content was measured by use of a validated high-pressure liquid chromatography method. An a priori acceptable range of 90% to 110% of the stated lomustine content was selected on the basis of US Pharmacopeia guidelines. RESULTS The measured amount of lomustine in all compounded capsules was less than the stated content (range, 59% to 95%) and was frequently outside the acceptable range (failure rate, 2/5 to 5/5). Coefficients of variation for lomustine content ranged from 4.1% to 16.7% for compounded low-dose capsules and from 1.1% to 10.8% for compounded high-dose capsules. The measured amount of lomustine in all FDA-approved capsules was slightly above the stated content (range, 104% to 110%) and consistently within the acceptable range. Coefficients of variation for lomustine content were 0.5% for low-dose and 2.3% for high-dose FDA-approved capsules. CONCLUSIONS AND CLINICAL RELEVANCE Compounded lomustine frequently did not contain the stated content of active drug and had a wider range of lomustine content variability than did the FDA-approved product. The sample size was small, and larger studies are needed to confirm these findings; however, we recommend that compounded veterinary formulations of lomustine not be used when appropriate doses can be achieved with FDA-approved capsules or combinations of FDA-approved capsules.

  12. Amendment to examination and investigation sample requirements--FDA. Direct final rule.

    PubMed

    1998-09-25

    The Food and Drug Administration (FDA) is amending its regulations regarding the collection of twice the quantity of food, drug, or cosmetic estimated to be sufficient for analysis. This action increases the dollar amount that FDA will consider to determine whether to routinely collect a reserve sample of a food, drug, or cosmetic product in addition to the quantity sufficient for analysis. Experience has demonstrated that the current dollar amount does not adequately cover the cost of most quantities sufficient for analysis plus reserve samples. This direct final rule is part of FDA's continuing effort to achieve the objectives of the President's "Reinventing Government" initiative, and is intended to reduce the burden of unnecessary regulations on food, drugs, and cosmetics without diminishing the protection of the public health. Elsewhere in this issue of the Federal Register, FDA is publishing a companion proposed rule under FDA's usual procedures for notice and comment to provide a procedural framework to finalize the rule in the event the agency receives any significant adverse comment and withdraws this direct final rule.

  13. Time series analyses of the effect of FDA communications on use of prescription weight loss medications.

    PubMed

    Block, Jason P; Choudhry, Niteesh K; Carpenter, Daniel P; Fischer, Michael A; Brennan, Troyen A; Tong, Angela Y; Matlin, Olga S; Shrank, William H

    2014-03-01

    To determine the impact of FDA safety communications regarding the weight loss medications sibutramine and orlistat. The 2008 to 2011 pharmacy claims data from CVS Caremark were used to determine the effect of the relevant FDA warnings on (1) use of sibutramine and orlistat, (2) their rates of discontinuation, and (3) substitution to an alternate weight loss medication in the 3-month period following discontinuation. The use of sibutramine, orlistat, or phentermine declined from 45 users per 100,000 Caremark enrollees in May 2008 to 24 users per 100,000 enrollees in December 2010. In the time series analyses of overall use of medications, a very small decline in the trend of use of sibutramine after the FDA communication (0.000002% per month decline after the communication; P < 0.001) was found. However, rates of discontinuation of sibutramine and orlistat were similar before and after relevant FDA communications (all P values >0.1 for both level and trend changes post-warning). Patients discontinuing sibutramine post-communication increased use of phentermine at a rate of 0.004% per month after discontinuation (P = 0.01). From 2008 to 2010, use of prescription weight loss medications was low and declined over time. FDA communications regarding the safety of these medications had limited effect on use. Copyright © 2013 The Obesity Society.

  14. Evidence behind FDA alerts for drugs with adverse cardiovascular effects: implications for clinical practice.

    PubMed

    Rackham, Daniel M; C Herink, Megan; Stevens, Ian G; Cardoza, Natalie M; Singh, Harleen

    2014-01-01

    The U.S. Food and Drug Administration (FDA) periodically publishes Drug Safety Communications and Drug Alerts notifying health care practitioners and the general public of important information regarding drug therapies following FDA approval. These alerts can result in both positive and negative effects on patient care. Most clinical trials are not designed to detect long-term safety end points, and postmarketing surveillance along with patient reported events are often instrumental in signaling the potential harmful effect of a drug. Recently, many cardiovascular (CV) safety announcements have been released for FDA-approved drugs. Because a premature warning could discourage a much needed treatment or prompt a sudden discontinuation, it is essential to evaluate the evidence supporting these FDA alerts to provide effective patient care and to avoid unwarranted changes in therapy. Conversely, paying attention to these warnings in cases involving high-risk patients can prevent adverse effects and litigation. This article reviews the evidence behind recent FDA alerts for drugs with adverse CV effects and discusses the clinical practice implications.

  15. Ensuring the safe and effective FDA regulation of fecal microbiota transplantation

    PubMed Central

    Sachs, Rachel E.; Edelstein, Carolyn A.

    2015-01-01

    Scientists, policymakers, and medical professionals alike have become increasingly worried about the rise of antibiotic resistance, and the growing number of infections due to bacteria like Clostridium difficile, which cause a significant number of deaths and are imposing increasing costs on our health care system. However, in the last few years, fecal microbiota transplantation (FMT), the transplantation of stool from a healthy donor into the bowel of a patient, has emerged as a startlingly effective means to treat recurrent C. difficile infections. At present, the FDA is proposing to regulate FMT as a biologic drug. However, this proposed classification is both underregulatory and overregulatory. The FDA's primary goal is to ensure that patients have access to safe, effective treatments—and as such they should regulate some aspects of FMT more stringently than they propose to, and others less so. This essay will examine the nature of the regulatory challenges the FDA will face in deciding to regulate FMT as a biologic drug, and will then evaluate available policy alternatives for the FDA to pursue, ultimately concluding that the FDA ought to consider adopting a hybrid regulatory model as it has done in the case of cord blood. PMID:27774199

  16. Credible deterrence: FDA and the Park Doctrine in the 21st century.

    PubMed

    O'Leary, Patrick

    2013-01-01

    One of FDA's most powerful enforcement tools is strict liability criminal prosecution of corporate officers under the Park Doctrine. Recent comments by high-ranking FDA officials about using this power more aggressively and recent cases apparently making good on this promise have spurred commentators to call for the doctrine's demise. Critics argue that strict liability for corporate officers violates fundamental notions of fairness and the appropriate relationship between guilt and liability in criminal law. As a response to these critics, this article argues that the Park Doctrine continues to serve a valuable purpose in deterring conduct that endangers the public health and that structural, political, and practical limitations on FDA's use of Park prosecutions have been, and will continue to be, effective protections against the abuses critics fear. This article proposes a model for understanding why and how FDA uses its prosecutorial powers and assesses a sample of recent high-profile prosecutions under this model to argue that the modern "escalation" of Park prosecutions is in fact a continuation of FDA's historical policy.

  17. FDA's health claim review: whey-protein partially hydrolyzed infant formula and atopic dermatitis.

    PubMed

    Chung, Carolyn S; Yamini, Sedigheh; Trumbo, Paula R

    2012-08-01

    In this review, we explain how the US Food and Drug Administration (FDA) used its evidence-based review system to evaluate the scientific evidence for a qualified health claim for 100% whey-protein partially hydrolyzed infant formula (W-PHF) and reduced risk of atopic dermatitis (AD). The labeling of health claims, including qualified health claims, on conventional foods and dietary supplements require premarket approval by the FDA. Health claims characterize the relationship between a substance (food or food component) and disease (eg, cancer or cardiovascular disease) or health-related condition (eg, hypertension). To determine whether sufficient evidence exists to support the qualified health claim, the FDA evaluated human intervention studies that evaluated the role of W-PHF in reducing the risk of AD. The FDA concluded there is little to very little evidence, respectively, to support a qualified health claim concerning the relationship between intake of W-PHF and a reduced risk of AD in partially breastfed and exclusively formula-fed infants throughout the first year after birth and up to 3 years of age. In addition, the FDA required a warning statement be displayed along with the health claim to indicate to consumers that partially hydrolyzed infant formulas are not hypoallergenic and should not be fed to infants who are allergic to milk or to infants with existing milk allergy symptoms.

  18. Right to experimental treatment: FDA new drug approval, constitutional rights, and the public's health.

    PubMed

    Leonard, Elizabeth Weeks

    2009-01-01

    On May 2, 2006, a divided panel of the U.S. Court of Appeals for the District of Columbia, in a startling opinion, Abigail Alliance for Better Access to Developmental Drugs v. Eschenbach, held that terminally ill patients who have exhausted all other available options have a constitutional right to experimental treatment that FDA has not yet approved. Although ultimately overturned by the full court, Abigail Alliance generated considerable interest from various constituencies. Meanwhile, FDA proposed similar regulatory amendments, as have lawmakers on both sides of the aisle in Congress. But proponents of expanded access fail to consider public health and consumer safety concerns. In particular, allowing patients to try unproven treatments, outside of controlled clinical trials risks both the study's outcome and the health of patients who might benefit from the deliberate, careful process of new drug approval as it currently operates under FDA's auspices.

  19. FDA approval of comparative claims for prescription drugs--the Moxam case.

    PubMed

    Marcus, D

    1983-01-01

    FDA allowance of comparative claims as part of the approved labeling for new prescription drugs creates special problems. Claims contained in prescription drug labeling are viewed by physicians as embodying not just the normal puffery of the manufacturer, but the considered views of government agency charged with protecting public health. Thus, labeling claims for prescription drugs have an impact and significance that promotional claims for other products do not. In the Moxam case--a dispute between Upjohn and Lilly over the FDA's approval of a comparative claim for a new Lilly antibiotic--the agency recognized this fundamental reality. Faced with the prospect of having to provide a procedure to permit competitors to challenge approval of comparative claims, the FDA has moved toward a policy of not permitting such claims in labeling, while allowing them in advertising.

  20. Medical devices; exemption from premarket notification and reserved devices; Class I--FDA. Proposed rule.

    PubMed

    1998-11-12

    The Food and Drug Administration (FDA) is proposing to amend its classification regulations to designate class I devices that are exempt from the premarket notification requirements, subject to certain limitations, and to designate those class I devices that remain subject to premarket notification requirements under the new statutory criteria for premarket notification requirements. The devices FDA is proposing to designate as exempt do not include class I devices that have been previously exempted by regulation from the premarket notification requirements. This action is being taken under the Federal Food, Drug, and Cosmetic Act (the act), as amended by the Medical Device Amendments of 1976 (the 1976 amendments), the Safe Medical Devices Act of 1990 (SMDA), and the Food and Drug Administration Modernization Act of 1997 (FDAMA). FDA is taking this action in order to implement a requirement of FDAMA.

  1. Ancestry-based pharmacogenomics, adverse reactions and carbamazepine: is the FDA warning correct?

    PubMed

    Payne, P W

    2014-10-01

    In an effort to prevent potentially fatal adverse reactions to carbamazepine, the US Food and Drug Administration (FDA) issued an alert in 2007 containing pharmacogenomic information, which is still in effect today. The alert states that carbamazepine-induced skin reactions are significantly more common in patients with the human leukocyte antigen (HLA)-B*1502 allele and that these people are almost exclusively from 'broad areas of Asia, including South Asian Indians.' This study reviews the medical evidence relied upon by the FDA and finds that the alert does not accurately reflect the medical evidence relied upon in 2007 or evidence that has been generated over the last 5 years since the label was created. The FDA drug labeling should be modified to reflect current medical evidence.

  2. FDA designations for therapeutics and their impact on drug development and regulatory review outcomes.

    PubMed

    Kesselheim, A S; Darrow, J J

    2015-01-01

    New prescription drugs receive approval from the US Food and Drug Administration (FDA) based on tests establishing safety and adequate and well-controlled trials demonstrating "substantial evidence" of efficacy. However, a number of legislative and regulatory initiatives, the most recent being the breakthrough therapy designation created in 2012, give the FDA flexibility to approve drugs on the basis of less rigorous data in situations of greater clinical need. These expedited development and review pathways now contribute to a majority of all new drug approvals and have important benefits in encouraging efficient availability of transformative drugs. They also have a number of risks, including a heightened possibility that the drugs will be discovered to be ineffective or unsafe after widespread use, and confusion by patients and physicians over what it means for a product to be "FDA approved."

  3. Under the law, FDA must grant different standards for new dietary ingredients and food additives.

    PubMed

    Mister, Steven; Hathcock, John

    2012-04-01

    The FDA's draft Guidance on notifications for new dietary ingredients attempts to narrow the scope of "old" dietary ingredients that do not require notification to FDA and repeats some mistakes from the past by going beyond what is required or permitted by the Food, Drug & Cosmetic Act, as amended by the Dietary Supplements Health and Education Act of 1994. The draft Guidance attempts to apply the notification requirement to new supplements, not just new ingredients, and it expands the working definition of "chemically altered" to include many changes that were not foreseen in the Congressional Record in 1994. Through these misinterpretations, FDA attempts to impose a food additives-like safety standard, and gain de facto premarket approval against the overt wishes of Congress.

  4. A new micromethod for the in vitro detection of antiplatelet antibodies: C-FDA thrombocytotoxicity

    SciTech Connect

    Lizak, G.E.; Grumet, F.C.

    1980-07-01

    A new microtechnique, C-FDA, for the in vitro detection of antiplatelet antibodies, is described. This technique is faster and simpler than either 51Cr thrombocytotoxicity or immunofluorescence (IF). C-FDA is more sensitive than 51Cr for all (anti-HLA, --P1A1, ABO, drug-related, and ITP-related) antibodies tested. Although IF was more sensitive for many types of antibodies, C-FDA was as good or better a clinical test method for all drug-related and isoimmune neonatal thrombocytopenia patient sera tested. Preliminary data also suggest that this method detects possible new non-HLA, non-ABO, nonP1A1 platelet antigens.

  5. Price, performance, and the FDA approval process: the example of home HIV testing.

    PubMed

    Paltiel, A David; Pollack, Harold A

    2010-01-01

    The Food and Drug Administration (FDA) is considering approval of an over-the-counter, rapid HIV test for home use. To support its decision, the FDA seeks evidence of the test's performance. It has asked the manufacturer to conduct field studies of the test's sensitivity and specificity when employed by untrained users. In this article, the authors argue that additional information should be sought to evaluate the prevalence of undetected HIV in the end-user The analytic framework produces the elementary but counterintuitive finding that the performance of the home HIV test- measured in terms of its ability to correctly detect the presence and absence of HIV infection among the people who purchase it-depends critically on the manufacturer's retail price. This finding has profound implications for the FDA's approval process.

  6. US FDA's revised consumption factor for polystyrene used in food-contact applications.

    PubMed

    Cassidy, K; Elyashiv-Barad, S

    2007-09-01

    US FDA's continual effort to evaluate the safety of food-contact materials includes periodically re-examining our established packaging factors, such as consumption and food-type distribution factors. The use of polystyrene in food-contact and disposable food-packaging applications has expanded and is expected to continue to increase in the future. Therefore, it is important to revise the polystyrene consumption factor to account for increases in consumer exposure to substances migrating from styrenic food packaging. The currently used consumption factor for polystyrene is 0.1, which is based on market data collected around 1980. US FDA has revised the polystyrene consumption factor utilizing three different sources of market data. Using consumption and population data, US FDA calculated a new consumption factor of 0.14 for polystyrene. This consumption factor has been further subdivided to allow for the refinement of exposure estimates for uses limited to specific subcategories of polystyrene packaging.

  7. Prescribing of FDA-approved and compounded hormone therapy differs by specialty.

    PubMed

    Constantine, Ginger D; Archer, David F; Graham, Shelli; Bernick, Brian A; Mirkin, Sebastian

    2016-10-01

    To determine the prescribing patterns of general practitioners (GPs), obstetrician/gynecologists (OB/GYNs), and wellness physicians (WPs) of menopausal hormone therapy (HT) for both compounded (CHT) and Food and Drug Administration (FDA)-approved products, using a survey of US physicians. Nine thousand one US physicians were invited to participate in a survey to report on their HT-prescribing patterns. Physicians were eligible if they prescribed HT for at least six patients per month. The survey was completed by 440 eligible physicians (893 responded of 9,001 invited) including 171 GPs, 170 OB/GYNs, and 84 WPs. Physicians prescribed HT for 15% to 30% of their female patients, with WPs numerically most likely to prescribe HT. Menopausal symptoms were the leading reason for HT prescriptions among all specialties. WPs seemed more likely to prescribe HT for general/cardiovascular health (28%), and for shorter durations, than other specialties. WPs prescribed proportionally more compounded (vs FDA-approved) estrogens/progestogens than GPs or OB/GYNs, but OB/GYNs seemed to prescribe more compounded dehydroepiandrosterone and testosterone (prescribed alone) than did others. OB/GYNs seemed least likely to consider CHT being more safe or effective than FDA-approved HT. Symptom relief was the main determinant of efficacy for all specialties; WPs also used blood (61%) or saliva testing (25%) for dose adjustment. Although all physician specialties surveyed prescribed HT, differences in prescribing CHT versus FDA-approved formulations by medical specialty/practice seemed to exist. Of those surveyed, OB/GYNs and GPs prescribed proportionally more FDA-approved HT, whereas WPs, similarly, prescribed more CHT. More discussion is needed concerning physicians' decisions to prescribe CHT versus FDA-approved formulations.

  8. Prescribing of FDA-approved and compounded hormone therapy differs by specialty

    PubMed Central

    Constantine, Ginger D.; Archer, David F.; Graham, Shelli; Bernick, Brian A.; Mirkin, Sebastian

    2016-01-01

    Abstract Objective: To determine the prescribing patterns of general practitioners (GPs), obstetrician/gynecologists (OB/GYNs), and wellness physicians (WPs) of menopausal hormone therapy (HT) for both compounded (CHT) and Food and Drug Administration (FDA)-approved products, using a survey of US physicians. Methods: Nine thousand one US physicians were invited to participate in a survey to report on their HT-prescribing patterns. Physicians were eligible if they prescribed HT for at least six patients per month. Results: The survey was completed by 440 eligible physicians (893 responded of 9,001 invited) including 171 GPs, 170 OB/GYNs, and 84 WPs. Physicians prescribed HT for 15% to 30% of their female patients, with WPs numerically most likely to prescribe HT. Menopausal symptoms were the leading reason for HT prescriptions among all specialties. WPs seemed more likely to prescribe HT for general/cardiovascular health (28%), and for shorter durations, than other specialties. WPs prescribed proportionally more compounded (vs FDA-approved) estrogens/progestogens than GPs or OB/GYNs, but OB/GYNs seemed to prescribe more compounded dehydroepiandrosterone and testosterone (prescribed alone) than did others. OB/GYNs seemed least likely to consider CHT being more safe or effective than FDA-approved HT. Symptom relief was the main determinant of efficacy for all specialties; WPs also used blood (61%) or saliva testing (25%) for dose adjustment. Conclusions: Although all physician specialties surveyed prescribed HT, differences in prescribing CHT versus FDA-approved formulations by medical specialty/practice seemed to exist. Of those surveyed, OB/GYNs and GPs prescribed proportionally more FDA-approved HT, whereas WPs, similarly, prescribed more CHT. More discussion is needed concerning physicians’ decisions to prescribe CHT versus FDA-approved formulations. PMID:27648594

  9. Warnings without guidance: patient responses to an FDA warning about ezetimibe.

    PubMed

    Shrank, William H; Choudhry, Niteesh K; Tong, Angela; Myers, Jessica; Fischer, Michael A; Swanton, Kellie; Slezak, Julie; Brennan, Troyen A; Liberman, Joshua N; Moffit, Susan; Avorn, Jerry; Carpenter, Daniel

    2012-06-01

    In January 2008, the Food and Drug Administration (FDA) communicated concerns about the efficacy of ezetimibe, but did not provide clear clinical guidance, and substantial media attention ensued. We investigated the proportion of patients who discontinued therapy and switched to a clinically appropriate alternative after the FDA communication. Using claims data from a national pharmacy benefits manager, we created a rolling cohort of new users of ezetimibe between January 2006 and August 2008 and created a supply diary for each patient in the year after cohort entry. A patient was identified as nonpersistent if a gap of 90 days was seen in the diary. Using segmented linear regression, we compared rates of nonpersistence before and after the FDA communication and assessed patient-level characteristics associated with discontinuation. Among nonpersistent patients, we determined whether a patient made a clinically appropriate switch in the subsequent 90 days by adding a new cholesterol-lowering medication or by increasing the dose of an existing one. We used a weighted t test to compare the rates of appropriate switching before and after the communication. Among 867,027 new ezetimibe users, 407,006 (46.9%) were nonpersistent in the first year. After the FDA communication, the monthly level of ezetimibe nonpersistence increased by 5.7 percentage points (P<0.0001). Younger patients, those who lived in low-income zip codes, and female patients were less likely to discontinue therapy (P<0.0001 for all). Among nonpersistent patients, rates of clinically appropriate switching increased from 10.8% before to 16.5% after the FDA warning (P = 0.004). A substantial increase in ezetimibe nonpersistence rates was seen after an FDA communication regarding its efficacy and following associated media attention, and a small proportion of patients made a clinically appropriate switch after discontinuation. Further consideration is needed to deliver messages that promote appropriate use

  10. Considerations when submitting nanotherapeutics to FDA/CDER for regulatory review.

    PubMed

    Tyner, Katherine; Sadrieh, Nakissa

    2011-01-01

    The Food and Drug Administration (FDA) does not, as yet, have specific guidances for products containing nanoscale materials. As announced in the report issued by the FDA Nanotechnology Task Force (July 2007), however, there are recommendations to various centers within the FDA to develop guidances for industry. Regardless of the lack of explicit FDA guidances, there are therapeutics currently on the market containing nanoscale materials, and additional novel nanomaterial-containing therapeutics are being developed with the hopes of being submitted for regulatory review and approval. While, for the most part, these novel nanomaterial-containing products are being evaluated using the same regulatory requirements as products that do not contain nanomaterials, it is increasingly evident that at least in the area of characterization of nanomaterials used in drug products, there may be areas where special focus is needed. Specific areas include the validity of applying small molecule principles and methodologies to nanomaterial-containing products, the effects the nanomaterial will impart to the rest of the formulation (or vice versa), and how the physicochemical properties may be impacted by biological settings. Similarly, for safety evaluation, biodistribution studies will be at the core of any evaluation of products containing nanomaterials. These biodistribution studies will, in effect, be indicative of where the nanoparticles are traveling and possibly accumulating, therefore subjecting those sites to increased likelihood of toxicological effects. This chapter focuses on questions and considerations that may arise for sponsors during product characterization, as well as considerations for the appropriate design and conduct of in vivo toxicology studies. This chapter will also review how current FDA guidances apply to nanotherapeutics.This chapter reflects the current thinking and experience of the authors. However, this is not a policy document and should not be

  11. We really need to talk: adapting FDA processes to rapid change.

    PubMed

    Lykken, Sara

    2013-01-01

    The rapidly evolving realm of modern commerce strains traditional regulatory paradigms. This paper traces the historical evolution of FDA crisis-response regulation and provides examples of ways in which the definitions and procedures resulting from that past continue to be challenged by new products as market entrants, some in good faith and others not, take actions that create disconnects between actual product and marketing controls and those that consumers might expect. The paper then explores some of the techniques used by other federal agencies that have faced similar challenges in environments characterized by rapid innovation, and draws from this analysis suggestions for improvement of the FDA's warning letter system.

  12. FDA-Approved Anti-Obesity Drugs in the United States.

    PubMed

    Daneschvar, Homayoun L; Aronson, Mark D; Smetana, Gerald W

    2016-08-01

    Obesity is a growing health problem in our society and its treatment has been challenging. In recent decades, several anti-obesity drugs have been withdrawn from the market because of reported and documented adverse effects. After years of interruption, the US Food and Drug Administration (FDA) has recently approved multiple new anti-obesity drugs. The majority of these medications are taken orally, and only one is administered subcutaneously. In this article, we review the efficacy, adverse effects, and mechanism of action of all 5 FDA-approved drugs. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Nanotechnology Laboratory Continues Partnership with FDA and National Institute of Standards and Technology | Poster

    Cancer.gov

    The NCI-funded Nanotechnology Characterization Laboratory (NCL)—a leader in evaluating promising nanomedicines to fight cancer—recently renewed its collaboration with the U.S. Food and Drug Administration (FDA) and the National Institute of Standards and Technology (NIST) to continue its groundbreaking work on characterizing nanomedicines and moving them toward the clinic. In partnership with NIST and the FDA, NCL has laid a solid, scientific foundation for using the power of nanotechnology to increase the potency and target the delivery

  14. Exact Sciences' experience with the FDA and CMS parallel review program.

    PubMed

    Ridge, John R; Statz, Sandra

    2015-01-01

    Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death among men and women combined in the USA. Although the benefits of early CRC detection are widely recognized, screening rates are suboptimal. Cologuard is a multitarget stool DNA screening test that offers a unique non-invasive option for CRC screening. Cologuard was the first product to be reviewed under a pilot parallel review program jointly conducted by the US FDA and the Centers for Medicare & Medicaid Services (CMS). This parallel review process shortened the overall review for Cologuard and resulted in a preliminary National Coverage Determination that coincided with FDA approval.

  15. Nanotechnology Laboratory Continues Partnership with FDA and National Institute of Standards and Technology | Poster

    Cancer.gov

    The NCI-funded Nanotechnology Characterization Laboratory (NCL)—a leader in evaluating promising nanomedicines to fight cancer—recently renewed its collaboration with the U.S. Food and Drug Administration (FDA) and the National Institute of Standards and Technology (NIST) to continue its groundbreaking work on characterizing nanomedicines and moving them toward the clinic. In partnership with NIST and the FDA, NCL has laid a solid, scientific foundation for using the power of nanotechnology to increase the potency and target the delivery

  16. Discrepancies in the primary PLATO trial publication and the FDA reviews.

    PubMed

    Serebruany, Victor L

    2014-03-01

    The results of major indication seeking Phase 3 clinical trials are reported at international meetings, and simultaneously published In top medical journals. However, the data presented during such dual release do not disclose all the trial findings, suffer from overoptimistic interpretations heavily favoring the study sponsor. Ironically, after the New Drug Application is submitted for regulatory approval, and when the FDA secondary reviews become available for public, the benefit/risk assessment of a new drug is usually considered much less impressive. However, the community may ignore pivotal unreported findings later outlined in the government documents taking for granted the facts presented in the primary publication. The discrepancies between initial publication and the FDA files are not only confusing to the readership, but hold additional risks for patients. Indeed, if physicians are impressed with the initial interpretation of the trial, and do not have broad access to the FDA verified facts, chances are new agents will be prescribed based on exaggerated benefit and less safety concerns. The current pattern also hurts the reputation of the journal publishers, editors and reviewers challenging their trust and credibility. We here outline the disparity between the primary PLATO trial publication in the New England Journal of Medicine against the FDA verified numbers, and discuss how to avoid such mismatches in the future.

  17. 21 CFR 1271.3 - How does FDA define important terms in this part?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS General Provisions § 1271.3 How does FDA... use means the implantation, transplantation, infusion, or transfer of human cells or tissue back into the individual from whom the cells or tissue were recovered. (b) Establishment means a place...

  18. 21 CFR 1271.27 - Will FDA assign me a registration number?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Will FDA assign me a registration number? 1271.27 Section 1271.27 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION HUMAN...

  19. DMSO, Hobby Shops and the FDA: The Diffusion of a Health Policy Dilemma.

    ERIC Educational Resources Information Center

    Weinstock, Edward; Davis, Phillip

    1985-01-01

    Despite being banned by the FDA, DMSO (dimethyl sulfoxide) usage has spread rapidly among arthritic victims and weekend athletes. This study looked at current and past users to learn how they discovered DMSO, their reactions to buying an illegal drug, and possible implications for public health policy. (MT)

  20. 78 FR 19492 - Draft Guidance for Industry on Formal Meetings Between FDA and Biosimilar Biological Product...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-01

    ... Product Development. 7. Meeting Type Being Requested (i.e., Biosimilar Initial Advisory meeting, BPD Type... detail of the data should be appropriate to the meeting type requested and the product development stage... formal meetings between FDA and sponsors or applicants relating to the development and review...

  1. 75 FR 28622 - FDA Transparency Initiative: Draft Proposals for Public Comment Regarding Disclosure Policies of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-21

    ... of the second phase of the Transparency Initiative, the Food and Drug Administration (FDA) is... draft proposals may require extensive resources to implement, and some may require changes to... received over 1,500 comments. The Task Force is proceeding with the Transparency Initiative in three phases...

  2. ADVERSE PRE- AND POSTNATAL EVENTS REPORTED TO FDA IN ASSOCIATION WITH MATERNAL ATENOLOL TREATMENT IN PREGNANCY

    EPA Science Inventory

    Atenolol is a beta-adrenoreceptor blocker used for treatment of hypertension in pregnancy. This study evaluates the reporting frequency of adverse pre- and postnatal outcomes in a series of 70 cases of maternal exposure during gestation, derived from 140 reports to FDA with Ateno...

  3. 76 FR 38184 - Agency Information Collection Activities; Proposed Collection; Comment Request; FDA Recall...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-29

    ... remove or correct foods and drugs (human or animal), cosmetics, medical devices, biologics, and tobacco... HUMAN SERVICES Food and Drug Administration Agency Information Collection Activities; Proposed... techniques, when appropriate, and other forms of information technology. FDA Recall Regulations--21 CFR Part...

  4. Language and Nutrition (Mis)Information: Food Labels, FDA Policies and Meaning

    ERIC Educational Resources Information Center

    Taylor, Christy Marie

    2013-01-01

    In this dissertation, I address the ways in which food manufacturers can exploit the often vague and ambiguous nature of FDA policies concerning language and images used on food labels. Employing qualitative analysis methods (Strauss, 1987; Denzin and Lincoln, 2003; Mackey and Gass, 2005) that drew upon critical discourse analysis (Fairclough,…

  5. 21 CFR Appendix B to Part 101 - Graphic Enhancements Used by the FDA

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Graphic Enhancements Used by the FDA B Appendix B to Part 101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION FOOD LABELING Pt. 101, App. B Appendix B to Part...

  6. Impact of FDA Actions, DTCA, and Public Information on the Market for Pain Medication.

    PubMed

    Bradford, W David; Kleit, Andrew N

    2015-07-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most important classes of prescription drugs used by primary care physicians to manage pain. The NSAID class of products has a somewhat controversial history, around which a complex regulatory and informational environment has developed. This history includes a boxed warning mandated by the Food and Drug Administration (FDA) for all NSAIDs in 2005. We investigate the impact that various information shocks have had on the use of prescription medications for pain in primary care in the USA. We accomplish this by extracting data on nearly 600,000 patients from a unique nationwide electronic medical record database and estimate the probability of any active prescription for the four types of pain medications as a function of FDA actions, advertising, media coverage, and patient characteristics. We find that even after accounting for multiple sources of information, the FDA label changes and boxed warnings had a significant effect on pain medication prescribing. The boxed warning did not have the same impact on the use of all NSAID inhibitors. We find that the boxed warning reduced the use of NSAID COX-2 inhibitor use, which was the focus of much of the press attention. In contrast, however, the warning actually increased the use of non-COX-2 NSAID inhibitors. Thus, the efficacy of the FDA's black box warning is clearly mixed.

  7. 21 CFR 1271.3 - How does FDA define important terms in this part?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord... HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS General Provisions § 1271.3 How does FDA... use means the implantation, transplantation, infusion, or transfer of human cells or tissue back...

  8. 21 CFR 1271.3 - How does FDA define important terms in this part?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ..., dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord... HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS General Provisions § 1271.3 How does FDA... use means the implantation, transplantation, infusion, or transfer of human cells or tissue back...

  9. 21 CFR 1271.3 - How does FDA define important terms in this part?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ..., dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord... HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS General Provisions § 1271.3 How does FDA... use means the implantation, transplantation, infusion, or transfer of human cells or tissue back...

  10. 21 CFR 1271.3 - How does FDA define important terms in this part?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord... HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS General Provisions § 1271.3 How does FDA... use means the implantation, transplantation, infusion, or transfer of human cells or tissue back...

  11. 21 CFR 14.171 - Utilization of an advisory committee on the initiative of FDA.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Utilization of an advisory committee on the... Human Prescription Drugs § 14.171 Utilization of an advisory committee on the initiative of FDA. (a) Any... pose significant safety hazards, or which present narrow benefit-risk considerations requiring a...

  12. 21 CFR 14.171 - Utilization of an advisory committee on the initiative of FDA.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Utilization of an advisory committee on the... Human Prescription Drugs § 14.171 Utilization of an advisory committee on the initiative of FDA. (a) Any... pose significant safety hazards, or which present narrow benefit-risk considerations requiring a...

  13. 21 CFR 14.171 - Utilization of an advisory committee on the initiative of FDA.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Utilization of an advisory committee on the... Human Prescription Drugs § 14.171 Utilization of an advisory committee on the initiative of FDA. (a) Any... pose significant safety hazards, or which present narrow benefit-risk considerations requiring a...

  14. Language and Nutrition (Mis)Information: Food Labels, FDA Policies and Meaning

    ERIC Educational Resources Information Center

    Taylor, Christy Marie

    2013-01-01

    In this dissertation, I address the ways in which food manufacturers can exploit the often vague and ambiguous nature of FDA policies concerning language and images used on food labels. Employing qualitative analysis methods (Strauss, 1987; Denzin and Lincoln, 2003; Mackey and Gass, 2005) that drew upon critical discourse analysis (Fairclough,…

  15. 21 CFR 830.100 - FDA accreditation of an issuing agency.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false FDA accreditation of an issuing agency. 830.100 Section 830.100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... according to a single set of consistent, fair, and reasonable terms and conditions. (5) Will protect...

  16. 21 CFR 1.393 - What information must FDA include in the detention order?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...; (7) The address and location where the article of food is to be detained and the appropriate storage... 21 Food and Drugs 1 2014-04-01 2014-04-01 false What information must FDA include in the detention order? 1.393 Section 1.393 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  17. 21 CFR 1.393 - What information must FDA include in the detention order?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...; (7) The address and location where the article of food is to be detained and the appropriate storage... 21 Food and Drugs 1 2012-04-01 2012-04-01 false What information must FDA include in the detention order? 1.393 Section 1.393 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  18. DMSO, Hobby Shops and the FDA: The Diffusion of a Health Policy Dilemma.

    ERIC Educational Resources Information Center

    Weinstock, Edward; Davis, Phillip

    1985-01-01

    Despite being banned by the FDA, DMSO (dimethyl sulfoxide) usage has spread rapidly among arthritic victims and weekend athletes. This study looked at current and past users to learn how they discovered DMSO, their reactions to buying an illegal drug, and possible implications for public health policy. (MT)

  19. Summaries of Safety Labeling Changes Approved by the FDA: Boxed Warnings Highlights July-September 2016.

    PubMed

    Rubio, Teresa

    2016-12-01

    The FDA's MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. Search of Drug Safety Labeling Changes (SLC) database was conducted on October 10, 2016 for date range "7/1/2016-9/30/2016", labeling section "Boxed Warning". These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. (Drug Safety Labeling Changes are available at: http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/?source=govdelivery&utm_medium=email&utm_source=govdelivery.) Boxed warnings are ordinarily used to highlight either: adverse reactions so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using the drug; OR serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; OR FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

  20. The rosiglitazone decision process at FDA and EMA. What should we learn?

    PubMed

    Pouwels, Koen B; van Grootheest, Kees

    2012-01-01

    In September 2010 the EMA decided to suspend the market authorisation of rosiglitazone, while the FDA decided to restrict the use of rosiglitazone. These actions were taken approximately 10 years after the introduction of rosiglitazone, because rosiglitazone might be associated with an increased risk of ischemic heart disease. It is often stated that the first signs of an increased risk of ischemic heart disease were noticed in 2004, however already in 2001 the FDA concluded, based on data available to the EMA at the time of initial approval, that rosiglitazone should not be used in combination with insulin, because this combination therapy was associated with an increased risk of cardiac failure and ischemic heart disease. Remarkably, in 2007, when the evidence against this combination therapy had increased, the EMA made a decision that encouraged the use of insulin in combination with rosiglitazone, while the FDA tried to restrict this combination therapy. Despite the publication of several studies, including a large randomized controlled study, the cardiovascular risk of rosiglitazone still has not been definitively established. The weight given to the benefits and the risks seems mainly a subjective decision. To prevent new cases like rosiglitazone, more attention should be given to evaluation of study protocols of safety trials prior to their starts. This paper gives a critical overview of the decision making process at the FDA and the EMA on the basis of public available information.

  1. Computational Cell Cycle Profiling of Cancer Cells for Prioritizing FDA-Approved Drugs with Repurposing Potential.

    PubMed

    Lo, Yu-Chen; Senese, Silvia; France, Bryan; Gholkar, Ankur A; Damoiseaux, Robert; Torres, Jorge Z

    2017-09-12

    Discovery of first-in-class medicines for treating cancer is limited by concerns with their toxicity and safety profiles, while repurposing known drugs for new anticancer indications has become a viable alternative. Here, we have developed a new approach that utilizes cell cycle arresting patterns as unique molecular signatures for prioritizing FDA-approved drugs with repurposing potential. As proof-of-principle, we conducted large-scale cell cycle profiling of 884 FDA-approved drugs. Using cell cycle indexes that measure changes in cell cycle profile patterns upon chemical perturbation, we identified 36 compounds that inhibited cancer cell viability including 6 compounds that were previously undescribed. Further cell cycle fingerprint analysis and 3D chemical structural similarity clustering identified unexpected FDA-approved drugs that induced DNA damage, including clinically relevant microtubule destabilizers, which was confirmed experimentally via cell-based assays. Our study shows that computational cell cycle profiling can be used as an approach for prioritizing FDA-approved drugs with repurposing potential, which could aid the development of cancer therapeutics.

  2. FDA Accelerates Testing and Review of Experimental Brain Cancer Drug | FNLCR Staging

    Cancer.gov

    An investigational brain cancer drug made with disabled polio virus and manufactured at the Frederick National Lab has won breakthrough status from the Food and Drug Administration (FDA) to fast-track its further refinement and clinical testing.  Br

  3. FDA Accelerates Testing and Review of Experimental Brain Cancer Drug | FNLCR

    Cancer.gov

    An investigational brain cancer drug made with disabled polio virus and manufactured at the Frederick National Lab has won breakthrough status from the Food and Drug Administration (FDA) to fast-track its further refinement and clinical testing.  Br

  4. FDA Approves Immunotherapy for a Cancer that Affects Infants and Children | FNLCR

    Cancer.gov

    The U.S. Food and Drug Administration (FDA) has approved dinutuximab (ch14.18) as an immunotherapy for neuroblastoma, a rare type of childhood cancer that offers poor prognosis for about half of the children who are affected.  The National Cancer In

  5. FDA Approves Immunotherapy for a Cancer that Affects Infants and Children | FNLCR Staging

    Cancer.gov

    The U.S. Food and Drug Administration (FDA) has approved dinutuximab (ch14.18) as an immunotherapy for neuroblastoma, a rare type of childhood cancer that offers poor prognosis for about half of the children who are affected.  The National Cancer In

  6. Applying the FDA definition of whole grains to the evidence for cardiovascular disease health claims.

    PubMed

    De Moura, Fabiana F; Lewis, Kara D; Falk, Michael C

    2009-11-01

    The U.S. FDA defines whole grains as consisting of the intact, ground, cracked, or flaked fruit of the grains whose principal components, the starchy endosperm, germ, and bran, are present in the same relative proportions as they exist in the intact grain. We evaluated the effect of applying the FDA definition of whole grains to the strength of scientific evidence in support of claims for risk reduction of cardiovascular disease (CVD). We concluded that using the FDA definition for whole grains as a selection criterion is limiting, because the majority of existing studies often use a broader meaning to define whole grains. When considering only whole grain studies that met the FDA definition, we found insufficient scientific evidence to support a claim that whole grain intake reduces the risk of CVD. However, a whole grain and reduced risk of CVD health claim is supported when using a broader concept of whole grain to include studies that considered intake of fiber-rich bran and germ as well as whole grain. This type of analysis is complicated by diversity in nutrients and bioactive components among different types of whole grains.

  7. Current perspectives on the US FDA regulatory framework for intelligent drug-delivery systems.

    PubMed

    Sapsford, Kim E; Lauritsen, Kristina; Tyner, Katherine M

    2012-12-01

    The US FDA is the US agency responsible for regulating intelligent drug-delivery systems (IDDS). IDDS can be classified as a device, drug, biologic or combination product. In this perspective, the current regulatory framework for IDDS and future perspectives on how the field is expected to evolve from a regulatory standpoint is discussed.

  8. 21 CFR 1.405 - When does FDA have to issue a decision on an appeal?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... confirming or revoking the detention by noon on the fifth calendar day after the appeal is filed; after your... final decision within the 5-calendar day period after the appeal is filed. If FDA either fails to... detention order within the 5-calendar day period, the detention order is deemed terminated. (b) If...

  9. Advancing Product Quality: a Summary of the Inaugural FDA/PQRI Conference.

    PubMed

    Yu, Lawrence X; Baker, Jeffrey; Berlam, Susan C; Boam, Ashley; Brandreth, E J; Buhse, Lucinda; Cosgrove, Thomas; Doleski, David; Ensor, Lynne; Famulare, Joseph; Ganapathy, Mohan; Grampp, Gustavo; Hussong, David; Iser, Robert; Johnston, Gordon; Kesisoglou, Filippos; Khan, Mansoor; Kozlowski, Steven; Lacana, Emanuela; Lee, Sau L; Miller, Stephen; Miksinski, Sarah Pope; Moore, Christine M V; Mullin, Theresa; Raju, G K; Raw, Andre; Rosencrance, Susan; Rosolowsky, Mark; Stinavage, Paul; Thomas, Hayden; Wesdyk, Russell; Windisch, Joerg; Vaithiyalingam, Sivakumar

    2015-07-01

    On September 16 and 17, 2014, the Food and Drug Administration (FDA) and Product Quality Research Institute (PQRI) inaugurated their Conference on Evolving Product Quality. The Conference is conceived as an annual forum in which scientists from regulatory agencies, industry, and academia may exchange viewpoints and work together to advance pharmaceutical quality. This Conference Summary Report highlights key topics of this conference, including (1) risk-based approaches to pharmaceutical development, manufacturing, regulatory assessment, and post-approval changes; (2) FDA-proposed quality metrics for products, facilities, and quality management systems; (3) performance-based quality assessment and clinically relevant specifications; (4) recent developments and implementation of continuous manufacturing processes, question-based review, and European Medicines Agency (EMA)-FDA pilot for Quality-by-Design (QbD) applications; and (5) breakthrough therapies, biosimilars, and international harmonization, focusing on ICH M7 and Q3D guidelines. The second FDA/PQRI conference on advancing product quality is planned for October 5-7, 2015.

  10. 21 CFR 1.405 - When does FDA have to issue a decision on an appeal?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... on an appeal? (a) The presiding officer must issue a written report that includes a proposed decision... final decision within the 5-calendar day period after the appeal is filed. If FDA either fails to provide you with an opportunity to request an informal hearing, or fails to confirm or terminate the...

  11. Assuring safety of inherently unsafe medications: the FDA risk evaluation and mitigation strategies.

    PubMed

    Nelson, Lewis S; Loh, Meredith; Perrone, Jeanmarie

    2014-06-01

    The decision to approve a drug for clinical use is based on an understanding of its benefits versus the risks. Although efficacy is generally understood at the time of submission to the FDA for approval, the risks are more difficult to assess. Both PubMed (from 2000 to 2012) and the FDA website (www.fda.gov) were searched using the search terms "risk evaluation and mitigation strategy" (REMS). Articles for review were selected by relevance to topic, and their references were searched as well for additional relevant resources. Since the search results were not expected to contain research studies, formal quality assessment and inclusion and exclusion criteria were not utilized resulting in a narrative review. Few directly relevant research studies exist, although supporting documents such as government reports were available. For effective drugs with unclear or concerning safety records, the FDA has the option of requiring a risk evaluation and mitigation strategy, which allows a systematic approach to track and assure safe medication use. Over 100 different medications are currently covered by REMS, and each REMS is developed individually based on the needs of the specific drug or class. Although likely associated with improvements in medication safety, the potential benefit, limitations, and consequences of REMS are not yet fully understood.

  12. Evaluation of hepatic impairment dosing recommendations in FDA-approved product labels.

    PubMed

    Chang, Yang; Burckart, Gilbert J; Lesko, Lawrence J; Dowling, Thomas C

    2013-09-01

    Pharmacokinetic (PK) studies in patients with liver disease are an important clinical pharmacology component of drug development. In 2003, FDA released the guidance for industry on "Pharmacokinetics in Patients with Impaired Hepatic Function," which provides recommendations to sponsors on study design, data analysis, and impact on dosing and labeling. We evaluated the quality and consistency of hepatic dosing recommendations, and compared contemporary clinical practice of dosing in patients with impaired hepatic function with product labels. All new molecular entities (NME) and labels approved by the FDA during the period of January 2004 to December 2011 were reviewed. The fraction of the dose hepatically eliminated, quality of hepatic impairment PK studies reported, and any dose recommendations provided in the label and in a tertiary clinical reference (Micromedex) were reviewed. Out of 157 NMEs, 67 met the criteria for evaluation of dosing in hepatic disease. Problem areas were identified related to the lack of specific hepatic metabolism information in 90% of FDA-approved labels, inconsistent terminology, and "use with caution in liver disease" in 27% of NME. Updating the FDA guidance on PK studies in patients with impaired hepatic function could provide a standardized approach to improve the clinical usefulness of this dosing information for practitioners.

  13. 21 CFR 1.378 - What criteria does FDA use to order a detention?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ....378 Section 1.378 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... employee of FDA may order the detention of any article of food that is found during an inspection... the article of food is adulterated or misbranded....

  14. 21 CFR 14.15 - Committees working under a contract with FDA.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... means. It is in any event to be filed with the Division of Dockets Management not less than 15 days... open session. After approval, the minutes are to be forwarded to the Division of Dockets Management and... involved is to apply the principles relating to conflicts of interest that FDA uses in establishing...

  15. Existing FDA pathways have potential to ensure early access to, and appropriate use of, specialty drugs.

    PubMed

    Kesselheim, Aaron S; Tan, Yongtian Tina; Darrow, Jonathan J; Avorn, Jerry

    2014-10-01

    Specialty drugs are notable among prescription drugs in that they offer the possibility of substantial clinical improvement, come with important risks of adverse events and mortality, can be complex to manufacture or administer, and are usually extremely costly. The Food and Drug Administration (FDA) plays a critical role in ensuring that patients who could benefit from specialty drugs have access to them in a timely fashion. In this article we review the different strategies that the FDA can use to approve and influence the post-approval prescribing of specialty drugs. When specialty drugs show promise in early clinical trials, the FDA can expedite the drugs' availability to patients through expanded access programs and expedited approval pathways that speed regulatory authorization. After approval, to ensure that specialty drugs are directed to the patients who are most likely to benefit from them, the FDA can limit the scope of the drugs' indications, encourage the development of companion diagnostic tests to indicate which patients should receive the drugs, or require that manufacturers subject them to Risk Evaluation and Mitigation Strategies to ensure that their use is appropriately limited to a restricted population that is aware of the drugs' risks and benefits. Implementing these existing regulatory approaches can promote timely patient access to specialty drugs while preventing expensive and potentially inappropriate overuse.

  16. MSC-based product characterization for clinical trials: an FDA perspective.

    PubMed

    Mendicino, Michael; Bailey, Alexander M; Wonnacott, Keith; Puri, Raj K; Bauer, Steven R

    2014-02-06

    Proposals submitted to the FDA for MSC-based products are undergoing a rapid expansion that is characterized by increased variability in donor and tissue sources, manufacturing processes, proposed functional mechanisms, and characterization methods. Here we discuss the diversity in MSC-based clinical trial product proposals and highlight potential challenges for clinical translation.

  17. FDA Bioinformatics Tool for Microbial Genomics Research on Molecular Characterization of Bacterial Foodborne Pathogens Using Microarrays

    USDA-ARS?s Scientific Manuscript database

    Background: Advances in microbial genomics and bioinformatics are offering greater insights into the emergence and spread of foodborne pathogens in outbreak scenarios. The Food and Drug Administration (FDA) has developed the genomics tool ArrayTrackTM, which provides extensive functionalities to man...

  18. 21 CFR 111.610 - What records must be made available to FDA?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 2 2011-04-01 2011-04-01 false What records must be made available to FDA? 111.610 Section 111.610 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING...

  19. ADVERSE PRE- AND POSTNATAL EVENTS REPORTED TO FDA IN ASSOCIATION WITH MATERNAL ATENOLOL TREATMENT IN PREGNANCY

    EPA Science Inventory

    Atenolol is a beta-adrenoreceptor blocker used for treatment of hypertension in pregnancy. This study evaluates the reporting frequency of adverse pre- and postnatal outcomes in a series of 70 cases of maternal exposure during gestation, derived from 140 reports to FDA with Ateno...

  20. 21 CFR 807.100 - FDA action on a premarket notification.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... removed from the market at the initiative of the Commissioner of Food and Drugs or has not been determined... 21 Food and Drugs 8 2010-04-01 2010-04-01 false FDA action on a premarket notification. 807.100 Section 807.100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

  1. 21 CFR 807.100 - FDA action on a premarket notification.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... removed from the market at the initiative of the Commissioner of Food and Drugs or has not been determined... 21 Food and Drugs 8 2011-04-01 2011-04-01 false FDA action on a premarket notification. 807.100 Section 807.100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

  2. 21 CFR 111.610 - What records must be made available to FDA?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 2 2012-04-01 2012-04-01 false What records must be made available to FDA? 111.610 Section 111.610 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN..., PACKAGING, LABELING, OR HOLDING OPERATIONS FOR DIETARY SUPPLEMENTS Records and Recordkeeping § 111.610 What...

  3. 21 CFR 111.610 - What records must be made available to FDA?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 2 2013-04-01 2013-04-01 false What records must be made available to FDA? 111.610 Section 111.610 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN..., PACKAGING, LABELING, OR HOLDING OPERATIONS FOR DIETARY SUPPLEMENTS Records and Recordkeeping § 111.610 What...

  4. Extending FDA guidance to include consumer medication information (CMI) delivery on mobile devices.

    PubMed

    Sage, Adam; Blalock, Susan J; Carpenter, Delesha

    This paper describes the current state of consumer-focused mobile health application use and the current U.S. Food and Drug Administration (FDA) guidance on the distribution of consumer medication information (CMI), and discusses recommendations and considerations for the FDA to expand CMI guidance to include CMI in mobile applications. Smartphone-based health interventions have been linked to increased medication adherence and improved health outcomes. Trends in smartphone ownership present opportunities to more effectively communicate and disseminate medication information; however, current FDA guidance for CMI does not outline how to effectively communicate CMI on a mobile platform, particularly in regards to user-centered design and information sourcing. As evidence supporting the potential effectiveness of mobile communication in health care continues to increase, CMI developers, regulating entities, and researchers should take note. Although mobile-based CMI offers an innovative mechanism to deliver medication information, caution should be exercised. Specifically, considerations for developing mobile CMI include consumers' digital literacy, user experience (e.g., usability), and the quality and accuracy of new widely used sources of information (e.g., crowd-sourced reviews and ratings). Recommended changes to FDA guidance for CMI include altering the language about scientific accuracy to address more novel methods of information gathering (e.g., anecdotal experiences and Google Consumer Surveys) and including guidance for usability testing of mobile health applications. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Use of surrogate outcomes in US FDA drug approvals, 2003–2012: a survey

    PubMed Central

    Yu, Tsung; Hsu, Yea-Jen; Fain, Kevin M; Boyd, Cynthia M; Holbrook, Janet T; Puhan, Milo A

    2015-01-01

    Objective To evaluate, across a spectrum of diseases, how often surrogate outcomes are used as a basis for drug approvals by the US Food and Drug Administration (FDA), and whether and how the rationale for using treatment effects on surrogates as predictors of treatment effects on patient-centred outcomes is discussed. Study design and setting We used the Drugs@FDA website to identify drug approvals produced from 2003 to 2012 by the FDA. We focused on four diseases (chronic obstructive pulmonary disease (COPD), type 1 or 2 diabetes, glaucoma and osteoporosis) for which surrogates are commonly used in trials. We reviewed the drug labels and medical reviews to provide empirical evidence on how surrogate outcomes are handled by the FDA. Results Of 1043 approvals screened, 58 (6%) were for the four diseases of interest. Most drugs for COPD (7/9, 78%), diabetes (26/26, 100%) and glaucoma (9/9, 100%) were approved based on surrogates while for osteoporosis, most drugs (10/14, 71%) were also approved for patient-centred outcomes (fractures). The rationale for using surrogates was discussed in 11 of the 43 (26%) drug approvals based on surrogates. In these drug approvals, we found drug approvals for diabetes are more likely than the other examined conditions to contain a discussion of trial evidence demonstrating that treatment effects on surrogate outcomes predict treatment effects on patient-centred outcomes. Conclusions Our results suggest that the FDA did not use a consistent approach to address surrogates in assessing the benefits and harms of drugs for COPD, type 1 or 2 diabetes, glaucoma and osteoporosis. For evaluating new drugs, patient-centred outcomes should be chosen whenever possible. If the use of surrogate outcomes is necessary, then a consistent approach is important to review the evidence for surrogacy and consider surrogate's usage in the treatment and population under study. PMID:26614616

  6. Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome.

    PubMed

    Raynal, Noël J-M; Da Costa, Elodie M; Lee, Justin T; Gharibyan, Vazganush; Ahmed, Saira; Zhang, Hanghang; Sato, Takahiro; Malouf, Gabriel G; Issa, Jean-Pierre J

    2017-02-01

    Epigenetic drugs, such as DNA methylation inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi), are approved in monotherapy for cancer treatment. These drugs reprogram gene expression profiles, reactivate tumor suppressor genes (TSG) producing cancer cell differentiation and apoptosis. Epigenetic drugs have been shown to synergize with other epigenetic drugs or various anticancer drugs. To discover new molecular entities that enhance epigenetic therapy, we performed a high-throughput screening using FDA-approved libraries in combination with DNMTi or HDACi. As a screening model, we used YB5 system, a human colon cancer cell line, which contains an epigenetically silenced CMV-GFP locus, mimicking TSG silencing in cancer. CMV-GFP reactivation is triggered by DNMTi or HDACi and responds synergistically to DNMTi/HDACi combination, which phenocopies TSG reactivation upon epigenetic therapy. GFP fluorescence was used as a quantitative readout for epigenetic activity. We discovered that 45 FDA-approved drugs (4% of all drugs tested) in our FDA-approved libraries enhanced DNMTi and HDACi activity, mainly belonging to anticancer and antiarrhythmic drug classes. Transcriptome analysis revealed that combination of decitabine (DNMTi) with the antiarrhythmic proscillaridin A produced profound gene expression reprogramming, which was associated with downregulation of 153 epigenetic regulators, including two known oncogenes in colon cancer (SYMD3 and KDM8). Also, we identified about 85 FDA-approved drugs that antagonized DNMTi and HDACi activity through cytotoxic mechanisms, suggesting detrimental drug interactions for patients undergoing epigenetic therapy. Overall, our drug screening identified new combinations of epigenetic and FDA-approved drugs, which can be rapidly implemented into clinical trials. Mol Cancer Ther; 16(2); 397-407. ©2016 AACR.

  7. Physicians' Trust in the FDA's Use of Product-Specific Pathways for Generic Drug Approval.

    PubMed

    Kesselheim, Aaron S; Eddings, Wesley; Raj, Tara; Campbell, Eric G; Franklin, Jessica M; Ross, Kathryn M; Fulchino, Lisa A; Avorn, Jerry; Gagne, Joshua J

    2016-01-01

    Generic drugs are cost-effective versions of brand-name drugs approved by the Food and Drug Administration (FDA) following proof of pharmaceutical equivalence and bioequivalence. Generic drugs are widely prescribed by physicians, although there is disagreement over the clinical comparability of generic drugs to brand-name drugs within the physician community. The objective of this survey was to assess physicians' perceptions of generic drugs and the generic drug approval process. A survey was administered to a national sample of primary care internists and specialists between August 2014 and January 2015. In total, 1,152 physicians comprising of internists with no reported specialty certification and those with specialty certification in hematology, infectious diseases, and endocrinology were surveyed. The survey assessed physicians' perceptions of the FDA's generic drug approval process, as well as their experiences prescribing six generic drugs approved between 2008 and 2012 using product-specific approval pathways and selected comparator drugs. Among 718 respondents (62% response rate), a majority were comfortable with the FDA's process in ensuring the safety and effectiveness of generic drugs overall (91%) and with letting the FDA determine which tests were necessary to determine bioequivalence in a particular drug (92%). A minority (13-26%) still reported being uncomfortable prescribing generic drugs approved using product-specific pathways. Overall, few physicians heard reports of concerns about generic versions of the study drugs or their comparators, with no differences between the two groups. Physicians tended to hear about concerns about the safety or effectiveness of generic drugs from patients, pharmacists, and physician colleagues. Physicians hold largely positive views of the FDA's generic drug approval process even when some questioned the performance of certain generic drugs in comparison to brand-name drugs. Better education about the generic drug

  8. From bench to FDA to bedside: US regulatory trends for new stem cell therapies.

    PubMed

    Knoepfler, Paul S

    2015-03-01

    The phrase "bench-to-bedside" is commonly used to describe the translation of basic discoveries such as those on stem cells to the clinic for therapeutic use in human patients. However, there is a key intermediate step in between the bench and the bedside involving governmental regulatory oversight such as by the Food and Drug Administration (FDA) in the United States (US). Thus, it might be more accurate in most cases to describe the stem cell biological drug development process in this way: from bench to FDA to bedside. The intermediate development and regulatory stage for stem cell-based biological drugs is a multifactorial, continually evolving part of the process of developing a biological drug such as a stem cell-based regenerative medicine product. In some situations, stem cell-related products may not be classified as biological drugs in which case the FDA plays a relatively minor role. However, this middle stage is generally a major element of the process and is often colloquially referred to in an ominous way as "The Valley of Death". This moniker seems appropriate because it is at this point, and in particular in the work that ensues after Phase 1, clinical trials that most drug product development is terminated, often due to lack of funding, diseases being refractory to treatment, or regulatory issues. Not surprisingly, workarounds to deal with or entirely avoid this difficult stage of the process are evolving both inside and outside the domains of official regulatory authorities. In some cases these efforts involve the FDA invoking new mechanisms of accelerating the bench to beside process, but in other cases these new pathways bypass the FDA in part or entirely. Together these rapidly changing stem cell product development and regulatory pathways raise many scientific, ethical, and medical questions. These emerging trends and their potential consequences are reviewed here.

  9. From Bench to FDA to Bedside: US Regulatory Trends for New Stem Cell Therapies

    PubMed Central

    Knoepfler, Paul S.

    2015-01-01

    The phrase “bench to bedside” is commonly used to describe the translation of basic discoveries such as those on stem cells to the clinic for therapeutic use in human patients. However, there is a key intermediate step in between the bench and the bedside involving governmental regulatory oversight such as by the Food and Drug Administration (FDA) in the United States (US). Thus, it might be more accurate in most cases to describe the stem cell biological drug development process in this way: from bench to FDA to bedside. The intermediate development and regulatory stage for stem cell-based biological drugs is a multifactorial, continually evolving part of the process of developing a biological drug such as a stem cell-based regenerative medicine product. In some situations, stem cell-related products may not be classified as biological drugs in which case the FDA plays a relatively minor role. However, this middle stage is generally a major element of the process and is often colloquially referred to in an ominous way as “The Valley of Death”. This moniker seems appropriate because it is at this point and in particular in the work that ensues after Phase 1 clinical trials that most drug product development is terminated, often due to lack of funding, diseases being refractory to treatment, or regulatory issues. Not surprisingly, workarounds to deal with or entirely avoid this difficult stage of the process are evolving both inside and outside the domains of official regulatory authorities. In some cases these efforts involve the FDA invoking new mechanisms of accelerating the bench to beside process, but in other cases these new pathways bypass the FDA in part or entirely. Together these rapidly changing stem cell product development and regulatory pathways raise many scientific, ethical, and medical questions. These emerging trends and their potential consequences are reviewed here. PMID:25489841

  10. Addressing technical challenges associated with the FDA's proposed rules for the UVA in vitro testing procedure.

    PubMed

    Dueva-Koganov, Olga V; Rocafort, Colleen; Orofino, Steven; Osterwalder, Uli; Brito, Juan

    2009-01-01

    The proposed rules of the Food and Drug Administration (FDA) for the UVA in vitro testing procedure were applied to the evaluation of various sunscreen formulations and the following technical challenges were observed: when proposed roughened quartz substrates were used, the required coefficient-of-variation criteria were not met, and the dynamic ranges of the available transmittance analyzers were exceeded for sunscreens with high SPF values. In the proposed rules, the FDA requested comment regarding the suitability of other possible substrates. In this research, two modifications to the FDA's proposed rules were evaluated: (a) the use of an alternative substrate, Vitro Skin N-19 (IMS, Inc.) instead of roughened quartz substrate and (b) an increase in application time from 10 seconds to 30 seconds to ensure a uniform distribution of sunscreen product over the application area of the substrate. These two modifications allowed meeting the required coefficient-of-variation criteria without exceeding the dynamic ranges of the available transmittance analyzers. The modified test conditions were utilized for the evaluation of six commercial sunscreens, which fulfilled criteria of "medium" or "high" categories-based on their UVAI/UV ratios. These findings were in agreement with the statement in the proposed rules that the FDA is aware of the difficulty for current sunscreen formulations to meet the "highest" category and believes that allowing such a category will foster additional research and development in this area. To determine if it was possible to achieve a UVA rating greater than 0.95, two experimental sunscreen prototypes with bisoctrizole (USAN), bemotrizinol (USAN), avobenzone, and octocrylene were tested under the modified test conditions and attained the "highest" category. It should be noted that bisoctrizole and bemotrizinol are being evaluated by the FDA under TEA and are not permitted in the US at this time, but they are approved for use in the rest of

  11. Point-Counterpoint: The FDA Has a Role in Regulation of Laboratory-Developed Tests

    PubMed Central

    2016-01-01

    Since the Food and Drug Administration (FDA) released its draft guidance on the regulation of laboratory-developed tests (LDTs) in October 2014, there has been a flurry of responses from commercial and hospital-based laboratory directors, clinicians, professional organizations, and diagnostic companies. The FDA defines an LDT as an “in vitro diagnostic device that is intended for clinical use and is designed, manufactured, and used within a single laboratory.” The draft guidance outlines a risk-based approach, with oversight of high-risk and moderate-risk tests being phased in over 9 years. High-risk tests would be regulated first and require premarket approval. Subsequently, moderate-risk tests would require a 510(k) premarket submission to the FDA and low-risk tests would need only to be registered. Oversight discretion would be exercised for LDTs focused on rare diseases (defined as fewer than 4,000 tests, not cases, per year nationally) and unmet clinical needs (defined as those tests for which there is no alternative FDA-cleared or -approved test). There was an open comment period followed by a public hearing in early January of 2015, and we are currently awaiting the final decision regarding the regulation of LDTs. Given that LDTs have been developed by many laboratories and are essential for the diagnosis and monitoring of an array of infectious diseases, changes in their regulation will have far-reaching implications for clinical microbiology laboratories. In this Point-Counterpoint, Angela Caliendo discusses the potential benefits of the FDA guidance for LDTs whereas Kim Hanson discusses the concerns associated with implementing the guidance and why these regulations may not improve clinical care. PMID:26791369

  12. Point-Counterpoint: The FDA Has a Role in Regulation of Laboratory-Developed Tests.

    PubMed

    Caliendo, Angela M; Hanson, Kimberly E

    2016-04-01

    Since the Food and Drug Administration (FDA) released its draft guidance on the regulation of laboratory-developed tests (LDTs) in October 2014, there has been a flurry of responses from commercial and hospital-based laboratory directors, clinicians, professional organizations, and diagnostic companies. The FDA defines an LDT as an "in vitrodiagnostic device that is intended for clinical use and is designed, manufactured, and used within a single laboratory." The draft guidance outlines a risk-based approach, with oversight of high-risk and moderate-risk tests being phased in over 9 years. High-risk tests would be regulated first and require premarket approval. Subsequently, moderate-risk tests would require a 510(k) premarket submission to the FDA and low-risk tests would need only to be registered. Oversight discretion would be exercised for LDTs focused on rare diseases (defined as fewer than 4,000 tests, not cases, per year nationally) and unmet clinical needs (defined as those tests for which there is no alternative FDA-cleared or -approved test). There was an open comment period followed by a public hearing in early January of 2015, and we are currently awaiting the final decision regarding the regulation of LDTs. Given that LDTs have been developed by many laboratories and are essential for the diagnosis and monitoring of an array of infectious diseases, changes in their regulation will have far-reaching implications for clinical microbiology laboratories. In this Point-Counterpoint, Angela Caliendo discusses the potential benefits of the FDA guidance for LDTs whereas Kim Hanson discusses the concerns associated with implementing the guidance and why these regulations may not improve clinical care. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  13. FDA & digital mammography: why has FDA required full field digital mammography systems to be regulated as potentially dangerous devices for more than 10 years?

    PubMed

    Nields, Morgan W

    2010-05-01

    Digital mammography is routinely used in the US to screen asymptomatic women for breast cancer and currently over 50% of US screening centers employ the technology. In spite of FDAs knowledge that digital mammography requires less radiation than film mammography and that its equivalence has been proven in a prospective randomized trial, the agency has failed to allow the technology market access via the 510(k) pre market clearance pathway. As a result of the restrictive Pre Market Approval process, only four suppliers have received FDA approval. The resulting lack of a competitive market has kept costs high, restricted technological innovation, and impeded product improvements as a result of PMA requirements. Meanwhile, at least twelve companies are on the market in the EU and the resulting competitive market has lowered costs and provided increased technological choice. A cultural change with new leadership occurred in the early 90's at FDA. The historical culture at the Center for Devices and Radiological Health of collaboration and education gave way to one characterized by a lack of reliance on outside scientific expertise, tolerance of decision making by unqualified reviewers, and an emphasis on enforcement and punishment. Digital mammography fell victim to this cultural change and as a result major innovations like breast CT and computer aided detection technologies are also withheld from the market. The medical device law, currently under review by the Institute of Medicine, should be amended by the Congress so that new technologies can be appropriately classified in accordance with the risk based assessment classification system detailed in Chapter V of the Federal Food, Drug, and Cosmetic Act. A panel of scientific experts chartered by the NIH or IOM should determine the classification appropriate for new technologies that have no historical regulatory framework. This would be binding on FDA. Unless the law is changed we will likely again experience

  14. 21 CFR 170.105 - The Food and Drug Administration's (FDA's) determination that a premarket notification for a food...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... (CONTINUED) FOOD ADDITIVES Premarket Notifications § 170.105 The Food and Drug Administration's (FDA's... 21 Food and Drugs 3 2014-04-01 2014-04-01 false The Food and Drug Administration's (FDA's) determination that a premarket notification for a food contact substance (FCN) is no longer effective. 170.105...

  15. 78 FR 29141 - Center for Devices and Radiological Health Appeals Processes; Guidance for Industry and FDA Staff...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-17

    ... HUMAN SERVICES Food and Drug Administration Center for Devices and Radiological Health Appeals Processes; Guidance for Industry and FDA Staff; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of the guidance...

  16. OpenVigil FDA – Inspection of U.S. American Adverse Drug Events Pharmacovigilance Data and Novel Clinical Applications

    PubMed Central

    Böhm, Ruwen; von Hehn, Leocadie; Herdegen, Thomas; Klein, Hans-Joachim; Bruhn, Oliver; Petri, Holger; Höcker, Jan

    2016-01-01

    Pharmacovigilance contributes to health care. However, direct access to the underlying data for academic institutions and individual physicians or pharmacists is intricate, and easily employable analysis modes for everyday clinical situations are missing. This underlines the need for a tool to bring pharmacovigilance to the clinics. To address these issues, we have developed OpenVigil FDA, a novel web-based pharmacovigilance analysis tool which uses the openFDA online interface of the Food and Drug Administration (FDA) to access U.S. American and international pharmacovigilance data from the Adverse Event Reporting System (AERS). OpenVigil FDA provides disproportionality analyses to (i) identify the drug most likely evoking a new adverse event, (ii) compare two drugs concerning their safety profile, (iii) check arbitrary combinations of two drugs for unknown drug-drug interactions and (iv) enhance the relevance of results by identifying confounding factors and eliminating them using background correction. We present examples for these applications and discuss the promises and limits of pharmacovigilance, openFDA and OpenVigil FDA. OpenVigil FDA is the first public available tool to apply pharmacovigilance findings directly to real-life clinical problems. OpenVigil FDA does not require special licenses or statistical programs. PMID:27326858

  17. 21 CFR 1.383 - What expedited procedures apply when FDA initiates a seizure action against a detained perishable...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... a seizure action against a detained perishable food? 1.383 Section 1.383 Food and Drugs FOOD AND... procedures apply when FDA initiates a seizure action against a detained perishable food? If FDA initiates a seizure action under section 304(a) of the act against a perishable food subject to a detention order...

  18. 21 CFR 1.383 - What expedited procedures apply when FDA initiates a seizure action against a detained perishable...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... a seizure action against a detained perishable food? 1.383 Section 1.383 Food and Drugs FOOD AND... procedures apply when FDA initiates a seizure action against a detained perishable food? If FDA initiates a seizure action under section 304(a) of the act against a perishable food subject to a detention order...

  19. 21 CFR 1.383 - What expedited procedures apply when FDA initiates a seizure action against a detained perishable...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... a seizure action against a detained perishable food? 1.383 Section 1.383 Food and Drugs FOOD AND... procedures apply when FDA initiates a seizure action against a detained perishable food? If FDA initiates a seizure action under section 304(a) of the act against a perishable food subject to a detention order...

  20. 21 CFR 1.383 - What expedited procedures apply when FDA initiates a seizure action against a detained perishable...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... a seizure action against a detained perishable food? 1.383 Section 1.383 Food and Drugs FOOD AND... procedures apply when FDA initiates a seizure action against a detained perishable food? If FDA initiates a seizure action under section 304(a) of the act against a perishable food subject to a detention order...

  1. Top 100 bestselling drugs represent an arena struggling for new FDA approvals: drug age as an efficiency indicator.

    PubMed

    Polanski, Jaroslaw; Bogocz, Jacek; Tkocz, Aleksandra

    2015-11-01

    We analyzed a list of the top 100 bestselling drugs as a struggling market for new FDA approvals. Using the time from drug approval by the FDA as a measure of drug age, our analysis showed that the top 100 bestselling drugs are getting older. This reflects the stalled launch of new drugs into the market during recent years.

  2. Geographic Variation in Rosiglitazone Use Surrounding FDA Warnings in the Department of Veterans Affairs.

    PubMed

    Ahuja, Vishal; Sohn, Min-Woong; Birge, John R; Syverson, Chad; Budiman-Mak, Elly; Emanuele, Nicholas; Cooper, Jennifer M; Huang, Elbert S

    2015-12-01

    Geographic variation in the use of prescription drugs, particularly those deemed harmful by the FDA, may lead to variation in patient exposure to adverse drug events. One such drug is the glucose-lowering drug rosiglitazone, for which the FDA issued a safety alert on May 21, 2007, following the publication of a meta-analysis that suggested a 43% increase in the risk of myocardial infarction with the use of rosiglitazone. This alert was followed by a black box warning on August 14, 2007, that was updated 3 months later. While large declines have been documented in rosiglitazone use in clinical practice, little is known about how the use of rosiglitazone and other glucose-lowering drugs varied within the Department of Veterans Affairs (VA), surrounding the FDA alerts. Understanding this variation within integrated health care systems is essential to formulating policies that enhance patient protection and quality of care. To document variation in the use of rosiglitazone and other glucose- lowering drugs across 21 Veterans Integrated Service Networks (VISNs). We conducted a retrospective analysis of drug use patterns for all major diabetes drugs in a national cohort of 550,550 veterans with diabetes from 2003 to 2008. This included the time periods when rosiglitazone was added to (November 2003) and removed from (October 2007) the VA national formulary (VANF). We employed multivariable logistic regression models to statistically estimate the association between a patient's location and the patient's odds of using rosiglitazone. Aggregate rosiglitazone use increased monotonically from 7.7%, in the quarter it was added to the VANF (November 4, 2003), to a peak of 15.3% in the quarter when the FDA issued the safety alert. Rosiglitazone use decreased sharply afterwards, reaching 3.4% by the end of the study period (September 30, 2008). The use of pioglitazone, another glucose-lowering drug in the same class as rosiglitazone, was low when the FDA issued the safety alert

  3. Geographic Variation in Rosiglitazone Use Surrounding FDA Warnings in the Department of Veterans Affairs

    PubMed Central

    Ahuja, Vishal; Sohn, Min-Woong; Birge, John R.; Syverson, Chad; Budiman-Mak, Elly; Emanuele, Nicholas; Cooper, Jennifer M.; Huang, Elbert S.

    2016-01-01

    BACKGROUND Geographic variation in the use of prescription drugs, particularly those deemed harmful by the FDA, may lead to variation in patient exposure to adverse drug events. One such drug is the glucose-lowering drug rosiglitazone, for which the FDA issued a safety alert on May 21, 2007, following the publication of a meta-analysis that suggested a 43% increase in the risk of myocardial infarction with the use of rosiglitazone. This alert was followed by a black box warning on August 14, 2007, that was updated 3 months later. While large declines have been documented in rosiglitazone use in clinical practice, little is known about how the use of rosiglitazone and other glucose-lowering drugs varied within the Department of Veterans Affairs (VA), surrounding the FDA alerts. Understanding this variation within integrated health care systems is essential to formulating policies that enhance patient protection and quality of care. OBJECTIVE To document variation in the use of rosiglitazone and other glucose-lowering drugs across 21 Veterans Integrated Service Networks (VISNs). METHODS We conducted a retrospective analysis of drug use patterns for all major diabetes drugs in a national cohort of 550,550 veterans with diabetes from 2003 to 2008. This included the time periods when rosiglitazone was added to (November 2003) and removed from (October 2007) the VA national formulary (VANF). We employed multivariable logistic regression models to statistically estimate the association between a patient’s location and the patient’s odds of using rosiglitazone. RESULTS Aggregate rosiglitazone use increased monotonically from 7.7%, in the quarter it was added to the VANF (November 4, 2003), to a peak of 15.3% in the quarter when the FDA issued the safety alert. Rosiglitazone use decreased sharply afterwards, reaching 3.4% by the end of the study period (September 30, 2008). The use of pioglitazone, another glucose-lowering drug in the same class as rosiglitazone, was

  4. Pharmacotherapeutics of Intranasal Scopolamine: FDA Regulations and Procedures for Clinical Applications

    NASA Technical Reports Server (NTRS)

    Das, H.; Daniels, V. R.; Vaksman, Z.; Boyd, J. L.; Buckey, J. C.; Locke, J. P.; Putcha, L.

    2007-01-01

    Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during the early flight days of a space mission. Bioavailability of oral (PO) SMS medications is often low and highly variable; additionally, physiological changes in a microgravity environment exacerbate variability and decrease bioavailability. These factors prompted NASA to develop an intranasal dosage form of scopolamine (INSCOP) suitable for the treatment of SMS. However, to assure safety and efficacy of treatment in space, NASA physicians prescribe commercially available pharmaceutical products only. Development of a pharmaceutical preparation for clinical use must follow distinct clinical phases of testing, phase I through IV to be exact, before it can be approved by the FDA for approval for clinical use. After a physician sponsored Investigative New Drug (IND) application was approved by the FDA, a phase I clinical trial of INSCOP formulation was completed in normal human subjects and results published. The current project includes three phase II clinical protocols for the assessment of pharmacokinetics and pharmacodynamics (PK/PD), efficacy, and safety of INSCOP. Three clinical protocols that were submitted to FDA to accomplish the project objectives: 1) 002-A, a FDA Phase II dose ranging study with four dose levels between 0.1 and 0.4 mg in 12 subjects to assess PK/PD, 2) 002-B, a phase II clinical efficacy study in eighteen healthy subjects to compare efficacy of 0.2 (low dose) and 0.4 mg (high dose) INSCOP for prophylactic treatment of motion-induces (off-axis vertical rotation) symptoms, and (3) 002-C, a phase II clinical study with twelve subjects to determine bioavailability and pharmacodynamics of two doses (0.2 and 0.4 mg) of INSCOP in simulated microgravity, antiorthostatic bedrest. All regulatory procedures were competed that include certification for Good laboratory Procedures by Theradex , clinical documentation, personnel training

  5. The crime of saving lives. The FDA, John Najarian, and Minnesota ALG.

    PubMed

    Wilson, L G

    1995-10-01

    The indictment of John Najarian, MD, and Richard Condie at Minneapolis, Minn, on April 10, 1995, was a defining episode in the prolonged agony that has ensued since August 1992, when the federal Food and Drug Administration (FDA) placed Minnesota Anti-Lymphocyte Globulin (MALG) on clinical hold, bringing to an end its use as an immunosuppressive agent for patients undergoing transplantation. The principal charge in the indictment is that from about 1968 until 1992--the whole period of the development and use of MALG--Dr Najarian and Mr Condie conspired to defraud the United States by impeding the FDA in its oversight of biological drugs and that they did so for the purpose of financial gain. If the charges can be considered seriously, they mean that Dr Najarian's purpose in the development and manufacture of MALG was to make money, presumably for himself, and that the possible benefit of MALG to the patients was of secondary concern to him. Several difficulties arise immediately. In 1968, MALG offered a promising new approach to immunosuppression. In a relatively crude form, it had been used at the University of Colorado with striking improvement in the survival of patients undergoing transplantation and transplanted organs, but it was painful to administer by intramuscular injections and, in addition to other side effects, produced muscular spasms. Dr Najarian and his colleagues succeeded in purifying MALG so that the pure globulin could be injected into a central vein. The process of purification was complicated and expensive, so it was hardly practical for each transplant center to produce MALG for itself. Thus, in 1969, when Dr Najarian submitted an investigational new drug application (IND) to the FDA, he stated that his purpose was to manufacture MALG not only for patients at the University of Minnesota Hospital but also for patients at other transplant centers, which were not in a position to make it for themselves. He asked the FDA to approve recovery of

  6. A proposal for financing postmarketing drug safety studies by augmenting FDA user fees.

    PubMed

    Carpenter, Daniel

    2005-01-01

    I propose to raise funds for postapproval studies of long-term drug safety by augmenting the existing "user-fee" system. Fees would be raised by an amount deemed optimal for revenue collection, and the U.S. Food and Drug Administration (FDA) would direct the incremental funds to a combination of randomized controlled trials, epidemiological studies, and postmarketing surveillance. User-fee augmentation is an achievable, incremental reform that would subsidize information that is now undersupplied in the U.S. health care system; spread the burden of funding postmarketing safety studies among pharmaceutical sponsors; and help restore public, scientific, and professional confidence in the FDA and its user-fee system.

  7. Impact of FDA guidance for developing diabetes drugs on trial design: from policy to practice.

    PubMed

    Bethel, M Angelyn; Sourij, Harald

    2012-02-01

    In 2008, the US Food and Drug Administration (FDA) issued guidance requiring robust assessment of cardiovascular safety for all antidiabetic drugs to be licensed in the future. Here, we review the circumstances giving rise to the FDA guidance and describe the characteristics of clinical trials registered on ClinicalTrials.gov in the 36 months before and after the guidance was issued. We noted a doubling in the number of cardiovascular outcome trials registered and a sixfold increase in the median number of patients included in cardiovascular outcome trials in the latter 36 months. As the size and duration of follow-up for these trials increases, the clinical trials industry will need to adapt. The present review summarizes current attempts to streamline trial design and management to meet the requirements efficiently while adhering to the highest scientific standards.

  8. Inspection of computer-supported toxicological data submitted to the FDA.

    PubMed

    Taylor, D W

    1984-01-01

    The FDA's Good Laboratory Practice Regulations (GLP) have been formally amended (once) and two formed advisory opinions have been issued. The FDA is now in the process of reviewing the GLPs to comply with both the Regulatory Flexibility Act of 1980 and Executive Order 12291 of 1981. Inspections since 1979 have revealed compliance progress; however, certain areas of the GLPs have been a problem--the definition of "raw data," the documentation process for the maintenance of "raw data," standard operating procedures, and study protocols. The increasing use of computers for supporting toxicology/pathology studies raises several questions concerning the impact of the GLPs on computerized data collection/reporting. This paper will address the above questions and discuss systems, procedures, interpretations, and some unresolved problems, as well as provide practical approaches for internal review of computer-supported nonclinical laboratory studies.

  9. Repurposing FDA-approved drugs as therapeutics to treat Rift Valley fever virus infection

    PubMed Central

    Benedict, Ashwini; Bansal, Neha; Senina, Svetlana; Hooper, Idris; Lundberg, Lindsay; de la Fuente, Cynthia; Narayanan, Aarthi; Gutting, Bradford; Kehn-Hall, Kylene

    2015-01-01

    There are currently no FDA-approved therapeutics available to treat Rift Valley fever virus (RVFV) infection. In an effort to repurpose drugs for RVFV treatment, a library of FDA-approved drugs was screened to determine their ability to inhibit RVFV. Several drugs from varying compound classes, including inhibitors of growth factor receptors, microtubule assembly/disassembly, and DNA synthesis, were found to reduce RVFV replication. The hepatocellular and renal cell carcinoma drug, sorafenib, was the most effective inhibitor, being non-toxic and demonstrating inhibition of RVFV in a cell-type and virus strain independent manner. Mechanism of action studies indicated that sorafenib targets at least two stages in the virus infectious cycle, RNA synthesis and viral egress. Computational modeling studies also support this conclusion. siRNA knockdown of Raf proteins indicated that non-classical targets of sorafenib are likely important for the replication of RVFV. PMID:26217313

  10. Price, Performance, and the FDA Approval Process: The Example of Home HIV Testing

    PubMed Central

    Paltiel, A. David; Pollack, Harold A.

    2010-01-01

    The Food and Drug Administration (FDA) is considering approval of an over-the-counter, rapid HIV test for home use. To support its decision, the FDA seeks evidence of the test’s performance. It has asked the manufacturer to conduct field studies of the test’s sensitivity and specificity when employed by untrained users. In this paper, we argue that additional information should be sought to evaluate the prevalence of undetected HIV in the end-user population. Our analytic framework produces the elementary but counterintuitive finding that the performance of the home HIV test – measured in terms of its ability to correctly detect the presence and absence of HIV infection among the people who purchase it – depends critically on the manufacturer’s retail price. This finding has profound implications for the FDA’s approval process. PMID:19429837

  11. Use of vaginal mesh in the face of recent FDA warnings and litigation.

    PubMed

    Mucowski, Sara J; Jurnalov, Catalin; Phelps, John Y

    2010-08-01

    Choosing to use mesh in vaginal reconstructive surgery for pelvic organ prolapse or stress urinary incontinence is perplexing in the face of recent US Food and Drug Administration (FDA) warnings. In October 2008, the FDA alerted practitioners to complications associated with transvaginal placement of surgical mesh. Litigation is another concern. A Google search of "transvaginal mesh" results in numerous hits for plaintiff attorneys seeking patients with complications related to use of mesh. In light of a recent decision by the US Supreme Court and strategies by manufactures of medical devices to escape liability, it is imperative that gynecologic surgeons using transvaginal mesh document proper informed consent in the medical records. The purpose of this commentary is not to deter gynecologic surgeons from using transvaginal mesh when appropriate, but to provide an overview of current medical-legal controversies and stress the importance of documenting informed consent. Copyright (c) 2010 Mosby, Inc. All rights reserved.

  12. FDA direct-to-consumer advertising for prescription drugs: what are consumer preferences and response tendencies?

    PubMed

    Khanfar, Nile; Loudon, David; Sircar-Ramsewak, Feroza

    2007-01-01

    The effect of direct-to-consumer (DTC) television advertising of prescription medications is a growing concern of the United States (U.S.) Congress, state legislatures, and the Food and Drug Administration (FDA). This research study was conducted in order to examine consumers' perceived preferences of DTC television advertisement in relation to "reminder" "help-seeking," and "product-claim" FDA-approved advertisement categories. An additional objective was to examine the influence of DTC television advertising of prescription drugs on consumers' tendency to seek more information about the medication and/or the medical condition. The research indicates that DTC television drug ads appear to be insufficient for consumers to make informed decisions. Their mixed perception and acceptance of the advertisements seem to influence them to seek more information from a variety of medical sources.

  13. FDA regulation of dietary supplements and requirements regarding adverse event reporting.

    PubMed

    Frankos, V H; Street, D A; O'Neill, R K

    2010-02-01

    In 1994, the Dietary Supplement Health and Education Act (DSHEA) amended the Federal Food, Drug, and Cosmetic Act (FDC Act) to set up a distinct regulatory framework for what we now call dietary supplements. The DSHEA was passed with the intent of striking a balance between providing consumers access to safe dietary supplements to help maintain or improve their health and giving the US Food and Drug Administration (FDA) authority to regulate and take action against manufacturers of supplements or supplement ingredients that present safety problems, are presented with false or misleading claims, or are adulterated or misbranded. This article will present FDA's recent experience in collecting and evaluating dietary supplement adverse event data for the purpose of assuring the public that the dietary supplements they purchase are safe.

  14. FDA, CE mark or something else?-Thinking fast and slow.

    PubMed

    Mishra, Sundeep

    There is a robust debate going on among the Medical Device stake-holders whether FDA is better or CE mark or something else. Currently process of obtaining an FDA approval is bogged down by ever-increasing unpredictability, inconsistency, prolonged time, and huge expense but CE mark has its own problems. Historically, the Japanese review process has tended to be the slowest among the big three but recently with the introduction of accelerated review process there has been a significant progress. While the goal of an innovator/manufacturer is to develop, manufacture and market a medical device that addresses an unmet clinical need, the requisite regulatory approval process can be very confusing. Not only there is a whole lot of jargon tossed around by regulatory affair professionals: "substantial equivalence," "PMDA," "CE mark," "Notified body," "510K" and "PMA" but the actual approval process can also be very tardy, inconsistent and expensive.

  15. FDA Adverse Event Reporting System: Recruiting Doctors to Make Surveillance a Little Less Passive.

    PubMed

    Mann, Justin M

    2015-01-01

    Within the last few decades, a shift has taken place in FDA's approach to drug development, with greater emphasis put on postmarketing data collection and less on the traditional premarketing scheme. The FDA Adverse Event Reporting System (FAERS) is the primary system for collecting Adverse Events, but has been criticized for years for the low reporting rate into the system and the poor quality of the information submitted. This paper argues that physicians need to be required to submit adverse event reports to FAERS, because such a requirement (1) would produce a greater number of the high quality reports necessary to better determine causality; (2) is merely an extension of physicians' ethical obligations; and (3) aligns with the approach in the Vaccine Adverse Event Reporting System (VAERS). Furthermore, advances in electronic health records can aid in reporting efficiency.

  16. Violations of exhibiting and FDA rules at an American Psychiatric Association annual meeting.

    PubMed

    Lurie, Peter; Tran, Tung; Wolfe, Sidney Manuel; Goodman, Robert

    2005-12-01

    We conducted a cross-sectional study of all exhibit booths for the 24 pharmaceutical companies at the 2002 American Psychiatric Association (APA) convention. We collected and categorized one of each item distributed by the companies at each booth. A total of 268 items were collected from 24 companies (median=8). The most common categories of items were "reprints or pamphlets" (37%) and "noneducational gifts" (27%), including music CDs and invitations to dinners and museums. There were a total of 16 violations of the APA's own exhibit rules: eight companies had one violation and two companies had four violations. Four companies engaged in FDA-prohibited off-label promotion; one also violated the APA code. Over half of all companies (54%) were in violation of either APA rules or FDA regulations. The APA's voluntary code has failed to adequately reduce inappropriate promotional activity at the annual APA meeting.

  17. The complications of controlling agency time discretion: FDA review deadlines and postmarket drug safety.

    PubMed

    Carpenter, Daniel; Chattopadhyay, Jacqueline; Moffitt, Susan; Nall, Clayton

    2012-01-01

    Public agencies have discretion on the time domain, and politicians deploy numerous policy instruments to constrain it. Yet little is known about how administrative procedures that affect timing also affect the quality of agency decisions. We examine whether administrative deadlines shape decision timing and the observed quality of decisions. Using a unique and rich dataset of FDA drug approvals that allows us to examine decision timing and quality, we find that this administrative tool induces a piling of decisions before deadlines, and that these “just-before-deadline” approvals are linked with higher rates of postmarket safety problems (market withdrawals, severe safety warnings, safety alerts). Examination of data from FDA advisory committees suggests that the deadlines may impede quality by impairing late-stage deliberation and agency risk communication. Our results both support and challenge reigning theories about administrative procedures, suggesting they embody expected control-expertise trade-offs, but may also create unanticipated constituency losses.

  18. Regulating (for the benefit of) future persons: a different perspective on the FDA's jurisdiction to regulate human reproductive cloning.

    PubMed

    Javitt, Gail H; Hudson, Kathy

    2003-01-01

    The Food and Drug Administration (FDA) has taken the position that human reproductive cloning falls within its regulatory jurisdiction. This position has been subject to criticism on both procedural and substantive grounds. Some have contended that the FDA has failed to follow administrative law principles in asserting its jurisdiction, while others claim the FDA is ill suited to the task of addressing the ethical and social implications of human cloning. This Article argues, that, notwithstanding these criticisms, the FDA could plausibly assert jurisdiction over human cloning as a form of human gene therapy, an area in which the FDA is already regarded as having primary regulatory authority. Such an assertion would require that the FDA's jurisdiction extend to products affecting future persons, i.e., those not yet born. This Article demonstrates, for the first time, that such jurisdiction was implicit in the enactment of the 1962 Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act and that the FDA has historically relied on such authority in promulgating regulations for drugs and devices.

  19. An evaluation of the FDA's analysis of the costs and benefits of the graphic warning label regulation

    PubMed Central

    Chaloupka, Frank J; Warner, Kenneth E; Acemoğlu, Daron; Gruber, Jonathan; Laux, Fritz; Max, Wendy; Newhouse, Joseph; Schelling, Thomas; Sindelar, Jody

    2015-01-01

    The Family Smoking Prevention and Tobacco Control Act of 2009 gave the Food and Drug Administration (FDA) regulatory authority over cigarettes and smokeless tobacco products and authorised it to assert jurisdiction over other tobacco products. As with other Federal agencies, FDA is required to assess the costs and benefits of its significant regulatory actions. To date, FDA has issued economic impact analyses of one proposed and one final rule requiring graphic warning labels (GWLs) on cigarette packaging and, most recently, of a proposed rule that would assert FDA’s authority over tobacco products other than cigarettes and smokeless tobacco. Given the controversy over the FDA's approach to assessing net economic benefits in its proposed and final rules on GWLs and the importance of having economic impact analyses prepared in accordance with sound economic analysis, a group of prominent economists met in early 2014 to review that approach and, where indicated, to offer suggestions for an improved analysis. We concluded that the analysis of the impact of GWLs on smoking substantially underestimated the benefits and overestimated the costs, leading the FDA to substantially underestimate the net benefits of the GWLs. We hope that the FDA will find our evaluation useful in subsequent analyses, not only of GWLs but also of other regulations regarding tobacco products. Most of what we discuss applies to all instances of evaluating the costs and benefits of tobacco product regulation and, we believe, should be considered in FDA's future analyses of proposed rules. PMID:25550419

  20. Rationale, Procedures, and Response Rates for the 2015 Administration of NCI's Health Information National Trends Survey: HINTS-FDA 2015.

    PubMed

    Blake, Kelly D; Portnoy, David B; Kaufman, Annette R; Lin, Chung-Tung Jordan; Lo, Serena C; Backlund, Eric; Cantor, David; Hicks, Lloyd; Lin, Amy; Caporaso, Andrew; Davis, Terisa; Moser, Richard P; Hesse, Bradford W

    2016-12-01

    The National Cancer Institute (NCI) developed the Health Information National Trends Survey (HINTS) to monitor population trends in cancer communication practices, information preferences, health risk behaviors, attitudes, and cancer knowledge. The U.S. Food and Drug Administration (FDA) recognized HINTS as a unique data resource for informing its health communication endeavors and partnered with NCI to field HINTS-FDA 2015. HINTS-FDA 2015 was a self-administered paper instrument sent by mail May 29 to September 8, 2015, using a random probability-based sample of U.S. postal addresses stratified by county-level smoking rates, with an oversampling of high and medium-high smoking strata to increase the yield of current smokers responding to the survey. The response rate for HINTS-FDA 2015 was 33% (N = 3,738). The yield of current smokers (n = 495) was lower than expected, but the sampling strategy achieved the goal of obtaining more former smokers (n = 1,132). Public-use HINTS-FDA 2015 data and supporting documentation have been available for download and secondary data analyses since June 2016 at http://hints.cancer.gov . NCI and FDA encourage the use of HINTS-FDA for health communication research and practice related to tobacco-related communications, public knowledge, and behaviors as well as beliefs and actions related to medical products and dietary supplements.

  1. News Media Coverage of FDA Warnings on Pediatric Antidepressant Use and Suicidality

    PubMed Central

    Busch, Susan H.

    2009-01-01

    Objective In 2004, after an 18-month investigation, the Food and Drug Administration (FDA) directed pharmaceutical manufacturers to add a black box warning to antidepressants regarding an increased risk of suicidality in children. It has been suggested that news media reporting played a critical role in the sharp declines in pediatric antidepressant use that occurred concurrent with this investigation. Our objective was to evaluate the quality, content and overall impression conveyed in news coverage of this issue. Methods We collected all news stories on pediatric antidepressant use and suicidality published in a convenience sample of 10 of the highest circulation print newspapers in the U.S., the three major television networks and a major cable news network in 2003 and 2004 (N=167). Two researchers coded news articles using a nine-item instrument. Item inter-rater reliability was .84 or greater. Results The quality of news reporting on key health messages included in FDA warnings was mixed. The overwhelming majority of news stories correctly described a risk of suicidality associated with pediatric antidepressant use as opposed to suicide itself. However, other key health messages highlighted in FDA warnings were often absent from news coverage. In terms of content, news stories, in particular television news, were more likely to include anecdotes of children harmed versus children helped by antidepressants while expert sources quoted were more likely to emphasize the benefits of antidepressants over their risks. However, the majority of news stories conveyed neither the overall impression that the risks of pediatric antidepressant use outweighed the benefits nor that the benefits outweighed the risks, and coverage became increasingly neutral over time. Conclusions Including key health messages in FDA safety warnings was not sufficient to ensure their communication to the public via the lay press, even though this information might have mitigated risks of

  2. FDA approval of a fourth acellular pertussis vaccine for use among infants and young children.

    PubMed

    1998-11-06

    On July 29, 1998, the Food and Drug Administration (FDA) licensed North American Vaccine, Inc. (Beltsville, Maryland) to distribute a combined diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) (Certiva) for the first four doses of the diphtheria and tetanus toxoids and pertussis vaccination series administered to infants and children aged 6 weeks-6 years. Certiva is the fourth acellular pertussis vaccine to be licensed for use in infants and young children in the United States.

  3. Participatory surveillance of diabetes device safety: a social media-based complement to traditional FDA reporting

    PubMed Central

    Mandl, Kenneth D; McNabb, Marion; Marks, Norman; Weitzman, Elissa R; Kelemen, Skyler; Eggleston, Emma M; Quinn, Maryanne

    2014-01-01

    Background and objective Malfunctions or poor usability of devices measuring glucose or delivering insulin are reportable to the FDA. Manufacturers submit 99.9% of these reports. We test online social networks as a complementary source to traditional FDA reporting of device-related adverse events. Methods Participatory surveillance of members of a non-profit online social network, TuDiabetes.org, from October 2011 to September 2012. Subjects were volunteers from a group within TuDiabetes, actively engaged online in participatory surveillance. They used the free TuAnalyze app, a privacy-preserving method to report detailed clinical information, available through the network. Network members were polled about finger-stick blood glucose monitors, continuous glucose monitors, and insulin delivery devices, including insulin pumps and insulin pens. Results Of 549 participants, 75 reported device-related adverse events, nearly half (48.0%) requiring intervention from another person to manage the event. Only three (4.0%) of these were reported by participants to the FDA. All TuAnalyze reports contained outcome information compared with 22% of reports to the FDA. Hypoglycemia and hyperglycemia were experienced by 48.0% and 49.3% of participants, respectively. Discussion Members of an online community readily engaged in participatory surveillance. While polling distributed online populations does not yield generalizable, denominator-based rates, this approach can characterize risk within online communities using a bidirectional communication channel that enables reach-back and intervention. Conclusions Engagement of distributed communities in social networks is a viable complementary approach to traditional public health surveillance for adverse events related to medical devices. PMID:24355131

  4. FDA regulations regarding iodine addition to foods and labeling of foods containing added iodine.

    PubMed

    Trumbo, Paula R

    2016-09-01

    The US Food and Drug Administration (FDA) regulates the addition of iodine to infant formulas, the iodization of salt, and the addition of salt and iodine to foods. The required amount of iodine in infant formulas is based on caloric content, and the label must provide the iodine content per 100 kcal. Cuprous iodide and potassium iodide may be added to table salt as a source of dietary iodine at a maximum amount of 0.01%; if added, the label must indicate that the salt is iodized. Table salt to which iodine has not been added must bear the statement, "This salt does not supply iodide, a necessary nutrient." If a nutrient is to be appropriately added to a food for the purpose of correcting a dietary insufficiency, there should be sufficient scientific information available to demonstrate a nutritional deficiency and/or identify a public health problem. Furthermore, the population groups that would benefit from the proposed fortification should be identified. If iodine is added to a food, the percent Daily Value of iodine must be listed. There are no FDA regulations governing ingredient standards for dietary supplements. As a result, some dietary supplements include iodine and others do not. If a supplement contains iodine, the Supplement Facts label must list iodine as a nutrient ingredient. If iodine is not listed on the Supplement Facts label, then it has not been added. There are similarities between the FDA, which establishes US food regulations and policies, and the Codex Alimentarius (Codex), which develops international food standards and guidelines under the aegis of the FAO and the WHO. Both the FDA and Codex call for the labeling of table salt to indicate fortification with iodine, voluntary labeling of iodine on foods, and a Daily Value (called a Nutrient Reference Value by Codex) of 150 μg for iodine. © 2016 American Society for Nutrition.

  5. FDA regulations regarding iodine addition to foods and labeling of foods containing added iodine12

    PubMed Central

    Trumbo, Paula R

    2016-01-01

    The US Food and Drug Administration (FDA) regulates the addition of iodine to infant formulas, the iodization of salt, and the addition of salt and iodine to foods. The required amount of iodine in infant formulas is based on caloric content, and the label must provide the iodine content per 100 kcal. Cuprous iodide and potassium iodide may be added to table salt as a source of dietary iodine at a maximum amount of 0.01%; if added, the label must indicate that the salt is iodized. Table salt to which iodine has not been added must bear the statement, “This salt does not supply iodide, a necessary nutrient.” If a nutrient is to be appropriately added to a food for the purpose of correcting a dietary insufficiency, there should be sufficient scientific information available to demonstrate a nutritional deficiency and/or identify a public health problem. Furthermore, the population groups that would benefit from the proposed fortification should be identified. If iodine is added to a food, the percent Daily Value of iodine must be listed. There are no FDA regulations governing ingredient standards for dietary supplements. As a result, some dietary supplements include iodine and others do not. If a supplement contains iodine, the Supplement Facts label must list iodine as a nutrient ingredient. If iodine is not listed on the Supplement Facts label, then it has not been added. There are similarities between the FDA, which establishes US food regulations and policies, and the Codex Alimentarius (Codex), which develops international food standards and guidelines under the aegis of the FAO and the WHO. Both the FDA and Codex call for the labeling of table salt to indicate fortification with iodine, voluntary labeling of iodine on foods, and a Daily Value (called a Nutrient Reference Value by Codex) of 150 μg for iodine. PMID:27534626

  6. NCI and FDA to Study Cancer Proteogenomics Together | Office of Cancer Clinical Proteomics Research

    Cancer.gov

    The National Cancer Institute (NCI) Office of Cancer Clinical Proteomics Research (OCCPR), part of the National Institutes of Health, and the U.S. Food and Drug Administration (FDA) has signed a Memorandum of Understanding (MOU) in proteogenomic regulatory science.  This will allow the agencies to share information that will accelerate the development of proteogenomic technologies and biomarkers, as it relates to precision medicine in cancer.

  7. The Safe Medical Devices Act of 1990: are hospitals ready to deal with the FDA?

    PubMed

    Loob, W H

    1991-01-01

    The Safe Medical Devices Act of 1990, long anticipated by regulatory affairs and compliance professionals in the medical device manufacturing industry, was signed by President George Bush on November 28, 1990. The law will significantly alter the structure of medical device regulatory mechanisms, and will expand the scope of the FDA's activities. The new medical device legislation sets requirements for hospitals as well as industry.

  8. FDA Approves Two HPV Vaccines: Cervarix for Girls, Gardasil for Boys | Division of Cancer Prevention

    Cancer.gov

    The FDA has approved a second vaccine to prevent cervical cancer and cervical precancers, the vaccine’s manufacturer, GlaxoSmithKline (GSK), announced last week. The approval is based on data from a large clinical trial showing that the vaccine, Cervarix, prevented precancerous lesions in 93 percent of those who received the full vaccine sequence of three injections over 6 months. |

  9. FDA Approves Test to Aid Post-PSA Biopsy Decisions | Division of Cancer Prevention

    Cancer.gov

    The Food and Drug Administration (FDA) has approved a test to help men with elevated prostate-specific antigen (PSA) test scores decide whether to have a biopsy to test for prostate cancer. The Access Hybritech p2PSA test is approved for use in men aged 50 or older who have a PSA test score between 4 and 10 ng/ml but who show no signs of cancer during a digital rectal exam. |

  10. Participatory surveillance of diabetes device safety: a social media-based complement to traditional FDA reporting.

    PubMed

    Mandl, Kenneth D; McNabb, Marion; Marks, Norman; Weitzman, Elissa R; Kelemen, Skyler; Eggleston, Emma M; Quinn, Maryanne

    2014-01-01

    Malfunctions or poor usability of devices measuring glucose or delivering insulin are reportable to the FDA. Manufacturers submit 99.9% of these reports. We test online social networks as a complementary source to traditional FDA reporting of device-related adverse events. Participatory surveillance of members of a non-profit online social network, TuDiabetes.org, from October 2011 to September 2012. Subjects were volunteers from a group within TuDiabetes, actively engaged online in participatory surveillance. They used the free TuAnalyze app, a privacy-preserving method to report detailed clinical information, available through the network. Network members were polled about finger-stick blood glucose monitors, continuous glucose monitors, and insulin delivery devices, including insulin pumps and insulin pens. Of 549 participants, 75 reported device-related adverse events, nearly half (48.0%) requiring intervention from another person to manage the event. Only three (4.0%) of these were reported by participants to the FDA. All TuAnalyze reports contained outcome information compared with 22% of reports to the FDA. Hypoglycemia and hyperglycemia were experienced by 48.0% and 49.3% of participants, respectively. Members of an online community readily engaged in participatory surveillance. While polling distributed online populations does not yield generalizable, denominator-based rates, this approach can characterize risk within online communities using a bidirectional communication channel that enables reach-back and intervention. Engagement of distributed communities in social networks is a viable complementary approach to traditional public health surveillance for adverse events related to medical devices. 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.

  11. The FDA's Experience with Emerging Genomics Technologies-Past, Present, and Future.

    PubMed

    Xu, Joshua; Thakkar, Shraddha; Gong, Binsheng; Tong, Weida

    2016-07-01

    The rapid advancement of emerging genomics technologies and their application for assessing safety and efficacy of FDA-regulated products require a high standard of reliability and robustness supporting regulatory decision-making in the FDA. To facilitate the regulatory application, the FDA implemented a novel data submission program, Voluntary Genomics Data Submission (VGDS), and also to engage the stakeholders. As part of the endeavor, for the past 10 years, the FDA has led an international consortium of regulatory agencies, academia, pharmaceutical companies, and genomics platform providers, which was named MicroArray Quality Control Consortium (MAQC), to address issues such as reproducibility, precision, specificity/sensitivity, and data interpretation. Three projects have been completed so far assessing these genomics technologies: gene expression microarrays, whole genome genotyping arrays, and whole transcriptome sequencing (i.e., RNA-seq). The resultant studies provide the basic parameters for fit-for-purpose application of these new data streams in regulatory environments, and the solutions have been made available to the public through peer-reviewed publications. The latest MAQC project is also called the SEquencing Quality Control (SEQC) project focused on next-generation sequencing. Using reference samples with built-in controls, SEQC studies have demonstrated that relative gene expression can be measured accurately and reliably across laboratories and RNA-seq platforms. Besides prediction performance comparable to microarrays in clinical settings and safety assessments, RNA-seq is shown to have better sensitivity for low expression and reveal novel transcriptomic features. Future effort of MAQC will be focused on quality control of whole genome sequencing and targeted sequencing.

  12. FDA regulation of tobacco advertising and youth smoking. Historical, social, and constitutional perspectives.

    PubMed

    Gostin, L O; Arno, P S; Brandt, A M

    1997-02-05

    Perspectives on tobacco control in American society have shifted markedly. As the view that smoking as a voluntarily assumed health risk has declined, the social and political environment has become more conducive to industry regulation. This transformation can be traced to the mounting evidence of the health risks of secondary smoke; the addictive quality of nicotine; the vulnerability and exploitation of young people; and industry knowledge of the harmful effects of tobacco. Regulation of tobacco advertising and promotions by the Food and Drug Administration (FDA) raises serious concerns about constitutional protection for commercial speech. However, the minimal informational value of tobacco advertising suggests that it should be afforded a low level of constitutional protection. The FDA regulations impose reasonable "time, place, and manner" restrictions, leave open alternative channels of communication, restrict messages that are harmful to the public health, do not restrict political speech, prevent misleading messages, and help deter the unlawful sale of tobacco products to minors. The regulations meet the traditional criteria for regulating commercial speech, in that the government's asserted interest is strong, the agency's regulations directly advance that interest, and the regulations are no more extensive than necessary. Thus, the judiciary should defend the FDA's historical social and legislative mission to protect the public health.

  13. Editorial Perspective: How should child psychologists and psychiatrists interpret FDA device approval? Caveat emptor.

    PubMed

    Arns, Martijn; Loo, Sandra K; Sterman, M Barry; Heinrich, Hartmut; Kuntsi, Jonna; Asherson, Philip; Banaschewski, Tobias; Brandeis, Daniel

    2016-05-01

    Recently several new tests have received US Federal Drug Administration (FDA) marketing approval as aids in the diagnostic process for attention deficit hyperactivity disorder (ADHD), including the Neuropsychiatric electroencephalogram (EEG)-Based ADHD Assessment Aid (NEBA) Health test. The NEBA test relies upon an EEG-based measure, called the theta to beta ratio (TBR). Although this measure has yielded large differences between ADHD and non-ADHD groups in studies prior to 2009, recent studies and a meta-analysis could not replicate these findings. In this article, we have used the NEBA device as an exemplar for a discussion that distinguishes between FDA de novo marketing approval for a device and any claims that that device is empirically supported, scientifically validated with replicated findings. It is understood that the aims of each differ; however, for many, including the lay public as well as some mental health professionals, these terms may be confused and treated as though they are synonymous. With regard to the TBR measure, there is no reliable association or replication for its clinical usage in the ADHD diagnostic process. The recommendation for potential consumers of the NEBA Health test (as well as perhaps for other existing FDA-approved diagnostic tests) is caveat emptor (let the buyer beware!).

  14. Heparin crisis 2008: a tipping point for increased FDA enforcement in the pharma sector?

    PubMed

    Rosania, Larry

    2010-01-01

    Against a backdrop of steady deregulation, the pharmaceutical industry is increasingly outsourcing manufacturing, resulting in decentralized control of the global supply chain. Established products such as heparin have been held to outdated analytical standards. Ten million Americans receive heparin every year; Baxter International accounts for half of this market. In 2008, contamination of Baxter's heparin--sourced in China--resulted in about 350 adverse events and 150 deaths in the United States. In future, increasingly stringent FDA inspections and enforcement are expected for imported drugs and ingredients. More regional FDA offices will be set up overseas. FDA funding will likely be supplemented in future by user fees charged to importers. For newer products, companies will face pressure to adopt Quality by Design, with solid control of the global supply chain and a proactive focus on GMP. Older products will be held to modern standards. Long-term, imports of drugs and ingredients from developing markets will continue. This makes sense to companies from an economic standpoint, but protections will be essential to ensure that it is also justifiable from a public health perspective.

  15. The FDA alert on suicidality and antiepileptic drugs: Fire or false alarm?

    PubMed

    Hesdorffer, Dale C; Kanner, Andres M

    2009-05-01

    In January 2008, the U.S. Food and Drug Administration (FDA) issued an alert about an increased risk for suicidality in 199 clinical trials of 11 antiepileptic drugs (AEDs) for three different indications, including epilepsy. An advisory panel voted against a black-box warning on AED labels, and the FDA has accepted this recommendation. We discuss three potential problems with the alert. First, adverse event data were used rather than systematically collected data. Second, the 11 drugs grouped together as a single class of AEDs have different mechanisms of action and very different relative risks, many of which were not statistically significant and some of which were smaller than one. These facts suggest that they should not be grouped as a class. Third, the risk of adverse effects from uncontrolled seizures almost certainly outweighs the small risk of suicidality. We place our comments in the context of a review of the literature on suicidality and depression in epilepsy and the sparse literature on AEDs and suicidality. We recommend that all patients with epilepsy be routinely evaluated for depression, anxiety, and suicidality, and that future clinical trials include validated instruments to systematically assess these conditions to determine whether the possible signal observed by the FDA is real.

  16. The impact of FDA guidance on pharmacogenomic data submissions on drug development.

    PubMed

    Little, Stephen

    2005-08-01

    After a long wait, the US Food and Drug Administration (FDA) finally released the much anticipated 'Guidance on Pharmacogenomic Data Submissions on Drug Development' in March 2005, but what impact will this have on the drug industry as a whole? It is becoming increasingly apparent that the field of pharmacogenomics can add value to both clinical trial design and the drug development process, but uptake by the pharmaceutical industry has so far been variable between companies. The opinion of the FDA is that the use of pharmacogenomics in drug development is a 'good thing' and one that it wishes to promote, hence, this new guidance is designed to assist drug companies to adopt pharmacogenomic technology in clinical development, and covers both targeted and exploratory aspects. While targeted pharmacogenomics must be included as part of any regulatory submission, exploratory approaches may be submitted voluntarily with assurances from the FDA that any such submissions will not be used to make regulatory decisions. With this regulatory framework now in place it is only a matter of time before it is known how the industry reacts and the impact it will have on drug development.

  17. Effects of FDA Advisories on the Pharmacologic Treatment of ADHD, 2004–2008

    PubMed Central

    Kornfield, Rachel; Watson, Sydeaka; Higashi, Ashley S.; Conti, Rena M.; Dusetzina, Stacie B.; Garfield, Craig F.; Dorsey, E. Ray; Huskamp, Haiden A.; Alexander, G. Caleb

    2014-01-01

    Objective This study assessed the effect of public health advisories issued between 2005 and 2007 by the U.S. Food and Drug Administration (FDA) on treatments of attention-deficit hyperactivity disorder (ADHD) and physician prescribing practices. Methods Data obtained from the IMS Health National Disease and Therapeutic Index, a nationally representative audit of ambulatory physicians, were used to examine trends in office visits by children and adolescents (under age 18) during which ADHD was treated with Adderall, other psychostimulants, or atomoxetine. Segmented time series regressions were conducted to determine changes in use associated with three advisories issued between 2005 and 2007. Results In 2004, before the first FDA advisory, Adderall accounted for 36% of ADHD pharmacotherapy treatment visits. Other stimulants accounted for 46%, and atomoxetine accounted for 19%. Overall pharmacotherapy treatment rates were stable over the study period, but by 2008 the treatment visits accounted for by Adderall (that is, market share) declined to 24%, and the market share for atomoxetine declined to 8%. The market share for substitute therapies—clonidine, guanfacine, and bupropion—was stable over this period, ranging from 5% to 7%. Despite the declines in the use of Adderall and atomoxetine over the study period, results from the regression models suggest that the advisories did not have a statistically significant effect on ADHD medication prescribing. Conclusions FDA advisories regarding potential cardiovascular and other risks of ADHD medications had little discernible incremental effect on the use of these medicines in this nationally representative ambulatory audit. PMID:23318985

  18. Biomarkers of Tobacco Exposure: Summary of an FDA-sponsored Public Workshop

    PubMed Central

    Chang, Cindy M.; Edwards, Selvin H.; Arab, Aarthi; Del Valle-Pinero, Arseima Y.; Yang, Ling; Hatsukami, Dorothy K.

    2016-01-01

    Since 2009, the United States (U.S.) Food and Drug Administration (FDA) Center for Tobacco Products (CTP) has had the authority to regulate the manufacturing, distribution, and marketing of tobacco products in order to reduce the death and disease caused by tobacco use. Biomarkers of exposure pertain to actual human exposure to chemicals arising from tobacco use and could play an important role across a number of FDA regulatory activities, including assessing new and modified risk tobacco products and identifying and evaluating potential product standards. On August 3–4, 2015, FDA/CTP hosted a public workshop focused on biomarkers of exposure with participants from government, industry, academia, and other organizations. The workshop was divided into four sessions focused on: 1) approaches to evaluating and selecting biomarkers; 2) biomarkers of exposure and relationship to disease risk; 3) currently-used biomarkers of exposure and biomarkers in development; and 4) biomarkers of exposure and the assessment of smokeless tobacco and electronic nicotine delivery systems (ENDS). This paper synthesizes the main findings from the workshop and highlights research areas that could further strengthen the science around biomarkers of exposure and help determine their application in tobacco product regulation. PMID:28151705

  19. Food and Drug Administration (FDA) drug approval end points for chronic cutaneous ulcer studies.

    PubMed

    Eaglstein, William H; Kirsner, Robert S; Robson, Martin C

    2012-01-01

    The rising costs of caring for chronic cutaneous ulcers (CCUs) and recent appreciation of the mortality of CCUs have led to consideration of the reasons for the failure to have new drug therapies. No new chemical entities to heal CCUs have been approved by the Food and Drug Administration (FDA) in over a decade, in part due to an inability to reach the FDA accepted end point of "complete wound closure." The frequent failure to reach the complete closure end point brings forward the question of the relevance of other healing end points such as improved quality of life, or partial healing. Because CCUs carry a prognosis and mortality rate worse than many cancers, it is reasonable to compare the FDA trial end points for cancer drug approval with those for CCUs. And the difference is quite striking. While there is only one end point for CCUs, there are five surrogate and three direct end points for cancers. In contrast to cancer, surrogate end points and partial healing are not acceptable for therapies aimed at CCUs. For example, making tumors smaller is an acceptable end point, but making CCUs smaller is not and improvement in the signs and symptoms of cancer is an acceptable end point for cancers but not CCUs. As CCUs carry a prognosis and mortality rate worse than many cancers, we believe a reconsideration of end points for CCUs is highly warranted.

  20. Biomarkers of Tobacco Exposure: Summary of an FDA-Sponsored Public Workshop.

    PubMed

    Chang, Cindy M; Edwards, Selvin H; Arab, Aarthi; Del Valle-Pinero, Arseima Y; Yang, Ling; Hatsukami, Dorothy K

    2017-03-01

    Since 2009, the FDA Center for Tobacco Products (CTP) has had the authority to regulate the manufacturing, distribution, and marketing of tobacco products in order to reduce the death and disease caused by tobacco use. Biomarkers of exposure pertain to actual human exposure to chemicals arising from tobacco use and could play an important role across a number of FDA regulatory activities, including assessing new and modified-risk tobacco products and identifying and evaluating potential product standards. On August 3-4, 2015, FDA/CTP hosted a public workshop focused on biomarkers of exposure with participants from government, industry, academia, and other organizations. The workshop was divided into four sessions focused on: (i) approaches to evaluating and selecting biomarkers; (ii) biomarkers of exposure and relationship to disease risk; (iii) currently used biomarkers of exposure and biomarkers in development; and (iv) biomarkers of exposure and the assessment of smokeless tobacco and electronic nicotine delivery systems. This article synthesizes the main findings from the workshop and highlights research areas that could further strengthen the science around biomarkers of exposure and help determine their application in tobacco product regulation. Cancer Epidemiol Biomarkers Prev; 26(3); 291-302. ©2016 AACR. ©2016 American Association for Cancer Research.

  1. Science, law, and politics in the Food and Drug Administration's genetically engineered foods policy: FDA's 1992 policy statement.

    PubMed

    Pelletier, David L

    2005-05-01

    The US Food and Drug Administration's (FDA's) 1992 policy statement was developed in the context of critical gaps in scientific knowledge concerning the compositional effects of genetic transformation and severe limitations in methods for safety testing. FDA acknowledged that pleiotropy and insertional mutagenesis may cause unintended changes, but it was unknown whether this happens to a greater extent in genetic engineering compared with traditional breeding. Moreover, the agency was not able to identify methods by which producers could screen for unintended allergens and toxicants. Despite these uncertainties, FDA granted genetically engineered foods the presumption of GRAS (Generally Recognized As Safe) and recommended that producers use voluntary consultations before marketing them.

  2. FDA MAUDE data on complications with lasers, light sources, and energy-based devices.

    PubMed

    Tremaine, Anne Marie; Avram, Mathew M

    2015-02-01

    It is essential for physicians to be fully informed regarding adverse events and malfunctions associated with medical devices that occur in routine practice. There is limited information on this important issue in the medical literature, and it is mostly based on initial studies and case reports. More advanced knowledge regarding device adverse events is necessary to guide physicians towards providing safe treatments. The FDA requires that manufacturers and device users submit medical device reports (MDRs) for suspected injuries from device use or malfunction. The database of MDRs, entitled Manufacturer and User Facility Device Experience (MAUDE) enables the FDA to monitor device performance and identify potential safety issues. We employed the following search strategy to identify reported adverse events. We searched the MAUDE electronic database on the FDA website in December 2013: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm We collected all reported cases between 1991 and December 2013. The search terms utilized included a comprehensive list of device manufacturers, specific product names, and the wavelengths/technology of the devices used in the field of dermatology. Our search yielded 1257 MDRs. Forty-five MDRs were excluded due to insufficient data. The data is broken down into the adverse events observed, such as, but not limited to: blistering, burns, scarring, dyschromia, fat loss, and nerve palsy. The MDRs describe the adverse event and attempt to determine if it was related to device malfunction versus operator error. Radiofrequency devices, diode lasers, and intense pulsed light devices were the most commonly reported devices related to injuries. 1257 MDRs, from a myriad of devices used in dermatology, have been reported to the FDA as of December 2013. Despite the underreporting of adverse events, the MAUDE database is an untapped resource of post-market surveillance of medical devices. The database can offer additional

  3. CLINICAL TRIAL EVIDENCE SUPPORTING FDA APPROVAL OF NOVEL THERAPEUTICS, 2005–2012

    PubMed Central

    Downing, Nicholas S.; Aminawung, Jenerius A.; Shah, Nilay D.; Krumholz, Harlan M.; Ross, Joseph S.

    2014-01-01

    Importance Many patients and physicians assume that the safety and effectiveness of newly approved therapeutics is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the Food and Drug Administration (FDA) has not been evaluated. Objectives To characterize pivotal efficacy trials, clinical trials that served as the basis of FDA approval, for newly approved novel therapeutics. Design and Setting Cross-sectional analysis using publicly available FDA documents for all novel therapeutics approved between 2005 and 2012. Main Outcome Measures We classified pivotal efficacy trials according to the following design features: randomization, blinding, comparator and trial endpoint. “Surrogate outcomes” were defined as any endpoint using a biomarker that is expected to predict clinical benefit. We also determined the number of patients, trial duration, and trial completion rates. Results Between 2005 and 2012, FDA approved 188 novel therapeutics for 206 indications on the basis of 448 pivotal efficacy trials. Median number of pivotal trials per indication was two (interquartile range: 1–2.5), although 74 (36.8%) indications were approved on the basis of a single pivotal trial. Nearly all trials were randomized (89.3%, 95% Confidence Interval [CI], 86.4%–92.2%), double-blinded (79.5%, 95% CI, 75.7%–83.2%), and used either an active or placebo comparator (87.1%, 95% CI, 83.9%–90.2%). Median number of patients enrolled per indication among all pivotal trials was 760 (interquartile range: 270–1550). At least one pivotal trial with a duration of 6 months or greater supported the approval of 68 (33.8%, 95% CI, 27.2%–40.4%) indications. Pivotal trials using surrogate endpoints as their primary outcome formed the exclusive basis of approval for 91 (45.3%, 95% CI, 38.3%–52.2%) indications, clinical outcomes for 67 (33.3%, 95% CI, 26.8%–39.9%), and clinical scales for 36 (17.9%, 95% CI, 12.6%–23.3%). Trial

  4. Drug Industry Groups Oppose FDA "Quality Metrics" Plan: The Agency Wants to Use Manufacturing Data to Attack Drug Shortages.

    PubMed

    Barlas, Stephen

    2017-07-01

    Raising their voices in nearly unanimous opposition, pharmaceutical manufacturers and their suppliers have mounted a campaign to dissuade the FDA from launching a voluntary program in 2018 that is aimed at reducing drug shortages.

  5. Finding, evaluating, and managing drug-related risks: approaches taken by the US Food and Drug Administration (FDA).

    PubMed

    Weaver, Joyce; Grenade, Lois La; Kwon, Hyon; Avigan, Mark

    2009-01-01

    Marketed pharmaceuticals are evaluated for safety by the US Food and Drug Administration (FDA) throughout the life cycle of the products. The FDA uses data from controlled clinical trials, from postmarketing case reports reported to the FDA's Adverse Event Reporting System, from epidemiological studies, and from registries to evaluate the safety of approved products. For some products, including some products used in dermatologic medicine, risks become apparent during the postmarketing period that require additional measures beyond product labeling and routine pharmacovigilance. The FDA continues to seek additional tools to assess risk, including pharmacogenomic biomarkers for adverse drug reactions and the use of large medical record and epidemiological databases for the systematic detection and characterization of drug-associated safety outcomes.

  6. FDA's proposed regulations to expand access to investigational drugs for treatment use: the status quo in the guise of reform.

    PubMed

    Rossen, Benjamin R

    2009-01-01

    On December 14, 2006, the Food and Drug Administration (FDA) proposed two new regulations in the Federal Register amending current regulations governing expanded access to investigational drugs for treatment use and charging for investigational drugs. The proposals come at a time when FDA has found itself under new pressure to provide seriously ill patients with early access to investigational drugs outside the framework of clinical trials. In recent years, patient advocacy groups have filed citizen petitions with FDA asking the agency to provide specific criteria to patients and sponsors seeking expanded access or to create an early approval mechanism to permit easier access to investigational therapies. Further, FDA has seen proposed federal legislation intended to ensure early patient access to investigational treatments and nearly lost a lawsuit in federal court in which terminally ill patients sought a fundamental right of access to investigational therapies under the Due Process Clause of the Constitution. The proposed rules seek to assuage patient activists, physicians, drug sponsors and other critics who contend that FDA must strike an appropriate balance between allowing patient access to promising treatments while protecting against undue risk and safeguarding the clinical trials process. Although FDA heralded the announcement of the rules as a key step forward to improving patient access, the proposal does not expand access beyond measures currently available under longstanding agency practice and, in fact, creates new regulatory barriers and disincentives to industry participation in expanded access programs. This article examines the proposal in light of historical agency regulation and recent pressures to expand access. Section II describes the historical development of FDA's statutory authority to regulate drugs and the traditional new drug approval process. Section III describes the various methods through which FDA has allowed expanded access to

  7. NCI, NHLBI, FDA, AACC, and CMS Collaborate in Advancing Proteomics Regulatory Science | Office of Cancer Clinical Proteomics Research

    Cancer.gov

    Despite great strides in proteomics and the growing number of articles citing the discovery of potential biomarkers, the actual rate of introduction of Food and Drug Administration (FDA) approved protein analytes has been relatively unchanged over the past 10 years. One of reasons for the lack of new protein-based biomarkers approved has been a lack of information and understanding by the proteomics research community to the regulatory process used by the FDA. To address this issue, Dr.

  8. Regulatory Advocacy Update: ASPS Comments in Response to the FDA Draft Guidance Documents on Human Cell and Tissue Products.

    PubMed

    Rubin, J Peter; D'Amico, Richard A; Rodriguez, Ricardo; Coleman, Sydney R; Cederna, Paul; Glasberg, Scot; Neumeister, Michael; Song, David H; Butler, Charles; Hume, Keith M

    2017-02-09

    The Food and Drug Administration (FDA) released draft guidance documents on Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P) Regulations. These proposed guidance documents can impact the practice of plastic surgery in the area of tissue grafting procedures. This article describes the relevant issues in these draft guidance documents, and presents the comments provided to the FDA by the American Society of Plastic Surgeons (ASPS).

  9. Messages about black-box warnings: a comparative analysis of reports from the FDA and lay media in the US.

    PubMed

    Yong, Pierre L; Bigman, Cabral; Flynn, David N; Mittermaier, Danielle; Long, Judith A

    2009-01-01

    The US FDA and lay media are important sources of information for the public about the risks of adverse events associated with drugs, yet the quality of FDA and US lay media reports about medication 'black-box' warnings, which highlight potentially severe adverse events from medications, is unknown. To determine and compare the content of FDA and US lay media reports about medication black-box warnings. We assessed FDA and US lay media reports about medication black-box warnings published or aired between 1 January 2003 and 31 December 2007 for the presence of six core message components, including (i) the affected drug's brand name; (ii) generic name; (iii) treatment indication; (iv) reason for the black-box warning; (v) clinical recommendations for patients, such as warning signs and symptoms of the adverse effect addressed by the black-box warning; and (vi) encouragement to discuss the issue with a healthcare provider, and additional characteristics. FDA reports presented more core information than lay media reports (median 5 vs 3 message components; p < 0.001). FDA reports were more likely to mention generic names (84.6% vs 18.1%; p < 0.001) of affected drugs, while lay media reports less frequently detailed clinical recommendations for patients (43.9% vs 96.2%; p < 0.001). Only 10.6% of lay media reports encouraged patients to seek additional information from their healthcare provider, compared with 48.1% of FDA reports (p < 0.001). FDA and US lay media reports about medication black-box warnings presented different information. This may reflect a difference in underlying motivation for reporting of news about risks of adverse drug events. It may also indicate a lack of agreement and understanding about the best methods to communicate risk information to the public, thus indicating areas for future research.

  10. The prevention and treatment of missing data in clinical trials: an FDA perspective on the importance of dealing with it.

    PubMed

    O'Neill, R T; Temple, R

    2012-03-01

    At the request of the Food and Drug Administration (FDA) and with its funding, the Panel on the Handling of Missing Data in Clinical Trials was created by the National Research Council's Committee on National Statistics. This panel recently published a report(1) with recommendations that will be of use not only to the FDA but also to the entire clinical trial community so that the latter can take measures to improve the conduct and analysis of clinical trials.

  11. Dose Uniformity of Scored and Unscored Tablets: Application of the FDA Tablet Scoring Guidance for Industry.

    PubMed

    Ciavarella, Anthony B; Khan, Mansoor A; Gupta, Abhay; Faustino, Patrick J

    This U.S. Food and Drug Administration (FDA) laboratory study examines the impact of tablet splitting, the effect of tablet splitters, and the presence of a tablet score on the dose uniformity of two model drugs. Whole tablets were purchased from five manufacturers for amlodipine and six for gabapentin. Two splitters were used for each drug product, and the gabapentin tablets were also split by hand. Whole and split amlodipine tablets were tested for content uniformity following the general chapter of the United States Pharmacopeia (USP) Uniformity of Dosage Units <905>, which is a requirement of the new FDA Guidance for Industry on tablet scoring. The USP weight variation method was used for gabapentin split tablets based on the recommendation of the guidance. All whole tablets met the USP acceptance criteria for the Uniformity of Dosage Units. Variation in whole tablet content ranged from 0.5 to 2.1 standard deviation (SD) of the percent label claim. Splitting the unscored amlodipine tablets resulted in a significant increase in dose variability of 6.5-25.4 SD when compared to whole tablets. Split tablets from all amlodipine drug products did not meet the USP acceptance criteria for content uniformity. Variation in the weight for gabapentin split tablets was greater than the whole tablets, ranging from 1.3 to 9.3 SD. All fully scored gabapentin products met the USP acceptance criteria for weight variation. Size, shape, and the presence or absence of a tablet score can affect the content uniformity and weight variation of amlodipine and gabapentin tablets. Tablet splitting produced higher variability. Differences in dose variability and fragmentation were observed between tablet splitters and hand splitting. These results are consistent with the FDA's concerns that tablet splitting can have an effect on the amount of drug present in a split tablet and available for absorption. Tablet splitting has become a very common practice in the United States and throughout

  12. Compounded non-FDA-approved menopausal hormone therapy prescriptions have increased: results of a pharmacy survey.

    PubMed

    Pinkerton, JoAnn V; Constantine, Ginger D

    2016-04-01

    From a survey of compounding pharmacists, specific questions regarding compounded menopausal hormone therapy were used to estimate compounded hormone therapy (CHT) prescribing in the United States. A national online survey was conducted by Rose Research--a market research company consisting of 12,250 US pharmacists from independent community pharmacies (ICPs) and compounding pharmacies (CPs). Pharmacists who completed the survey and met the prespecified criteria were eligible. Data from the survey were extrapolated to estimate overall CHT prescription volume and annual costs of CHT prescriptions for the United States based upon industry data from the National Community Pharmacists Association and IBISWorld. Surveys were completed by 483 pharmacies, including 365 ICPs and 118 CPs. On the basis of the survey responses and extrapolated industry data, an estimated 26 to 33 million CHT prescriptions were filled annually, with total sales estimated at $1.3 to $1.6 billion. CPs (vs ICPs) accounted for a higher proportion of CHT prescriptions. More than half of the ICPs (52%) and CPs (75%) expected continued compounding business growth, with most predicting 5% to 25% growth within 2 years, despite the potential effect of restrictive legislation regarding compounding. On the basis of extrapolated data from numbers of prescriptions reported by pharmacists participating in the survey, the volume of CHT seems to approach that of Food and Drug Administration (FDA)-approved menopausal hormone therapy, and growth in the CHT market is expected. Thus, physicians should educate themselves and the women consulting them about the differences between the FDA-approved and the less-tested CHT formulations. More research on the efficacy, safety, and consistency of non-FDA-approved CHT is needed.

  13. BCS Biowaivers: Similarities and Differences Among EMA, FDA, and WHO Requirements.

    PubMed

    Davit, Barbara M; Kanfer, Isadore; Tsang, Yu Chung; Cardot, Jean-Michel

    2016-05-01

    The Biopharmaceutics Classification System (BCS), based on aqueous solubility and intestinal permeability, has enjoyed wide use since 1995 as a mechanism for waiving in vivo bioavailability and bioequivalence studies. In 2000, the US-FDA was the first regulatory agency to publish guidance for industry describing how to meet criteria for requesting a waiver of in vivo bioavailability and bioequivalence studies for highly soluble, highly permeable (BCS Class I) drugs. Subsequently, the World Health Organization (WHO) and European Medicines Agency (EMA) published guidelines recommending how to obtain BCS biowaivers for BCS Class III drugs (high solubility, low permeability), in addition to Class I drugs. In 2015, the US-FDA became better harmonized with the EMA and WHO following publication of two guidances for industry outlining criteria for obtaining BCS biowaivers for both Class I and Class III drugs. A detailed review and comparison of the BCS Class I and Class III criteria currently recommended by the US-FDA, EMA, and WHO revealed good convergence of the three agencies with respect to BCS biowaiver criteria. The comparison also suggested that, by applying the most conservative of the three jurisdictional approaches, it should be possible for a sponsor to design the same set of BCS biowaiver studies in preparing a submission for worldwide filing to satisfy US, European, and emerging market regulators. It is hoped that the availability of BCS Class I and Class III biowaivers in multiple jurisdictions will encourage more sponsors to request waivers of in vivo bioavailability/bioequivalence testing using the BCS approach.

  14. Dose uniformity of scored and unscored tablets: Application of the FDA Tablet Scoring Guidance for Industry.

    PubMed

    Ciavarella, Anthony; Khan, Mansoor; Gupta, Abhay; Faustino, Patrick

    2016-06-20

    This FDA laboratory study examines the impact of tablet splitting, the effect of tablet splitters, and the presence of a tablet score on the dose uniformity of two model drugs. Whole tablets were purchased from five manufacturers for amlodipine and six for gabapentin. Two splitters were used for each drug product and the gabapentin tablets were also split by hand. Whole and split amlodipine tablets were tested for content uniformity following the general chapter of the United States Pharmacopeia (USP) Uniformity of Dosage Units <905>, which is a requirement of the new FDA Guidance for Industry on tablet scoring. The USP weight variation method was used for gabapentin split tablets based on the recommendation of the guidance. All whole tablets met the USP acceptance criteria for the Uniformity of Dosage Units. Variation in whole tablet content ranged from 0.5-2.1 standard deviation (SD) of the % label claim. Splitting the unscored amlodipine tablets resulted in a significant increase in dose variability of 6.5-25.4 SD when compared to whole tablets. Split tablets from all amlodipine drug products did not meet the USP acceptance criteria for content uniformity. Variation in the weight for gabapentin split tablets was greater than the whole tablets, ranging from 1.3-9.3 SD. All fully scored gabapentin products met the USP acceptance criteria for weight variation. Size, shape, and the presence or absence of a tablet score can affect the content uniformity and weight variation of amlodipine and gabapentin tablets. Tablet splitting produced higher variability. Differences in dose variability and fragmentation were observed between tablet splitters and hand splitting. These results are consistent with the FDA's concerns that tablet splitting "can affect how much drug is present in the split tablet and available for absorption" as stated in the guidance (1). Copyright © 2016, Parenteral Drug Association.

  15. New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

    PubMed Central

    Andersson, Jourdan A.; Fitts, Eric C.; Kirtley, Michelle L.; Ponnusamy, Duraisamy; Peniche, Alex G.; Dann, Sara M.; Motin, Vladimir L.; Chauhan, Sadhana; Rosenzweig, Jason A.; Sha, Jian

    2016-01-01

    Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens. PMID:27067323

  16. Justification of disintegration testing beyond current FDA criteria using in vitro and in silico models

    PubMed Central

    Uebbing, Lukas; Klumpp, Lukas; Webster, Gregory K; Löbenberg, Raimar

    2017-01-01

    Drug product performance testing is an important part of quality-by-design approaches, but this process often lacks the underlying mechanistic understanding of the complex interactions between the disintegration and dissolution processes involved. Whereas a recent draft guideline by the US Food and Drug Administration (FDA) has allowed the replacement of dissolution testing with disintegration testing, the mentioned criteria are not globally accepted. This study provides scientific justification for using disintegration testing rather than dissolution testing as a quality control method for certain immediate release (IR) formulations. A mechanistic approach, which is beyond the current FDA criteria, is presented. Dissolution testing via United States Pharmacopeial Convention Apparatus II at various paddle speeds was performed for immediate and extended release formulations of metronidazole. Dissolution profile fitting via DDSolver and dissolution profile predictions via DDDPlus™ were performed. The results showed that Fickian diffusion and drug particle properties (DPP) were responsible for the dissolution of the IR tablets, and that formulation factors (eg, coning) impacted dissolution only at lower rotation speeds. Dissolution was completely formulation controlled if extended release tablets were tested and DPP were not important. To demonstrate that disintegration is the most important dosage form attribute when dissolution is DPP controlled, disintegration, intrinsic dissolution and dissolution testing were performed in conventional and disintegration impacting media (DIM). Tablet disintegration was affected by DIM and model fitting to the Korsmeyer–Peppas equation showed a growing effect of the formulation in DIM. DDDPlus was able to predict tablet dissolution and the intrinsic dissolution profiles in conventional media and DIM. The study showed that disintegration has to occur before DPP-dependent dissolution can happen. The study suggests that

  17. Association of Attorney Advertising and FDA Action with Prescription Claims: A Time Series Segmented Regression Analysis.

    PubMed

    Tippett, Elizabeth C; Chen, Brian K

    2015-12-01

    Attorneys sponsor television advertisements that include repeated warnings about adverse drug events to solicit consumers for lawsuits against drug manufacturers. The relationship between such advertising, safety actions by the US Food and Drug Administration (FDA), and healthcare use is unknown. To investigate the relationship between attorney advertising, FDA actions, and prescription drug claims. The study examined total users per month and prescription rates for seven drugs with substantial attorney advertising volume and FDA or other safety interventions during 2009. Segmented regression analysis was used to detect pre-intervention trends, post-intervention level changes, and changes in post-intervention trends relative to the pre-intervention trends in the use of these seven drugs, using advertising volume, media hits, and the number of Medicare enrollees as covariates. Data for these variables were obtained from the Center for Medicare and Medicaid Services, Kantar Media, and LexisNexis. Several types of safety actions were associated with reductions in drug users and/or prescription rates, particularly for fentanyl, varenicline, and paroxetine. In most cases, attorney advertising volume rose in conjunction with major safety actions. Attorney advertising volume was positively correlated with prescription rates in five of seven drugs, likely because advertising volume began rising before safety actions, when prescription rates were still increasing. On the other hand, attorney advertising had mixed associations with the number of users per month. Regulatory and safety actions likely reduced the number of users and/or prescription rates for some drugs. Attorneys may have strategically chosen to begin advertising adverse drug events prior to major safety actions, but we found little evidence that attorney advertising reduced drug use. Further research is needed to better understand how consumers and physicians respond to attorney advertising.

  18. Has the tobacco industry evaded the FDA's ban on ‘Light’ cigarette descriptors?

    PubMed Central

    Connolly, Gregory N; Alpert, Hillel R

    2014-01-01

    Background Under the Family Smoking Prevention and Tobacco Control Act (FSPTCA), the Food and Drug Administration (FDA) banned the use of “Lights” descriptors or similar terms on tobacco products that convey messages of reduced risk. Manufacturers eliminated terms explicitly stated and substituted colour name descriptors corresponding to the banned terms. This paper examines whether the tobacco industry complied with or circumvented the law and potential FDA regulatory actions. Methods Philip Morris retailer manuals, manufacturers' annual reports filed with the Massachusetts Department of Public Health, a national public opinion survey, and market-wide cigarette sales data were examined. Results Manufacturers substituted “Gold” for “Light” and “Silver” for “Ultra-light” in the names of Marlboro sub-brands, and “Blue”, “Gold”, and “Silver” for banned descriptors in sub-brand names. Percent filter ventilation levels, used to generate the smoke yield ranges associated with “Lights” categories, appear to have been reassigned to the new colour brand name descriptors. Following the ban, 92% of smokers reported they could easily identify their usual brands, and 68% correctly named the package colour associated with their usual brand, while sales for “Lights” cigarettes remained unchanged. Conclusions Tobacco manufacturers appear to have evaded a critical element of the FSPTCA, the ban on misleading descriptors that convey reduced health risk messages. The FPSTCA provides regulatory mechanisms, including banning these products as adulterated (Section 902). Manufacturers could then apply for pre-market approval as new products and produce evidence for FDA evaluation and determination whether or not sales of these products are in the public health interest. PMID:23485704

  19. Analysis of Transitional and Turbulent Flow Through the FDA Benchmark Nozzle Model Using Laser Doppler Velocimetry.

    PubMed

    Taylor, Joshua O; Good, Bryan C; Paterno, Anthony V; Hariharan, Prasanna; Deutsch, Steven; Malinauskas, Richard A; Manning, Keefe B

    2016-09-01

    Transitional and turbulent flow through a simplified medical device model is analyzed as part of the FDA's Critical Path Initiative, designed to improve the process of bringing medical products to market. Computational predictions are often used in the development of devices and reliable in vitro data is needed to validate computational results, particularly estimations of the Reynolds stresses that could play a role in damaging blood elements. The high spatial resolution of laser Doppler velocimetry (LDV) is used to collect two component velocity data within the FDA benchmark nozzle model. Two flow conditions are used to produce flow encompassing laminar, transitional, and turbulent regimes, and viscous stresses, principal Reynolds stresses, and turbulence intensities are calculated from the measured LDV velocities. Axial velocities and viscous stresses are compared to data from a prior inter-laboratory study conducted with particle image velocimetry. Large velocity gradients are observed near the wall in the nozzle throat and in the jet shear layer located in the expansion downstream of the throat, with axial velocity changing as much as 4.5 m/s over 200 μm. Additionally, maximum Reynolds shear stresses of 1000-2000 Pa are calculated in the high shear regions, which are an order of magnitude higher than the peak viscous shear stresses (<100 Pa). It is important to consider the effects of both viscous and turbulent stresses when simulating flow through medical devices. Reynolds stresses above commonly accepted hemolysis thresholds are measured in the nozzle model, indicating that hemolysis may occur under certain flow conditions. As such, the presented turbulence quantities from LDV, which are also available for download at https://fdacfd.nci.nih.gov/ , provide an ideal validation test for computational simulations that seek to characterize the flow field and to predict hemolysis within the FDA nozzle geometry.

  20. Reductions in Use of Colchicine after FDA Enforcement of Market Exclusivity in a Commercially Insured Population.

    PubMed

    Kesselheim, Aaron S; Franklin, Jessica M; Kim, Seoyoung C; Seeger, John D; Solomon, Daniel H

    2015-11-01

    A brand-name version of colchicine (Colcrys) was introduced after its manufacturer conducted a clinical trial in acute gout patients, leading to higher prices for this drug. We analyzed the impact of the new single-source colchicine product on prescribing and patient health spending as well as incidence rates of potentially dangerous concomitant use of clarithromycin and cyclosporine after formal FDA approval. We conducted a retrospective cohort study of UnitedHealth-affiliated enrollees newly diagnosed with gout or FMF. Among gout and FMF patients separately, we assessed linear trends in colchicine prescriptions, prescription drug costs, and total health care costs from 2009 to September 2010 (market exclusivity announced) compared to January 2011 (market exclusivity enforced) through 2012. Next, we estimated trends in co-prescription within 15 days of clarithromycin, azithromycin (indicated on the Colcrys label for use in place of clarithromycin), and cyclosporine. Among gout patients, before Colcrys' market exclusivity, the odds of receiving colchicine within 30 days of gout diagnosis increased 1.4 %/month (OR: 1.014, 95 % CI: 1.011-1.018). Following FDA action, the odds decreased by 0.5 %/month (OR: 0.995, 95 % CI: 0.992-0.999) (p < 0.001). Similarly, among FMF patients, odds of initiating colchicine changed from an increase of 2.8 %/month to a decrease by 7.6 %/month (p = 0.01). Patients receiving colchicine experienced increases in average monthly prescription drug costs ($418 vs. $651, p < 0.001) and health care costs ($3,406 vs. $3,534, p < 0.001). Incidence rates of colchicine/clarithromycin co-prescription before and after FDA action did not change, while co-prescription of colchicine/cyclosporine increased after introduction of Colcrys [-0.75 monthly change in patients (95 % CI: -1.07, -0.43) vs. 0.13 (95 % CI: -0.16, 0.42), p < 0.001]. The FDA's actions were associated with a reduction in colchicine initiation and an increase

  1. Delegations of authority and organization; National Childhood Vaccine Injury Act of 1986--FDA. Final rule.

    PubMed

    1993-04-01

    The Food and Drug Administration (FDA) is amending the regulations for delegations of authority by adding new authorities delegated by the Assistant Secretary for Health to the Commissioner of Food and Drugs (the Commissioner). The new authorities are under certain provisions of the Public Health Service Act (the PHS Act) and of the National Childhood Vaccine Injury Act of 1986. The authorities added are being further redelegated, from the Commissioner to the Director, Center for Biologics Evaluation and Research (CBER), and the Associate Director for Policy Coordination and Public Affairs, CBER.

  2. AMCP Partnership Forum: Enabling the Exchange of Clinical and Economic Information Pre-FDA Approval.

    PubMed

    2017-01-01

    Current federal laws and FDA regulations have significantly restricted the sharing of clinical and health economic information on biopharmaceuticals that have yet to receive FDA approval. Over the past several years, organizations that make health care coverage decisions, including those that set copayments, premiums, and formulary placement, have expressed a need for receiving this information before approval, as long as appropriate safeguards exist to prevent this information from reaching unintended entities. Population health decision makers have indicated that waiting until FDA approval is often too late for the critical planning, budgeting, and forecasting associated with health benefit design, especially given the recent influx of high-cost medications and scrutiny for better evaluation and preparation. Recognizing that securities laws restrict the disclosure of nonpublic information and may need to be amended, permissible early dissemination would allow population health decision makers to incorporate clinical and economic information for pipeline drugs or expanded indications into financial forecasting for the following year's plan. Access to this information is needed 12-18 months before FDA approval when organizations are deciding on terms of coverage and budgetary assumptions for state health insurance rate filings, Medicare and Medicaid bids, contracts with health care purchasers, and other financial arrangements. The need for exchange of clinical economic information before FDA approval was first introduced at a previous Academy of Managed Care (AMCP) forum in March 2016, which addressed section 114 of the Food and Drug Administration Modernization Act and the communication of such information after FDA approval. To address preapproval information specifically, AMCP convened a Partnership Forum on September 13-14, 2016. This forum included a diverse group of stakeholders representing managed care, the biopharmaceutical industry, providers, patients

  3. Isotretinoin and inflammatory bowel disease: trial lawyer misuse of science and FDA warnings.

    PubMed

    Tenner, Scott

    2014-04-01

    Based on the Food and Drug Administration Adverse Event Reporting System (FAERS), the FDA and Hoffman La Roche issued warnings of a possible causal association between isotretinoin and inflammatory bowel disease. While scientists studied the association, trial lawyers used the courts to award large sums of money to plaintiffs despite the absence of clear scientific evidence of a causal effect. In this Issue of the Journal, a well-designed, large pharmaco-epidemiologic study shows no association. The story of isotretinoin highlights the problems that occur when the FAERS is used in litigation prior to further study and scientific analysis.

  4. FDA Approves Immunotherapy for a Cancer that Affects Infants and Children | Poster

    Cancer.gov

    By Frank Blanchard, Staff Writer The U.S. Food and Drug Administration (FDA) recently approved dinutuximab (ch14.18) as an immunotherapy for neuroblastoma, a rare type of childhood cancer that offers poor prognosis for about half of the children who are affected. The National Cancer Institute’s (NCI) Biopharmaceutical Development Program (BDP) at the Frederick National Laboratory for Cancer Research produced ch14.18 for the NCI-sponsored clinical trials that proved the drug’s effectiveness against the disease.

  5. Assessing the Impact of HL7/FDA Structured Product Label (SPL) Content for Medication Knowledge Management

    PubMed Central

    Schadow, Gunther

    2007-01-01

    The amount and quality of the SPL drug knowledge which has been released so far is assessed. All published labels were loaded into a relational database and classified to create vendor-independent descriptions. While SPL labels cover only 23% of RxNorm clinical drugs, they still describe 78% of actual community pharmacy dispenses records. SPL descriptions agree well with RxNorm. SPL can be used as the primary source of drug information for e-prescribing systems once the upcoming FDA listing rule takes effect. In the interim, existing gaps can be temporarily closed with RxNorm or other sources. PMID:18693916

  6. FDA Approves Immunotherapy for a Cancer that Affects Infants and Children | Poster

    Cancer.gov

    By Frank Blanchard, Staff Writer The U.S. Food and Drug Administration (FDA) recently approved dinutuximab (ch14.18) as an immunotherapy for neuroblastoma, a rare type of childhood cancer that offers poor prognosis for about half of the children who are affected. The National Cancer Institute’s (NCI) Biopharmaceutical Development Program (BDP) at the Frederick National Laboratory for Cancer Research produced ch14.18 for the NCI-sponsored clinical trials that proved the drug’s effectiveness against the disease.

  7. FDA advisory committees meet January 26 on Salk HIV-1 immunogen.

    PubMed

    1995-01-06

    Two advisory committees of the Food and Drug Administration (FDA) will meet to consider future trials of the HIV-1 immunogen developed by Dr. Jonas Salk. The Immune Response Corporation has already conducted several studies of the immunogen, and has found improvement in various immunological and other blood tests, and no adverse effects. However, the studies have not been large enough to show conclusively that the treatment has clinical benefit in delaying disease progression. The new, larger trials are intended to demonstrate a delay in disease progression and validate the use of blood-test markers of disease progression for studying an immune-based treatment.

  8. Changes in FDA enforcement activities following changes in federal administration: the case of regulatory letters released to pharmaceutical companies.

    PubMed

    Nguyen, Diane; Seoane-Vazquez, Enrique; Rodriguez-Monguio, Rosa; Montagne, Michael

    2013-01-22

    The United States (US) Food and Drug Administration (FDA) is responsible for the protection of the public health by assuring the safety, effectiveness and security of human drugs and biological products through the enforcement of the Federal Food, Drug and Cosmetic Act (FDCA) and related regulations. These enforcement activities include regulatory letters (i.e. warning letters and notice of violation) to pharmaceutical companies. A regulatory letter represents the FDA's first official notification to a pharmaceutical company that the FDA has discovered a product or activity in violation of the FDCA.This study analyzed trends in the pharmaceutical-related regulatory letters released by the FDA during the period 1997-2011 and assessed differences in the average number and type of regulatory letters released during the last four federal administrations. Data derived from the FDA webpage. Information about the FDA office releasing the letter, date, company, and drug-related violation was collected. Regulatory letters were classified by federal administration. Descriptive statistics were performed for the analysis. Between 1997 and 2011 the FDA released 2,467 regulatory letters related to pharmaceuticals. FDA headquarters offices released 50.6% and district offices 49.4% of the regulatory letters. The Office of Prescription Drug Promotion released the largest number of regulatory letters (850; 34.5% of the total), followed by the Office of Scientific Investigations (131; 5.3%), and the Office of Compliance (105; 4.3%). During the 2nd Clinton Administration (1997-2000) the average number of regulatory letters per year was 242.8 ± 45.6, during the Bush Administration (2001-2008) it was 120.4 ± 33.7, and during the first three years of the Obama administration (2009-2011) it was 177.7.0 ± 17.0. The average number of regulatory letters released by the Office of Prescription Drug Promotion also varied by administration: Clinton (122.3 ± 36.4), Bush (29.5

  9. Update on medical and regulatory issues pertaining to compounded and FDA-approved drugs, including hormone therapy

    PubMed Central

    Pinkerton, JoAnn V.; Pickar, James H.

    2016-01-01

    Abstract Objective: We review the historical regulation of drug compounding, concerns about widespread use of non-Food and Drug Admiistration (FDA)-approved compounded bioidentical hormone therapies (CBHTs), which do not have proper labeling and warnings, and anticipated impact of the 2013 Drug Quality and Security Act (DQSA) on compounding. Methods: US government websites were searched for documents concerning drug compounding regulation and oversight from 1938 (passage of Federal Food, Drug, and Cosmetic Act [FDCA]) through 2014, including chronologies, Congressional testimony, FDA guidelines and enforcements, and reports. The FDCA and DQSA were reviewed. PubMed and Google were searched for articles on compounded drugs, including CBHT. Results: Congress explicitly granted the FDA limited oversight of compounded drugs in a 1997 amendment to the FDCA, but the FDA has encountered obstacles in exercising that authority. After 64 patient deaths and 750 adversely affected patients from the 2012 meningitis outbreak due to contaminated compounded steroid injections, Congress passed the DQSA, authorizing the FDA to create a voluntary registration for facilities that manufacture and distribute sterile compounded drugs in bulk and reinforcing FDCA regulations for traditional compounding. Given history and current environment, concerns remain about CBHT product regulation and their lack of safety and efficacy data. Conclusions: The DQSA and its reinforcement of §503A of the FDCA solidifies FDA authority to enforce FDCA provisions against compounders of CBHT. The new law may improve compliance and accreditation by the compounding industry; support state and FDA oversight; and prevent the distribution of misbranded, adulterated, or inconsistently compounded medications, and false and misleading claims, thus reducing public health risk. PMID:26418479

  10. Comparison of the FDA and ASCO/CAP Criteria for HER2 Immunohistochemistry in Upper Urinary Tract Urothelial Carcinoma.

    PubMed

    Kim, Gilhyang; Chung, Yul Ri; Kim, Bohyun; Song, Boram; Moon, Kyung Chul

    2016-11-01

    Human epidermal growth factor receptor 2 (HER2) is one of the known oncogenes in urothelial carcinoma. However, the association between HER2 and the prognosis of upper urinary tract urothelial carcinoma (UUTUC) has not yet been fully clarified. The aim of this study was to evaluate HER2 expression using the United States Food and Drug Administration (FDA) criteria and American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria and compare their prognostic significance in UUTUC. HER2 expression was evaluated in 144 cases of UUTUC by immunohistochemistry (IHC) using tissue microarrays. We separately analyzed HER2 expression using the FDA and ASCO/CAP criteria. The IHC results were categorized into low (0, 1+) and high (2+, 3+) groups. Using the FDA criteria, 94 cases were negative, 38 cases were 1+, nine cases were 2+, and three cases were 3+. Using the ASCO/CAP criteria, 94 cases were negative, 34 cases were 1+, 13 cases were 2+, and three cases were 3+. Four cases showing 2+ according to the ASCO/CAP criteria were reclassified as 1+ by the FDA criteria. High HER2 expression by both the FDA criteria and ASCO/CAP criteria was significantly associated with International Society of Urological Pathology high grade (p = .001 and p < .001). The high HER2 expression group classified with the FDA criteria showed significantly shorter cancer-specific survival (p = .004), but the HER2 high and low expression groups classified with the ASCO/CAP criteria did not show significant differences (p = .161) in cancer-specific survival. HER2 high expression groups were significantly associated with shorter cancer-specific survival, and our study revealed that the FDA criteria are more suitable for determining HER2 expression in UUTUC.

  11. Comparison of the FDA and ASCO/CAP Criteria for HER2 Immunohistochemistry in Upper Urinary Tract Urothelial Carcinoma

    PubMed Central

    Kim, Gilhyang; Chung, Yul Ri; Kim, Bohyun; Song, Boram; Moon, Kyung Chul

    2016-01-01

    Background Human epidermal growth factor receptor 2 (HER2) is one of the known oncogenes in urothelial carcinoma. However, the association between HER2 and the prognosis of upper urinary tract urothelial carcinoma (UUTUC) has not yet been fully clarified. The aim of this study was to evaluate HER2 expression using the United States Food and Drug Administration (FDA) criteria and American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria and compare their prognostic significance in UUTUC. Methods HER2 expression was evaluated in 144 cases of UUTUC by immunohistochemistry (IHC) using tissue microarrays. We separately analyzed HER2 expression using the FDA and ASCO/CAP criteria. The IHC results were categorized into low (0, 1+) and high (2+, 3+) groups. Results Using the FDA criteria, 94 cases were negative, 38 cases were 1+, nine cases were 2+, and three cases were 3+. Using the ASCO/CAP criteria, 94 cases were negative, 34 cases were 1+, 13 cases were 2+, and three cases were 3+. Four cases showing 2+ according to the ASCO/CAP criteria were reclassified as 1+ by the FDA criteria. High HER2 expression by both the FDA criteria and ASCO/CAP criteria was significantly associated with International Society of Urological Pathology high grade (p = .001 and p < .001). The high HER2 expression group classified with the FDA criteria showed significantly shorter cancer-specific survival (p = .004), but the HER2 high and low expression groups classified with the ASCO/CAP criteria did not show significant differences (p = .161) in cancer-specific survival. Conclusions HER2 high expression groups were significantly associated with shorter cancer-specific survival, and our study revealed that the FDA criteria are more suitable for determining HER2 expression in UUTUC. PMID:27725621

  12. ClinicalTrials.gov and Drugs@FDA: A Comparison of Results Reporting for New Drug Approval Trials.

    PubMed

    Schwartz, Lisa M; Woloshin, Steven; Zheng, Eugene; Tse, Tony; Zarin, Deborah A

    2016-09-20

    Pharmaceutical companies and other trial sponsors must submit certain trial results to ClinicalTrials.gov. The validity of these results is unclear. To validate results posted on ClinicalTrials.gov against publicly available U.S. Food and Drug Administration (FDA) reviews on Drugs@FDA. ClinicalTrials.gov (registry and results database) and Drugs@FDA (medical and statistical reviews). 100 parallel-group, randomized trials for new drug approvals (January 2013 to July 2014) with results posted on ClinicalTrials.gov (15 March 2015). 2 assessors extracted, and another verified, the trial design, primary and secondary outcomes, adverse events, and deaths. Most trials were phase 3 (90%), double-blind (92%), and placebo-controlled (73%) and involved 32 drugs from 24 companies. Of 137 primary outcomes identified from ClinicalTrials.gov, 134 (98%) had corresponding data at Drugs@FDA, 130 (95%) had concordant definitions, and 107 (78%) had concordant results. Most differences were nominal (that is, relative difference <10%). Primary outcome results in 14 trials could not be validated. Of 1927 secondary outcomes from ClinicalTrials.gov, Drugs@FDA mentioned 1061 (55%) and included results data for 367 (19%). Of 96 trials with 1 or more serious adverse events in either source, 14 could be compared and 7 had discordant numbers of persons experiencing the adverse events. Of 62 trials with 1 or more deaths in either source, 25 could be compared and 17 were discordant. Unknown generalizability to uncontrolled or crossover trial results. Primary outcome definitions and results were largely concordant between ClinicalTrials.gov and Drugs@FDA. Half the secondary outcomes, as well as serious events and deaths, could not be validated because Drugs@FDA includes only "key outcomes" for regulatory decision making and frequently includes only adverse event results aggregated across multiple trials. National Library of Medicine.

  13. ClinicalTrials.gov and Drugs@FDA: A comparison of results reporting for new drug approval trials

    PubMed Central

    Schwartz, Lisa M.; Woloshin, Steven; Zheng, Eugene; Tse, Tony; Zarin, Deborah A.

    2016-01-01

    Background Pharmaceutical companies and other trial sponsors must submit certain trial results to ClinicalTrials.gov. The validity of these results is unclear. Purpose To validate results posted on ClinicalTrials.gov against publicly-available FDA reviews on Drugs@FDA. Data sources ClinicalTrials.gov (registry and results database) and Drugs@FDA (medical/statistical reviews). Study selection 100 parallel-group, randomized trials for new drug approvals (1/2013 – 7/2014) with results posted on ClinicalTrials.gov (3/15/2015). Data extraction Two assessors systematically extracted, and another verified, trial design, primary/secondary outcomes, adverse events, and deaths. Results The 100 trials were mostly phase 3 (90%) double-blind (92%), placebo-controlled (73%), representing 32 drugs from 24 companies. Of 137 primary outcomes from ClinicalTrials.gov, 134 (98%) had corresponding data in Drugs@FDA, 130 (95%) had concordant definitions, and 107 (78%) had concordant results; most differences were nominal (i.e. relative difference < 10%). Of 100 trials, primary outcome results in 14 could not be validated . Of 1,927 secondary outcomes from ClinicalTrials.gov, 1,061 (55%) definitions could be validated and 367 (19%) had results. Of 96 trials with ≥ 1 serious adverse event in either source, 14 could be compared and 7 were discordant. Of 62 trials with ≥ 1 death in either source, 25 could be compared and 17 were discordant. Limitations Unknown generalizability to uncontrolled or crossover trial results. Conclusion Primary outcome definitions and results were largely concordant between ClinicalTrials.gov and Drugs@FDA. Half of secondary outcomes could not be validated because Drugs@FDA only includes “key outcomes” for regulatory decision-making; nor could serious adverse events and deaths because Drugs@FDA frequently only includes results aggregated across multiple trials. PMID:27294570

  14. An FDA bioinformatics tool for microbial genomics research on molecular characterization of bacterial foodborne pathogens using microarrays.

    PubMed

    Fang, Hong; Xu, Joshua; Ding, Don; Jackson, Scott A; Patel, Isha R; Frye, Jonathan G; Zou, Wen; Nayak, Rajesh; Foley, Steven; Chen, James; Su, Zhenqiang; Ye, Yanbin; Turner, Steve; Harris, Steve; Zhou, Guangxu; Cerniglia, Carl; Tong, Weida

    2010-10-07

    Advances in microbial genomics and bioinformatics are offering greater insights into the emergence and spread of foodborne pathogens in outbreak scenarios. The Food and Drug Administration (FDA) has developed a genomics tool, ArrayTrack™, which provides extensive functionalities to manage, analyze, and interpret genomic data for mammalian species. ArrayTrack™ has been widely adopted by the research community and used for pharmacogenomics data review in the FDA's Voluntary Genomics Data Submission program. ArrayTrack™ has been extended to manage and analyze genomics data from bacterial pathogens of human, animal, and food origin. It was populated with bioinformatics data from public databases such as NCBI, Swiss-Prot, KEGG Pathway, and Gene Ontology to facilitate pathogen detection and characterization. ArrayTrack™'s data processing and visualization tools were enhanced with analysis capabilities designed specifically for microbial genomics including flag-based hierarchical clustering analysis (HCA), flag concordance heat maps, and mixed scatter plots. These specific functionalities were evaluated on data generated from a custom Affymetrix array (FDA-ECSG) previously developed within the FDA. The FDA-ECSG array represents 32 complete genomes of Escherichia coli and Shigella. The new functions were also used to analyze microarray data focusing on antimicrobial resistance genes from Salmonella isolates in a poultry production environment using a universal antimicrobial resistance microarray developed by the United States Department of Agriculture (USDA). The application of ArrayTrack™ to different microarray platforms demonstrates its utility in microbial genomics research, and thus will improve the capabilities of the FDA to rapidly identify foodborne bacteria and their genetic traits (e.g., antimicrobial resistance, virulence, etc.) during outbreak investigations. ArrayTrack™ is free to use and available to public, private, and academic researchers at

  15. In Vitro Tolerance of Drug-Naive Staphylococcus aureus Strain FDA209P to Vancomycin

    PubMed Central

    Singh, Madhuri; Sasaki, Takashi; Morimoto, Yuh; Hishinuma, Tomomi; Hiramatsu, Keiichi

    2016-01-01

    ABSTRACT The mechanisms underlying bacterial tolerance to antibiotics are unclear. A possible adaptation strategy was explored by exposure of drug-naive methicillin-susceptible Staphylococcus aureus strain FDA209P to vancomycin in vitro. Strains surviving vancomycin treatment (vancomycin survivor strains), which appeared after 96 h of exposure, were slow-growing derivatives of the parent strain. Although the vancomycin MICs for the survivor strains were within the susceptible range, the cytokilling effects of vancomycin at 20-fold the MIC were significantly lower for the survivor strains than for the parent strain. Whole-genome sequencing demonstrated that ileS, encoding isoleucyl-tRNA synthetase (IleRS), was mutated in two of the three vancomycin survivor strains. The IleRS Y723H mutation is located close to the isoleucyl-tRNA contact site and potentially affects the affinity of IleRS binding to isoleucyl-tRNA, thereby inhibiting protein synthesis and leading to vancomycin tolerance. Introduction of the mutation encoding IleRS Y723H into FDA209P by allelic replacement successfully transferred the vancomycin tolerance phenotype. We have identified mutation of ileS to be one of the bona fide genetic events leading to the acquisition of vancomycin tolerance in S. aureus, potentially acting via inhibition of the function of IleRS. PMID:27855063

  16. FDA cigarette warning labels lower craving and elicit frontoinsular activation in adolescent smokers

    PubMed Central

    Do, Kathy T.

    2015-01-01

    Cigarette smoking is an economically and epidemiologically expensive public health concern. Most adult smokers become addicted during adolescence, rendering it a crucial period for prevention and intervention. Although litigation claims have delayed implementation, graphic warning labels proposed by the U.S. Food and Drug Administration (FDA) may be a promising way to achieve this goal. We aimed to determine the efficacy of the labels in reducing in-scanner craving and to characterize the neurobiological responses in adolescent and adult smokers and non-smokers. While undergoing functional magnetic resonance imaging, thirty-nine 13- to 18-year-old adolescent and forty-one 25- to 30-year-old adult smokers and non-smokers rated their desire to smoke when presented with emotionally graphic warning labels and comparison non-graphic labels. Compared with adult smokers, adolescent smokers exhibited greater craving reduction in response to the warning labels. Although smokers evinced overall blunted recruitment of insula and dorsolateral prefrontal cortex (DLPFC) relative to non-smokers, an effect that was stronger in adolescent smokers, parametrically increasing activation of these regions was associated with greater craving reduction. Functional connectivity analyses suggest that greater DLPFC regulation of limbic regions predicted cigarette craving. These data underscore a prominent role of frontoinsular circuitry in predicting the efficacy of FDA graphic warning labels in craving reduction in adult and adolescent smokers. PMID:25887154

  17. A Retrospective Evaluation of the Use of Mass Spectrometry in FDA Biologics License Applications

    NASA Astrophysics Data System (ADS)

    Rogstad, Sarah; Faustino, Anneliese; Ruth, Ashley; Keire, David; Boyne, Michael; Park, Jun

    2017-05-01

    The characterization sections of biologics license applications (BLAs) approved by the United States Food and Drug Administration (FDA) between 2000 and 2015 were investigated to examine the extent of the use of mass spectrometry. Mass spectrometry was found to be integral to the characterization of these biotherapeutics. Of the 80 electronically submitted monoclonal antibody and protein biotherapeutic BLAs included in this study, 79 were found to use mass spectrometric workflows for protein or impurity characterization. To further examine how MS is being used in successful BLAs, the applications were filtered based on the type and number of quality attributes characterized, the mass spectrometric workflows used (peptide mapping, intact mass analysis, and cleaved glycan analysis), the methods used to introduce the proteins into the gas phase (ESI, MALDI, or LC-ESI), and the specific types of instrumentation used. Analyses were conducted over a time course based on the FDA BLA approval to determine if any trends in utilization could be observed over time. Additionally, the different classes of protein-based biotherapeutics among the approved BLAs were clustered to determine if any trends could be attributed to the specific type of biotherapeutic.

  18. USDA FSIS, FDA BAM, AOAC, and ISO culture methods BD BBL CHROMagar Listeria Media.

    PubMed

    Ritter, Vicki; Kircher, Susan; Sturm, Krista; Warns, Patty; Dick, Nancy

    2009-01-01

    BBL CHROMagar Listeria Media (CL) was evaluated for detection of Listeria monocytogenes in raw ground beef, smoked salmon, lettuce, and Brie cheese. The recovery of L. monocytogenes on CL was compared to the U.S. Food and Drug Administration (FDA) Bacteriological Analytical Manual (BAM), U.S. Department of Agriculture (USDA) Food Safety and Inspection Service (FSIS), AOAC, and International Organization for Standardization (ISO) reference-plated media using the recommended pre-enrichments and selective enrichments. Of the 265 food samples tested, 140 were tested using BAM, USDA, or AOAC methods and 125 were tested using ISO methods. CL produced comparable results with the reference methods on all matrixes with a sensitivity of 99.3% and a specificity of 100%. No false negatives were found in testing the food matrixes. There was no statistical difference in recovery based on Chi-square analysis. Known isolates were evaluated, and CL had a sensitivity and specificity of 100%. The results of this study demonstrate that CL is an effective medium for the recovery and detection of L. monocytogenes in raw ground beef, smoked salmon, lettuce, and Brie cheese using FDA BAM, USDA FSIS, AOAC, and ISO culture methods.

  19. ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy.

    PubMed

    Ottesen, Eric W

    2017-01-01

    Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza(™) (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza(™) showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza(™) is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza(™) underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols.

  20. Data Mining of the Public Version of the FDA Adverse Event Reporting System

    PubMed Central

    Sakaeda, Toshiyuki; Tamon, Akiko; Kadoyama, Kaori; Okuno, Yasushi

    2013-01-01

    The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS, formerly AERS) is a database that contains information on adverse event and medication error reports submitted to the FDA. Besides those from manufacturers, reports can be submitted from health care professionals and the public. The original system was started in 1969, but since the last major revision in 1997, reporting has markedly increased. Data mining algorithms have been developed for the quantitative detection of signals from such a large database, where a signal means a statistical association between a drug and an adverse event or a drug-associated adverse event, including the proportional reporting ratio (PRR), the reporting odds ratio (ROR), the information component (IC), and the empirical Bayes geometric mean (EBGM). A survey of our previous reports suggested that the ROR provided the highest number of signals, and the EBGM the lowest. Additionally, an analysis of warfarin-, aspirin- and clopidogrel-associated adverse events suggested that all EBGM-based signals were included in the PRR-based signals, and also in the IC- or ROR-based ones, and that the PRR- and IC-based signals were in the ROR-based ones. In this article, the latest information on this area is summarized for future pharmacoepidemiological studies and/or pharmacovigilance analyses. PMID:23794943

  1. Larval Zebrafish Model for FDA-Approved Drug Repositioning for Tobacco Dependence Treatment

    PubMed Central

    Cousin, Margot A.; Ebbert, Jon O.; Wiinamaki, Amanda R.; Urban, Mark D.; Argue, David P.; Ekker, Stephen C.; Klee, Eric W.

    2014-01-01

    Cigarette smoking remains the most preventable cause of death and excess health care costs in the United States, and is a leading cause of death among alcoholics. Long-term tobacco abstinence rates are low, and pharmacotherapeutic options are limited. Repositioning medications approved by the U.S. Food and Drug Administration (FDA) may efficiently provide clinicians with new treatment options. We developed a drug-repositioning paradigm using larval zebrafish locomotion and established predictive clinical validity using FDA-approved smoking cessation therapeutics. We evaluated 39 physician-vetted medications for nicotine-induced locomotor activation blockade. We further evaluated candidate medications for altered ethanol response, as well as in combination with varenicline for nicotine-response attenuation. Six medications specifically inhibited the nicotine response. Among this set, apomorphine and topiramate blocked both nicotine and ethanol responses. Both positively interact with varenicline in the Bliss Independence test, indicating potential synergistic interactions suggesting these are candidates for translation into Phase II clinical trials for smoking cessation. PMID:24658307

  2. ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy

    PubMed Central

    Ottesen, Eric W.

    2017-01-01

    Abstract Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza™ (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza™ showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza™ is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza™ underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols. PMID:28400976

  3. A Retrospective Evaluation of the Use of Mass Spectrometry in FDA Biologics License Applications

    NASA Astrophysics Data System (ADS)

    Rogstad, Sarah; Faustino, Anneliese; Ruth, Ashley; Keire, David; Boyne, Michael; Park, Jun

    2016-11-01

    The characterization sections of biologics license applications (BLAs) approved by the United States Food and Drug Administration (FDA) between 2000 and 2015 were investigated to examine the extent of the use of mass spectrometry. Mass spectrometry was found to be integral to the characterization of these biotherapeutics. Of the 80 electronically submitted monoclonal antibody and protein biotherapeutic BLAs included in this study, 79 were found to use mass spectrometric workflows for protein or impurity characterization. To further examine how MS is being used in successful BLAs, the applications were filtered based on the type and number of quality attributes characterized, the mass spectrometric workflows used (peptide mapping, intact mass analysis, and cleaved glycan analysis), the methods used to introduce the proteins into the gas phase (ESI, MALDI, or LC-ESI), and the specific types of instrumentation used. Analyses were conducted over a time course based on the FDA BLA approval to determine if any trends in utilization could be observed over time. Additionally, the different classes of protein-based biotherapeutics among the approved BLAs were clustered to determine if any trends could be attributed to the specific type of biotherapeutic.

  4. Modeling and simulation in dose determination for biodefense products approved under the FDA animal rule.

    PubMed

    Bergman, Kimberly L; Krudys, K; Seo, S K; Florian, J

    2017-04-01

    Development of effective medical countermeasures for biodefense is vital to United States biopreparedness and response in the age of terrorism, both foreign and domestic. A traditional drug development pathway toward approval is not possible for most biodefense-related indications, creating the need for alternative development pathways such as the FDA's Animal Rule. Under this unique regulatory mechanism, FDA-approval is based on adequate and well-controlled animal studies when it is neither ethical nor feasible to conduct human efficacy studies. Translation of animal efficacy findings to humans is accomplished by use of modeling and simulation techniques. Pharmacokinetic and exposure-response modeling allow effective dosing regimens in humans to be identified, which are expected to produce similar benefit to that observed in animal models of disease. In this review, the role of modeling and simulation in determining the human dose for biodefense products developed under the Food and Drug Administration's Animal Rule regulatory pathway is discussed, and case studies illustrating the utility of modeling and simulation in this area of development are presented.

  5. Generation of recombinant arenavirus for vaccine development in FDA-approved Vero cells.

    PubMed

    Cheng, Benson Y H; Ortiz-Riaño, Emilio; de la Torre, Juan Carlos; Martínez-Sobrido, Luis

    2013-08-01

    The development and implementation of arenavirus reverse genetics represents a significant breakthrough in the arenavirus field. The use of cell-based arenavirus minigenome systems together with the ability to generate recombinant infectious arenaviruses with predetermined mutations in their genomes has facilitated the investigation of the contribution of viral determinants to the different steps of the arenavirus life cycle, as well as virus-host interactions and mechanisms of arenavirus pathogenesis. In addition, the development of trisegmented arenaviruses has permitted the use of the arenavirus genome to express additional foreign genes of interest, thus opening the possibility of arenavirus-based vaccine vector applications. Likewise, the development of single-cycle infectious arenaviruses capable of expressing reporter genes provides a new experimental tool to improve the safety of research involving highly pathogenic human arenaviruses. The generation of recombinant arenaviruses using plasmid-based reverse genetics techniques has so far relied on the use of rodent cell lines, which poses some barriers for the development of Food and Drug Administration (FDA)-licensed vaccine or vaccine vectors. To overcome this obstacle, we describe here the efficient generation of recombinant arenaviruses in FDA-approved Vero cells.

  6. FDA-approved neurologic devices intended for use in infants, children, and adolescents.

    PubMed

    Peña, Carlos; Bowsher, Kristen; Samuels-Reid, Joy

    2004-10-12

    The US Food and Drug Administration (FDA) has approved several applications for the marketing of neurologic devices. Nineteen high risk Class III medical devices were approved for the central and peripheral nervous system for marketing between 1994 and 2003, and almost half (n = 8) include indications for use in children as well as adults. On July 24, 2003, the FDA Center for Devices and Radiologic Health released for public comment a draft guidance document entitled "Premarket Assessment of Pediatric Medical Devices," which included in its objectives, the types of information needed to provide reasonable assurance of the safety and effectiveness of medical devices intended for use in children. The draft guidance document is also relevant to the types of information needed to promote the safe and effective development of neurologic devices. We review risk assessment and ways to reduce risk for neurologic devices intended for use in children. We also discuss the deep brain stimulator, the cochlear implant, and the CSF shunt, and considerations for minimizing risks associated with brain development, physical growth, surgery, and human factors.

  7. FDA proposals to limit the hepatotoxicity of paracetamol (acetaminophen): are they reasonable?

    PubMed

    Graham, Garry G; Day, Richard O; Graudins, Andis; Mohamudally, Anthoulla

    2010-04-01

    Hepatotoxicity from paracetamol is of great concern because of the considerable number of patients who develop severe toxicity from this drug. A group of senior medical practitioners, academics and scientists were brought together on June 29 and 30, 2009 by the Food and Drug Administration of USA (FDA) with the aim of providing advice on how to limit the number of cases of hepatotoxicity due to paracetamol in USA. The most contentious recommendations were the reduction in the dose of paracetamol to 650 mg and the elimination of prescription combination products of paracetamol and opiates. The first recommendation indicates that many members of the committee consider, despite much evidence to the contrary, that therapeutic doses of paracetamol (up to 4 g daily) are associated with a significant incidence of hepatotoxicity. The second recommendation, if accepted by FDA, will require major changes in the therapeutic use of paracetamol and opiates. Adoption of these two recommendations may lead to the increased use of NSAIDs with the potential of increasing incidence of NSAIDs-related adverse reactions.

  8. Doxil®--the first FDA-approved nano-drug: lessons learned.

    PubMed

    Barenholz, Yechezkel

    2012-06-10

    Doxil®, the first FDA-approved nano-drug (1995), is based on three unrelated principles: (i) prolonged drug circulation time and avoidance of the RES due to the use of PEGylated nano-liposomes; (ii) high and stable remote loading of doxorubicin driven by a transmembrane ammonium sulfate gradient, which also allows for drug release at the tumor; and (iii) having the liposome lipid bilayer in a "liquid ordered" phase composed of the high-T(m) (53 °C) phosphatidylcholine, and cholesterol. Due to the EPR effect, Doxil is "passively targeted" to tumors and its doxorubicin is released and becomes available to tumor cells by as yet unknown means. This review summarizes historical and scientific perspectives of Doxil development and lessons learned from its development and 20 years of its use. It demonstrates the obligatory need for applying an understanding of the cross talk between physicochemical, nano-technological, and biological principles. However, in spite of the large reward, ~2 years after Doxil-related patents expired, there is still no FDA-approved generic "Doxil" available.

  9. Guidance for pharmacogenomic biomarker testing in labels of FDA-approved drugs.

    PubMed

    Vivot, Alexandre; Boutron, Isabelle; Ravaud, Philippe; Porcher, Raphaël

    2015-09-01

    The aim of this study was to compare guidance for genetic testing in US Food and Drug Administration (FDA)-approved drug labels in oncology to those of drugs for other therapeutic areas. We reviewed labels of all the FDA-approved drugs with labels containing pharmacogenomic information. We assessed whether genetic testing was required or recommended before prescription and, if not, the reason for pharmacogenomic labeling. We included 140 drugs corresponding to 158 drug-biomarker pairs. Overall, 46 (29%) of 158 pairs stated a requirement or recommendation for genetic biomarker testing in the label. This proportion was higher in oncology than in other areas (62 vs. 12%; P < 0.001). For the 112 drug-biomarker pairs (including 20 in oncology) without recommendation or requirement for genetic testing, the main reasons for pharmacogenomic labeling were change in pharmacologic end points (32%) and higher risk of toxicity (30%). For 11 (10%) pairs (including 1 in oncology), a genetic biomarker was mentioned only to inform that it was not relevant. In oncology, the main reasons for pharmacogenomic labeling were higher risk of toxicity (55%) and definition of the mechanism of action (25%). Inclusion of biomarkers in drug labels does not always correspond to required or recommended genetic testing, especially outside oncology.Genet Med 17 9, 733-738.

  10. Data mining of the public version of the FDA Adverse Event Reporting System.

    PubMed

    Sakaeda, Toshiyuki; Tamon, Akiko; Kadoyama, Kaori; Okuno, Yasushi

    2013-01-01

    The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS, formerly AERS) is a database that contains information on adverse event and medication error reports submitted to the FDA. Besides those from manufacturers, reports can be submitted from health care professionals and the public. The original system was started in 1969, but since the last major revision in 1997, reporting has markedly increased. Data mining algorithms have been developed for the quantitative detection of signals from such a large database, where a signal means a statistical association between a drug and an adverse event or a drug-associated adverse event, including the proportional reporting ratio (PRR), the reporting odds ratio (ROR), the information component (IC), and the empirical Bayes geometric mean (EBGM). A survey of our previous reports suggested that the ROR provided the highest number of signals, and the EBGM the lowest. Additionally, an analysis of warfarin-, aspirin- and clopidogrel-associated adverse events suggested that all EBGM-based signals were included in the PRR-based signals, and also in the IC- or ROR-based ones, and that the PRR- and IC-based signals were in the ROR-based ones. In this article, the latest information on this area is summarized for future pharmacoepidemiological studies and/or pharmacovigilance analyses.

  11. FDA guidance for ABSSSI trials: implications for conducting and interpreting clinical trials.

    PubMed

    Itani, Kamal M F; Shorr, Andrew F

    2014-01-01

    Recent guidance from the US Food and Drug Administration (FDA) on the conduct of clinical trials for acute bacterial skin and skin structure infection (ABSSSI) has changed the framework for clinical trial design and conduct. Notable changes included new disease state definitions, new primary endpoint definitions and the timing of assessments at these endpoints, and updated guidance on patient inclusion/exclusion criteria. Supportive evidence and statistical justification for the proposed noninferiority margins were described in detail. Although the updated guidelines are still considered drafts and have been adopted in some trials, they serve as the basis for study protocol discussions between pharmaceutical companies and the FDA in advancing the development of promising new agents. Not only will the new trial designs impact researchers and sponsors responsible for drug development programs, but they will also affect healthcare providers participating in clinical trials and the ways in which clinicians develop patient treatment plans based on the results of those trials. This review provides a summary of key changes that will impact future clinical trial design and outcomes.

  12. Large eddy simulation of the FDA benchmark nozzle for a Reynolds number of 6500.

    PubMed

    Janiga, Gábor

    2014-04-01

    This work investigates the flow in a benchmark nozzle model of an idealized medical device proposed by the FDA using computational fluid dynamics (CFD). It was in particular shown that a proper modeling of the transitional flow features is particularly challenging, leading to large discrepancies and inaccurate predictions from the different research groups using Reynolds-averaged Navier-Stokes (RANS) modeling. In spite of the relatively simple, axisymmetric computational geometry, the resulting turbulent flow is fairly complex and non-axisymmetric, in particular due to the sudden expansion. The resulting flow cannot be well predicted with simple modeling approaches. Due to the varying diameters and flow velocities encountered in the nozzle, different typical flow regions and regimes can be distinguished, from laminar to transitional and to weakly turbulent. The purpose of the present work is to re-examine the FDA-CFD benchmark nozzle model at a Reynolds number of 6500 using large eddy simulation (LES). The LES results are compared with published experimental data obtained by Particle Image Velocimetry (PIV) and an excellent agreement can be observed considering the temporally averaged flow velocities. Different flow regimes are characterized by computing the temporal energy spectra at different locations along the main axis.

  13. Mining FDA drug labels using an unsupervised learning technique - topic modeling

    PubMed Central

    2011-01-01

    Background The Food and Drug Administration (FDA) approved drug labels contain a broad array of information, ranging from adverse drug reactions (ADRs) to drug efficacy, risk-benefit consideration, and more. However, the labeling language used to describe these information is free text often containing ambiguous semantic descriptions, which poses a great challenge in retrieving useful information from the labeling text in a consistent and accurate fashion for comparative analysis across drugs. Consequently, this task has largely relied on the manual reading of the full text by experts, which is time consuming and labor intensive. Method In this study, a novel text mining method with unsupervised learning in nature, called topic modeling, was applied to the drug labeling with a goal of discovering “topics” that group drugs with similar safety concerns and/or therapeutic uses together. A total of 794 FDA-approved drug labels were used in this study. First, the three labeling sections (i.e., Boxed Warning, Warnings and Precautions, Adverse Reactions) of each drug label were processed by the Medical Dictionary for Regulatory Activities (MedDRA) to convert the free text of each label to the standard ADR terms. Next, the topic modeling approach with latent Dirichlet allocation (LDA) was applied to generate 100 topics, each associated with a set of drugs grouped together based on the probability analysis. Lastly, the efficacy of the topic modeling was evaluated based on known information about the therapeutic uses and safety data of drugs. Results The results demonstrate that drugs grouped by topics are associated with the same safety concerns and/or therapeutic uses with statistical significance (P<0.05). The identified topics have distinct context that can be directly linked to specific adverse events (e.g., liver injury or kidney injury) or therapeutic application (e.g., antiinfectives for systemic use). We were also able to identify potential adverse events that

  14. FDA hearing highlights opposition to dietary supplement practices; written comments due August 20. Food and Drug Administration.

    PubMed

    James, J S

    1999-08-06

    A July 1999 FDA hearing on dietary supplements revealed vehement opposition to the free rein regulations that are given to the dietary supplements industry. Unless abuses in the industry are somehow curbed, congressional action may occur. Industry representatives at an earlier FDA meeting criticized the agency for not cracking down on fraudulent or improper health-food products. It was suggested that the National Institutes of Health research the safety and efficacy of these products, with possible fees assessed from industry. The FDA has requested public feedback on how it should regulate the dietary supplement industry. Such regulation may make some supplements unavailable at any price in the United States, which could potentially harm people with serious illness. The key issue is how to halt unethical marketing while maintaining public access.

  15. Regulatory underpinnings of Global Health security: FDA's roles in preventing, detecting, and responding to global health threats.

    PubMed

    Courtney, Brooke; Bond, Katherine C; Maher, Carmen

    2014-01-01

    In February 2014, health officials from around the world announced the Global Health Security Agenda, a critical effort to strengthen national and global systems to prevent, detect, and respond to infectious disease threats and to foster stronger collaboration across borders. With its increasing global roles and broad range of regulatory responsibilities in ensuring the availability, safety, and security of medical and food products, the US Food and Drug Administration (FDA) is engaged in a range of efforts in support of global health security. This article provides an overview of FDA's global health security roles, focusing on its responsibilities related to the development and use of medical countermeasures (MCMs) for preventing, detecting, and responding to global infectious disease and other public health emergency threats. The article also discusses several areas-antimicrobial resistance, food safety, and supply chain integrity-in which FDA's global health security roles continue to evolve and extend beyond MCMs and, in some cases, beyond traditional infectious disease threats.

  16. FDA approval of expanded age indication for a tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine.

    PubMed

    2011-09-23

    On July 8, 2011, the Food and Drug Administration (FDA) approved an expanded age indication for the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) Boostrix (GlaxoSmithKline Biologicals, Rixensart, Belgium). Originally, Boostrix was licensed in 2005 for persons aged 10 through 18 years, but in 2008, FDA approved an expanded age indication for Boostrix to include persons aged 19 through 64 years. FDA has now expanded the age indication to include persons aged 65 years and older. Boostrix is now licensed for use in persons aged 10 years and older as a single-dose booster vaccination. This notice summarizes the indications for use of Boostrix. Recommendations of the Advisory Committee on Immunization Practices (ACIP) for Tdap vaccines have been published previously. Publication of revised Tdap recommendations within the next year is anticipated.

  17. Efficacy and safety concerns are important reasons why the FDA requires multiple reviews before approval of new drugs.

    PubMed

    Ross, Joseph S; Dzara, Kristina; Downing, Nicholas S

    2015-04-01

    The regulatory approval of new drugs by the Food and Drug Administration (FDA) is a long and complex process and often requires multiple cycles of review, potentially delaying patients' access to new and effective therapeutics. We used qualitative methods to characterize the safety and efficacy reasons why applications for novel therapeutics approved by the FDA between 2001 and 2011 required multiple review cycles prior to approval. Among ninety-six applications approved between 2001 and 2011 that required multiple review cycles, safety concerns contributed to seventy-four (77.1 percent) and efficacy concerns to forty-three (44.8 percent). Our study suggests that multiple review cycles appear to play an important role in allowing the FDA to protect public health and in ensuring adequate understanding of clinical benefits and risks prior to approval.

  18. Can the FDA improve oversight of foreign clinical trials?: Closing the information gap and moving towards a globalized regulatory scheme.

    PubMed

    Ourso, André

    2012-01-01

    Currently, pharmaceutical companies' utilization of foreign clinical trial data is a ubiquitous and indispensable aspect of gaining approval to market drugs in the United States. Cost benefits, a larger pool of ready volunteer subjects, and greater efficiency in clinical testing are some of the reasons for conducting clinical trials overseas. Despite these advantages, lack of proper oversight may have serious public health implications regarding the integrity of clinical research, ethical treatment of human subjects, and drug safety. Due to the expansive global nature of foreign clinical trials, there are concerns with the FDA's ability to monitor and regulate these trials. This article examines the FDA's oversight of foreign clinical trials and the agency's limitations regulating these trials. In addition to looking at steps the FDA is taking to address these limitations, the article examines other potential regulatory and cooperative actions that can be taken to effectively monitor foreign clinical trials and to ensure data integrity and patient safety.

  19. Impact of the FDA warning of potential ceftriaxone and calcium interactions on drug use policy in clinical practice.

    PubMed

    Esterly, John S; Steadman, Emily; Scheetz, Marc H

    2011-06-01

    In September 2007, the FDA issued an alert recommending that ceftriaxone and calcium-containing solutions should not be administered to any patient within 48 h of each other. Due to the widespread use of ceftriaxone, significant concern was expressed by the greater healthcare community about the warning, which the FDA eventually retracted in April of 2009. We sought to quantify the impact of the warning on healthcare institutions. A survey was administered to the membership of the Society of Infectious Diseases Pharmacists to quantify perceived changes in ceftriaxone use among healthcare institutions across the United States. A survey of Infectious Diseases experts was conducted. Participants were queried for hospital policies/drug use statistics during two times: immediately after the FDA warning and approximately 13 months post warning (preceding the FDA retraction). Related changes in formulary, drug-use policy, and the number of employee hours that were devoted to addressing the FDA warning were assessed. Ninety-four surveys representing 94 hospital systems were included in the analysis. Approximately half (n = 49, 52%) of respondent institutions enacted at least one drug-use policy change based on the warning; one institution removed ceftriaxone from a clinical protocol. Institutions' final interpretations of the warning differed slightly from initial understanding of the warning, and there was an overall minor decrease in the perceived use of ceftriaxone. The majority of those surveyed (n = 70, 74%) estimated that their respective institutions devoted between 1 and 49 employee hours to address the warning. Hospitals with ID pharmacists had minimal changes to ceftriaxone use after the 2007 FDA warning. Specialized pharmacists may be uniquely situated to help hospitals interpret global recommendations locally.

  20. Cigarette Graphic Warning Labels and Smoking Prevalence in Canada: A Critical Examination and Reformulation of the FDA Regulatory Impact Analysis

    PubMed Central

    Huang, Jidong; Chaloupka, Frank J.; Fong, Geoffrey T.

    2014-01-01

    Background The estimated effect of cigarette graphic warning labels (GWLs) on smoking rates is a key input to FDA's regulatory impact analysis (RIA), required by law as part of its rulemaking process. However, evidence on the impact of GWLs on smoking prevalence is scarce. Objective The goal of this paper is to critically analyze FDA's approach to estimating the impact of GWLs on smoking rates in its RIA, and to suggest a path forward to estimating the impact of the adoption of GWLs in Canada on Canadian national adult smoking prevalence. Methods A quasi-experimental methodology was employed to examine the impact of adoption of GWLs in Canada in 2000, using the U.S. as a control. Findings We found a statistically significant reduction in smoking rates after the adoption of GWLs in Canada in comparison to the U.S. Our analyses show that implementation of GWLs in Canada reduced smoking rates by 2.87 to 4.68 percentage points, a relative reduction of 12.1 to 19.6% — 33 to 53 times larger than FDA's estimates of a 0.088 percentage point reduction. We also demonstrated that FDA's estimate of the impact was flawed because it is highly sensitive to the changes in variable selection, model specification, and the time period analyzed. Conclusions Adopting GWLs on cigarette packages reduces smoking prevalence. Applying our analysis of the Canadian GWLs, we estimate that if the U.S. had adopted GWLs in 2012, the number of adult smokers in the U.S. would have decreased by 5.3 to 8.6 million in 2013. Our analysis demonstrates that FDA's approach to estimating the impact of GWLs on smoking rates is flawed. Rectifying these problems before this approach becomes the norm is critical for FDA's effective regulation of tobacco products. PMID:24218057

  1. Cigarette graphic warning labels and smoking prevalence in Canada: a critical examination and reformulation of the FDA regulatory impact analysis.

    PubMed

    Huang, Jidong; Chaloupka, Frank J; Fong, Geoffrey T

    2014-03-01

    The estimated effect of cigarette graphic warning labels (GWL) on smoking rates is a key input to the Food and Drug Administration's (FDA) regulatory impact analysis (RIA), required by law as part of its rule-making process. However, evidence on the impact of GWLs on smoking prevalence is scarce. The goal of this paper is to critically analyse FDA's approach to estimating the impact of GWLs on smoking rates in its RIA, and to suggest a path forward to estimating the impact of the adoption of GWLs in Canada on Canadian national adult smoking prevalence. A quasi-experimental methodology was employed to examine the impact of adoption of GWLs in Canada in 2000, using the USA as a control. We found a statistically significant reduction in smoking rates after the adoption of GWLs in Canada in comparison with the USA. Our analyses show that implementation of GWLs in Canada reduced smoking rates by 2.87-4.68 percentage points, a relative reduction of 12.1-19.6%; 33-53 times larger than FDA's estimates of a 0.088 percentage point reduction. We also demonstrated that FDA's estimate of the impact was flawed because it is highly sensitive to the changes in variable selection, model specification, and the time period analysed. Adopting GWLs on cigarette packages reduces smoking prevalence. Applying our analysis of the Canadian GWLs, we estimate that if the USA had adopted GWLs in 2012, the number of adult smokers in the USA would have decreased by 5.3-8.6 million in 2013. Our analysis demonstrates that FDA's approach to estimating the impact of GWLs on smoking rates is flawed. Rectifying these problems before this approach becomes the norm is critical for FDA's effective regulation of tobacco products.

  2. Regulatory and scientific issues regarding use of foreign data in support of new drug applications in the United States: an FDA perspective.

    PubMed

    Khin, N A; Yang, P; Hung, H M J; Maung-U, K; Chen, Y-F; Meeker-O'Connell, A; Okwesili, P; Yasuda, S U; Ball, L K; Huang, S-M; O'Neill, R T; Temple, R

    2013-08-01

    Globalization of clinical research has led to an increase in clinical trials conducted outside of the United States that are submitted to the US Food and Drug Administration (FDA) in new drug applications. This article discusses the FDA's experience with these submissions in specific therapeutic areas, including the extent of this practice, differences between the effectiveness and safety outcomes of studies conducted inside and outside the United States, and the FDA's approach to acceptance of these trials.

  3. FDA’s (Federal Drug Administration) Reviews of New Drugs: Changes Needed in Process for Reviewing and Reporting on Clinical Studies

    DTIC Science & Technology

    1988-09-01

    and the reliability of test data submitted to FDA in support of new drug applications. GAO reviewed the Division’s activities, including its...responsibilities relating to the approval of new drug and biologic products; the accuracy of FDA data and adequacy of oversight regarding clinical...investigators, institutional review boards, and toxicology laboratories involved in studies supporting new drug applications; FDA’s review of studies by clinical

  4. Real-Time Imaging of Electrical Signals with an Infrared FDA-Approved Dye

    PubMed Central

    Treger, Jeremy S.; Priest, Michael F.; Iezzi, Raymond; Bezanilla, Francisco

    2014-01-01

    Clinical methods used to assess the electrical activity of excitable cells are often limited by their poor spatial resolution or their invasiveness. One promising solution to this problem is to optically measure membrane potential using a voltage-sensitive dye, but thus far, none of these dyes have been available for human use. Here we report that indocyanine green (ICG), an infrared fluorescent dye with FDA approval as an intravenously administered contrast agent, is voltage-sensitive. The fluorescence of ICG can follow action potentials in artificial neurons and cultured rat neurons and cardiomyocytes. ICG also visualized electrical activity induced in living explants of rat brain. In humans, ICG labels excitable cells and is routinely visualized transdermally with high spatial resolution. As an infrared voltage-sensitive dye with a low toxicity profile that can be readily imaged in deep tissues, ICG may have significant utility for clinical and basic research applications previously intractable for potentiometric dyes. PMID:25229155

  5. An analysis of FDA-approved drugs for inflammation and autoimmune diseases.

    PubMed

    Kinch, Michael S; Merkel, Janie

    2015-08-01

    The term 'inflammation' captures a variety of disease processes linked with the immune system. An analysis of US Food and Drug Administration (FDA)-approved nuclear molecular entities (NMEs) reveals notable trends in terms of acute and chronic inflammatory indications. The number of NMEs peaked during the 1990s and has since declined by more than 50%. Whereas pharmaceutical companies have dominated the field, biotechnology companies now receive half of new approvals and academia has a relatively large role in terms of pivotal first patents. Another notable trend is that the relative number of NMEs targeting allergy has been decreasing, whereas those targeting autoimmune indications is increasing. Unlike other indications, NMEs for inflammation tend towards nuclear receptors and cytokines, and a disproportionate number of biologics target cytokine pathways.

  6. Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium.

    PubMed

    Dieterle, Frank; Sistare, Frank; Goodsaid, Federico; Papaluca, Marisa; Ozer, Josef S; Webb, Craig P; Baer, William; Senagore, Anthony; Schipper, Matthew J; Vonderscher, Jacky; Sultana, Stefan; Gerhold, David L; Phillips, Jonathan A; Maurer, Gérard; Carl, Kevin; Laurie, David; Harpur, Ernie; Sonee, Manisha; Ennulat, Daniela; Holder, Dan; Andrews-Cleavenger, Dina; Gu, Yi-Zhong; Thompson, Karol L; Goering, Peter L; Vidal, Jean-Marc; Abadie, Eric; Maciulaitis, Romaldas; Jacobson-Kram, David; Defelice, Albert F; Hausner, Elizabeth A; Blank, Melanie; Thompson, Aliza; Harlow, Patricia; Throckmorton, Douglas; Xiao, Shen; Xu, Nancy; Taylor, William; Vamvakas, Spiros; Flamion, Bruno; Lima, Beatriz Silva; Kasper, Peter; Pasanen, Markku; Prasad, Krishna; Troth, Sean; Bounous, Denise; Robinson-Gravatt, Denise; Betton, Graham; Davis, Myrtle A; Akunda, Jackie; McDuffie, James Eric; Suter, Laura; Obert, Leslie; Guffroy, Magalie; Pinches, Mark; Jayadev, Supriya; Blomme, Eric A; Beushausen, Sven A; Barlow, Valérie G; Collins, Nathaniel; Waring, Jeff; Honor, David; Snook, Sandra; Lee, Jinhe; Rossi, Phil; Walker, Elizabeth; Mattes, William

    2010-05-01

    The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.

  7. Novel algorithms for improved pattern recognition using the US FDA Adverse Event Network Analyzer.

    PubMed

    Botsis, Taxiarchis; Scott, John; Goud, Ravi; Toman, Pamela; Sutherland, Andrea; Ball, Robert

    2014-01-01

    The medical review of adverse event reports for medical products requires the processing of "big data" stored in spontaneous reporting systems, such as the US Vaccine Adverse Event Reporting System (VAERS). VAERS data are not well suited to traditional statistical analyses so we developed the FDA Adverse Event Network Analyzer (AENA) and three novel network analysis approaches to extract information from these data. Our new approaches include a weighting scheme based on co-occurring triplets in reports, a visualization layout inspired by the islands algorithm, and a network growth methodology for the detection of outliers. We explored and verified these approaches by analysing the historical signal of Intussusception (IS) after the administration of RotaShield vaccine (RV) in 1999. We believe that our study supports the use of AENA for pattern recognition in medical product safety and other clinical data.

  8. The FDA Perspective on Pre-Clinical Testing for High Intensity Focused Ultrasound Devices

    NASA Astrophysics Data System (ADS)

    Harris, Gerald R.

    2006-05-01

    In the U. S., the pre-market review of high intensity focused ultrasound (HIFU) devices is carried out under the authority of the 1976 Medical Device Amendments to the Food, Drug, and Cosmetic Act. Different regulatory mechanisms may apply depending on the complexity of the HIFU device and the indications for use, but in all cases pre-clinical testing is required. This testing typically includes ultrasound field characterization, thermal modeling and measurement, and may include demonstrating the accuracy of targeting and monitoring, if applicable. Because there are no guidance documents or standards for these tests at present, the U.S. Food and Drug Administration (FDA) welcomes working with interested parties to develop acceptable procedures that can be incorporated into the regulatory review process.

  9. An analysis of the FDA Food Safety Modernization Act: protection for consumers and boon for business.

    PubMed

    Strauss, Debra M

    2011-01-01

    This article analyzes components of the FDA Food Safety Modernization Act, which was prompted by incidents of food contamination, exploring the history of its passage and explaining its significance, as well as its limitations. As the first time in 70 years that food law has been changed substantially, this new law represents only an initial but significant step in the direction of improving food safety. With bipartisan support from both Congress and the President, this legislation embodies a mandate that food safety is at this moment becoming a priority. As a result, the time is ripe for a reassessment of other areas of food laws--particularly genetically modified foods and the use of milk and meat from cloned animals and their progeny--which are allowed under current U.S. law with no labeling, preapprovals, or post-market monitoring. These areas warrant special regulation consistent with the new proactive policy towards securing the safety of the food supply.

  10. The US FDA 'black box' warning for topical calcineurin inhibitors: an ongoing controversy.

    PubMed

    Ring, Johannes; Möhrenschlager, Matthias; Henkel, Verena

    2008-01-01

    Atopic dermatitis is a chronic inflammatory skin disease characterized by recurrent intense pruritus and a distinctive distribution of skin lesions. The topical calcineurin inhibitors tacrolimus and pimecrolimus were approved in the USA, as an ointment and a cream, respectively, for the treatment of atopic dermatitis in 2000 and 2001, respectively. In 2005, the Pediatric Advisory Committee of the US FDA implemented a 'black box' warning for tacrolimus ointment and pimecrolimus cream due to the lack of long-term safety data and the potential risk of the development of malignancies. This article focuses on the safety aspects of these agents by discussing the findings from preclinical and clinical studies and postmarketing reports with regard to malignancies occurring after the use of tacrolimus ointment and pimecrolimus cream.

  11. FDA's nozzle numerical simulation challenge: non-Newtonian fluid effects and blood damage.

    PubMed

    Trias, Miquel; Arbona, Antonio; Massó, Joan; Miñano, Borja; Bona, Carles

    2014-01-01

    Data from FDA's nozzle challenge-a study to assess the suitability of simulating fluid flow in an idealized medical device-is used to validate the simulations obtained from a numerical, finite-differences code. Various physiological indicators are computed and compared with experimental data from three different laboratories, getting a very good agreement. Special care is taken with the derivation of blood damage (hemolysis). The paper is focused on the laminar regime, in order to investigate non-Newtonian effects (non-constant fluid viscosity). The code can deal with these effects with just a small extra computational cost, improving Newtonian estimations up to a ten percent. The relevance of non-Newtonian effects for hemolysis parameters is discussed.

  12. DNA, drugs and chariots: on a decade of pharmacogenomics at the US FDA.

    PubMed

    Lesko, Lawrence J; Zineh, Issam

    2010-04-01

    Over the past 10 years, the US FDA has become a strong pharmacogenomics advocate as part of its mission to both protect and advance public health by enabling innovations that make medicines safer to use and more effective. The agency has evolved its advocacy cautiously on a foundation of science-based information from novel programs, such as the Voluntary Genomics Data Submission initiative, and on careful regulatory assessment of the extraordinary advances in clinical pharmacogenomics that have supported the update of drug labels with genetic information. This commentary goes into detail on the evolution of these achievements. However, many challenges remain for pharmacogenomics, and they will continue to evolve, and all stakeholders must work together. As the decade draws to a close, we have presented four major areas that need to be addressed collectively to assure that pharmacogenomics continues to mature over the next 10 years into a science that is essential to the practice of medicine.

  13. Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations.

    PubMed

    Ellis, Kyle J; Stouffer, George A; McLeod, Howard L; Lee, Craig R

    2009-11-01

    Antiplatelet therapy with clopidogrel is the current standard of care for coronary artery disease patients undergoing a percutaneous coronary intervention. However, approximately 25% of patients experience a subtherapeutic antiplatelet response. Clopidogrel is a prodrug that undergoes hepatic biotransformation by CYP2C19 into its active metabolite. Several studies have reported that, compared with wild-type individuals, CYP2C19 variant allele carriers exhibit a significantly lower capacity to metabolize clopidogrel into its active metabolite and inhibit platelet activation, and are therefore at significantly higher risk of adverse cardiovascular events. Consequently, the US FDA has recently changed clopidogrel's prescribing information to highlight the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics and clinical response. Future studies remain necessary to develop effective personalized therapeutic strategies for CYP2C19 variant allele carriers and other individuals at risk for clopidogrel nonresponsiveness.

  14. AAPS and US FDA Crystal City VI workshop on bioanalytical method validation for biomarkers.

    PubMed

    Lowes, Steve; Ackermann, Bradley L

    2016-02-01

    Crystal City VI Workshop on Bioanalytical Method Validation of Biomarkers, Renaissance Baltimore Harborplace Hotel, Baltimore, MD, USA, 28-29 September 2015 The Crystal City VI workshop was organized by the American Association of Pharmaceutical Scientists in association with the US FDA to continue discussion on the bioanalysis of biomarkers. An outcome of the Crystal City V workshop, convened following release of the draft FDA Guidance for Industry on Bioanalytical Methods Validation in 2013 was the need to have further discussion on biomarker methods. Biomarkers ultimately became the sole focal point for Crystal City VI, a meeting attended by approximately 200 people and composed of industry scientists and regulators from around the world. The meeting format included several panel discussions to maximize the opportunity for dialogue among participants. Following an initial session on the general topic of biomarker assays and intended use, more focused sessions were held on chromatographic (LC-MS) and ligand-binding assays. In addition to participation by the drug development community, significant representation was present from clinical testing laboratories. The experience of this latter group, collectively identified as practitioners of CLIA (Clinical Laboratory Improvement Amendments), helped shape the discussion and takeaways from the meeting. While the need to operate within the framework of the current BMV guidance was clearly acknowledged, a general understanding that biomarker methods validation cannot be adequately depicted by current PK-centric guidelines emerged as a consensus from the meeting. This report is not intended to constitute the official proceedings from Crystal City VI, which is expected to be published in early 2016.

  15. Neonatal Safety Information Reported to the FDA During Drug Development Studies

    PubMed Central

    Avant, Debbie; Baer, Gerri; Moore, Jason; Zheng, Panli; Sorbello, Alfred; Ariagno, Ron; Yao, Lynne; Burckart, Gilbert J.; Wang, Jian

    2017-01-01

    Background Relatively few neonatal drug development studies have been conducted, but an increase is expected with the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA). Understanding the safety of drugs studied in neonates is complicated by the unique nature of the population and the level of illness. The objective of this study was to examine neonatal safety data submitted to the FDA in studies pursuant to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) between 1998 and 2015. Methods FDA databases were searched for BPCA and/or PREA studies that enrolled neonates. Studies that enrolled a minimum of 3 neonates were analyzed for the presence and content of neonatal safety data. Results The analysis identified 40 drugs that were studied in 3 or more neonates. Of the 40 drugs, 36 drugs received a pediatric labeling change as a result of studies between 1998 and 2015, that included information from studies including neonates. Fourteen drugs were approved for use in neonates. Clinical trials for 20 of the drugs reported serious adverse events (SAEs) in neonates. The SAEs primarily involved cardiovascular events such as bradycardia and/or hypotension or laboratory abnormalities such as anemia, neutropenia, and electrolyte disturbances. Deaths were reported during studies of 9 drugs. Conclusions Our analysis revealed that SAEs were reported in studies involving 20 of the 40 drugs evaluated in neonates, with deaths identified in 9 of those studies. Patients enrolled in studies were often critically ill, which complicated determination of whether an adverse event was drug-related. We conclude that the traditional means for collecting safety information in drug development trials needs to be adjusted for neonates and will require the collaboration of regulators, industry, and the clinical and research communities to establish appropriate definitions and reporting strategies for the neonatal

  16. QUADrATiC: scalable gene expression connectivity mapping for repurposing FDA-approved therapeutics.

    PubMed

    O'Reilly, Paul G; Wen, Qing; Bankhead, Peter; Dunne, Philip D; McArt, Darragh G; McPherson, Suzanne; Hamilton, Peter W; Mills, Ken I; Zhang, Shu-Dong

    2016-05-04

    Gene expression connectivity mapping has proven to be a powerful and flexible tool for research. Its application has been shown in a broad range of research topics, most commonly as a means of identifying potential small molecule compounds, which may be further investigated as candidates for repurposing to treat diseases. The public release of voluminous data from the Library of Integrated Cellular Signatures (LINCS) programme further enhanced the utilities and potentials of gene expression connectivity mapping in biomedicine. We describe QUADrATiC ( http://go.qub.ac.uk/QUADrATiC ), a user-friendly tool for the exploration of gene expression connectivity on the subset of the LINCS data set corresponding to FDA-approved small molecule compounds. It enables the identification of compounds for repurposing therapeutic potentials. The software is designed to cope with the increased volume of data over existing tools, by taking advantage of multicore computing architectures to provide a scalable solution, which may be installed and operated on a range of computers, from laptops to servers. This scalability is provided by the use of the modern concurrent programming paradigm provided by the Akka framework. The QUADrATiC Graphical User Interface (GUI) has been developed using advanced Javascript frameworks, providing novel visualization capabilities for further analysis of connections. There is also a web services interface, allowing integration with other programs or scripts. QUADrATiC has been shown to provide an improvement over existing connectivity map software, in terms of scope (based on the LINCS data set), applicability (using FDA-approved compounds), usability and speed. It offers potential to biological researchers to analyze transcriptional data and generate potential therapeutics for focussed study in the lab. QUADrATiC represents a step change in the process of investigating gene expression connectivity and provides more biologically-relevant results than

  17. Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi.

    PubMed

    Planer, Joseph D; Hulverson, Matthew A; Arif, Jennifer A; Ranade, Ranae M; Don, Robert; Buckner, Frederick S

    2014-07-01

    An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper) have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC50's) in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC50 of 0.4 µM), a selective serotonin reuptake inhibitor (fluoxetine, EC50 of 4.4 µM), and an antifolate drug (pyrimethamine, EC50 of 3.8 µM) and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease.

  18. Development of hybrid fog detection algorithm (FDA) using satellite and ground observation data for nighttime

    NASA Astrophysics Data System (ADS)

    Kim, So-Hyeong; Han, Ji-Hae; Suh, Myoung-Seok

    2017-04-01

    In this study, we developed a hybrid fog detection algorithm (FDA) using AHI/Himawari-8 satellite and ground observation data for nighttime. In order to detect fog at nighttime, Dual Channel Difference (DCD) method based on the emissivity difference between SWIR and IR1 is most widely used. DCD is good at discriminating fog from other things (middle/high clouds, clear sea and land). However, it is difficult to distinguish fog from low clouds. In order to separate the low clouds from the pixels that satisfy the thresholds of fog in the DCD test, we conducted supplementary tests such as normalized local standard derivation (NLSD) of BT11 and the difference of fog top temperature (BT11) and air temperature (Ta) from NWP data (SST from OSTIA data). These tests are based on the larger homogeneity of fog top than low cloud tops and the similarity of fog top temperature and Ta (SST). Threshold values for the three tests were optimized through ROC analysis for the selected fog cases. In addition, considering the spatial continuity of fog, post-processing was performed to detect the missed pixels, in particular, at edge of fog or sub-pixel size fog. The final fog detection results are presented by fog probability (0 100 %). Validation was conducted by comparing fog detection probability with the ground observed visibility data from KMA. The validation results showed that POD and FAR are ranged from 0.70 0.94 and 0.45 0.72, respectively. The quantitative validation and visual inspection indicate that current FDA has a tendency to over-detect the fog. So, more works which reducing the FAR is needed. In the future, we will also validate sea fog using CALIPSO data.

  19. Electrosurgical injuries during robot assisted surgery: insights from the FDA MAUDE database

    NASA Astrophysics Data System (ADS)

    Fuller, Andrew; Vilos, George A.; Pautler, Stephen E.

    2012-02-01

    Introduction: The da Vinci surgical system requires the use of electrosurgical instruments. The re-use of such instruments creates the potential for stray electrical currents from capacitive coupling and/or insulation failure with subsequent injury. The morbidity of such injuries may negate many of the benefits of minimally invasive surgery. We sought to evaluate the rate and nature of electrosurgical injury (ESI) associated with this device. Methods: The Manufacturer and User Facility Device Experience (MAUDE) database is administered by the US Food and Drug Administration (FDA) and reports adverse events related to medical devices in the United States. We analyzed all incidents in the context of robotic surgery between January 2001 and June 2011 to identify those related to the use of electrosurgery. Results: In the past decade, a total of 605 reports have been submitted to the FDA with regard to adverse events related to the da Vinci robotic surgical platform. Of these, 24 (3.9%) were related to potential or actual ESI. Nine out of the 24 cases (37.5%) resulted in additional surgical intervention for repair. There were 6 bowel injuries of which only one was recognized and managed intra-operatively. The remainder required laparotomy between 5 and 8 days after the initial robotic procedure. Additionally, there were 3 skin burns. The remaining cases required conservative management or resulted in no harm. Conclusion: ESI in the context of robotic surgery is uncommon but remains under-recognized and under-reported. Surgeons performing robot assisted surgery should be aware that ESI can occur with robotic instruments and vigilance for intra- and post-operative complications is paramount.

  20. The FDA guidance for industry on PROs: the point of view of a pharmaceutical company

    PubMed Central

    Arpinelli, Fabio; Bamfi, Francesco

    2006-01-01

    The importance of the patients point of view on their health status is widely recognised. Patient-reported outcomes is a broad term encompassing a large variety of different health data reported by patients, as symptoms, functional status, Quality of Life and Health-Related Quality of Life. Measurements of Health-Related Quality of Life have been developed during many years of researches, and a lot of validated questionnaires exist. However, few attempts have been made to standardise the evaluation of instruments characteristics, no recommendations are made about interpretation on Health-Related Quality of Life results, especially regarding the clinical significance of a change leading a therapeutic approach. Moreover, the true value of Health-Related Quality of Life evaluations in clinical trials has not yet been completely defined. An important step towards a more structured and frequent use of Patient-Reported Outcomes in drug development is represented by the FDA Guidance, issued on February 2006. In our paper we aim to report some considerations on this Guidance. Our comments focus especially on the characteristics of instruments to use, the Minimal Important Difference, and the methods to calculate it. Furthermore, we present the advantages and opportunities of using the Patient-Reported Outcomes in drug development, as seen by a pharmaceutical company. The Patient-Reported Outcomes can provide additional data to make a drug more competitive than others of the same pharmacological class, and a well demonstrated positive impact on the patient' health status and daily life might allow a higher price and/or the inclusion in a reimbursement list. Applying extensively the FDA Guidance in the next trials could lead to a wider culture of subjective measurement, and to a greater consideration for the patient's opinions on his/her care. Moreover, prescribing doctors and payers could benefit from subjective information to better define the value of drugs. PMID:17076891

  1. Screening of FDA-Approved Drugs for Inhibitors against Japanese Encephalitis Virus Infection.

    PubMed

    Wang, Shaobo; Liu, Yang; Guo, Jiao; Wang, Peilin; Zhang, Leike; Xiao, Gengfu; Wang, Wei

    2017-08-16

    Japanese encephalitis virus (JEV), an arthropod-borne flavivirus, is a major cause of acute viral encephalitis in humans. There is no approved drug available for JEV-specific treatment, and the vaccines are not effective against all clinical JEV isolates. Herein, a high-throughput screening was performed against JEV from an FDA-approved drug library. Five hit drugs were identified that inhibited JEV infection with a selective index > 10. Antiviral activities of these five hit drugs against other flavivirus, including Zika virus, were also validated. As three of the five hit drugs were calcium inhibitors, additional types of calcium inhibitors were utilized that confirmed calcium was essential for JEV infection, most likely during viral replication. Adaptive mutant analysis uncovered that replacement of Q130, located in transmembrane domain 3 of the non-structural NS4B protein while relatively conserved in flavivirus, with R or K conferred JEV resistance to manidipine, a voltage-gated Ca(2+) channel (VGCC) inhibitor, without apparent loss of the viral growth profile. Furthermore, manidipine was indicated to protect mice against JEV-induced lethality by decreasing viral load in brain, while abrogating histopathological changes associated with JEV infection. This study provided five anti-flavivirus candidates and identified cytoplasmic calcium as a novel antiviral target for treatment of JEV infection. The findings reported here provide therapeutic possibilities for combating infections caused by flavivirus.IMPORTANCE Currently there is no approved therapy to treat Japanese Encephalitis Virus infection. Repurposing of the approved drugs will accelerate the development of the therapeutic stratagem. In this study, we screened an FDA-drugs library and identified five hit drugs, especially calcium inhibitors, exerting anti-flavivirus activity that blocked viral replication. The in vivo efficacy and toxicity of manidipine were investigated with a JEV-infected mouse model

  2. The FDA guidance for industry on PROs: the point of view of a pharmaceutical company.

    PubMed

    Arpinelli, Fabio; Bamfi, Francesco

    2006-10-31

    The importance of the patients point of view on their health status is widely recognised. Patient-reported outcomes is a broad term encompassing a large variety of different health data reported by patients, as symptoms, functional status, Quality of Life and Health-Related Quality of Life. Measurements of Health-Related Quality of Life have been developed during many years of researches, and a lot of validated questionnaires exist. However, few attempts have been made to standardise the evaluation of instruments characteristics, no recommendations are made about interpretation on Health-Related Quality of Life results, especially regarding the clinical significance of a change leading a therapeutic approach. Moreover, the true value of Health-Related Quality of Life evaluations in clinical trials has not yet been completely defined. An important step towards a more structured and frequent use of Patient-Reported Outcomes in drug development is represented by the FDA Guidance, issued on February 2006. In our paper we aim to report some considerations on this Guidance. Our comments focus especially on the characteristics of instruments to use, the Minimal Important Difference, and the methods to calculate it. Furthermore, we present the advantages and opportunities of using the Patient-Reported Outcomes in drug development, as seen by a pharmaceutical company. The Patient-Reported Outcomes can provide additional data to make a drug more competitive than others of the same pharmacological class, and a well demonstrated positive impact on the patient' health status and daily life might allow a higher price and/or the inclusion in a reimbursement list. Applying extensively the FDA Guidance in the next trials could lead to a wider culture of subjective measurement, and to a greater consideration for the patient's opinions on his/her care. Moreover, prescribing doctors and payers could benefit from subjective information to better define the value of drugs.

  3. The Effects of the FDA Warning on the Use of Droperidol by U.S. Emergency Physicians

    PubMed Central

    Richards, John R.; Weiss, Steven J.; Bretz, Stephen W.; Schneir, Aaron B.; Rinetti, Dauna; Derlet, Robert W.

    2003-01-01

    Objectives: To determine if emergency physicians’ (EP) use of droperidol has changed since the United States Food and Drag Administration (FDA) warning of December 2001 concerning QT interval prolongation, torsade de pointes, and sudden death; and to query EP opinions regarding droperidol before and after the FDA warning and regarding potential alternative drugs. Methods: An internet-based survey was designed with questions regarding droperidol use in the emergency department (ED). Data collected included EP demographics, use of droperidol before and after the FDA warning, use of alternative drugs, and incidence of arrhythmias. A representative sample of EPs were contacted by e-mail and asked to complete the survey. Results: A total of 2,000 e-mails resulted in 506 (25%) completed surveys. There was no second mailing. Responders’ average years practicing was 12.6 ± 9.2. EP responders worked in private/community (n=278, 55%), academic/county (n=187, 37%), and HMO (n=41, 8%) hospitals. The. majority (n=455, 90%) used droperidol and were aware of the FDA warning (n=460, 91%). Droperidol was no longer available at 122 (24%) of the respondents’ EDs as a result of the FDA warning. Prior to the FDA warning, EPs who had used droperidol used it as an antiemetic (n=408, 90%), for control of agitation (n=330, 73%), for treatment of headache (n=247, 54%), and for treatment of vertigo (n=106, 23%). After the FDA warning, 387 (85%) of EPs reported their use of droperidol had decreased or ceased altogether, and 68 (15%) always obtained an electrocardiogram prior to administration. Of those who used droperidol for agitation, 137 (42%) felt there were no other drugs with greater efficacy. Haloperidol was the most cited alternative agent (n=260, 79%) followed by benzodiazepines (n=223, 68%). Of those who used droperidol for antiemesis, 116 (28%) felt there were no other drugs with greater efficacy than droperidol; promethazine was the most cited alternative agent (n=260, 64

  4. The FDA, contraceptive marketing approval and products liability litigation: Depo-Provera and the risk of osteoporosis.

    PubMed

    Green, William

    2013-01-01

    The FDA approved Depo-Provera, an injectable contraceptive, in 1992 on the condition that its manufacturer conduct a post-approval study on the risk ofosteoporosis. Then in 2004, the agency revised the drug's labeling to include a boxed (i.e. Black Box) Warning on the risk ofosteoporosis. This article will analyze the FDA's Depo-Provera approval and label revision process: the agency's acceptance of Upjohn's New Drug Application, its Fertility and Maternal Health Advisory Committee's review of the human clinical studies and approval recommendation, its marketing approval of Depo-Provera, and its 2004 drug labeling revision. Then the article will analyze the post-2004 products liability litigation by women who claimed to have been injured by their use of the drug. None of the cases have survived the manufacturer's summary judgment motions, because the women have been unable to establish by expert and physician evidence that the FDA-approved labeling was inadequate to inform their physicians of the risk of osteoporosis, that the inadequate warnings caused their osteoporosis or osteopenia, and that these are compensable injuries. As a result, the manufacturer has been able to use the FDA labeling, state products liability law, and the learned intermediary doctrine to avoid liability. The conclusion will consider the lessons of these products liability cases for other women who have received Depo-Provera and suffered bone mineral density loss.

  5. 21 CFR 170.105 - The Food and Drug Administration's (FDA's) determination that a premarket notification for a food...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES Premarket Notifications § 170.105 The Food... 21 Food and Drugs 3 2011-04-01 2011-04-01 false The Food and Drug Administration's (FDA's) determination that a premarket notification for a food contact substance (FCN) is no longer effective. 170.105...

  6. 21 CFR 170.105 - The Food and Drug Administration's (FDA's) determination that a premarket notification for a food...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES Premarket Notifications § 170.105 The Food... 21 Food and Drugs 3 2013-04-01 2013-04-01 false The Food and Drug Administration's (FDA's) determination that a premarket notification for a food contact substance (FCN) is no longer effective. 170.105...

  7. 21 CFR 170.105 - The Food and Drug Administration's (FDA's) determination that a premarket notification for a food...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES Premarket Notifications § 170.105 The Food... 21 Food and Drugs 3 2012-04-01 2012-04-01 false The Food and Drug Administration's (FDA's) determination that a premarket notification for a food contact substance (FCN) is no longer effective. 170.105...

  8. 21 CFR 170.105 - The Food and Drug Administration's (FDA's) determination that a premarket notification for a food...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES Premarket Notifications § 170.105 The Food... 21 Food and Drugs 3 2010-04-01 2009-04-01 true The Food and Drug Administration's (FDA's) determination that a premarket notification for a food contact substance (FCN) is no longer effective. 170.105...

  9. 77 FR 52036 - Privacy Act of 1974; Report of a New System of Records; FDA Records Related to Research...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-28

    ... transcripts or recordings of interviews; Statistical, scientific, and forensic analyses; Interim and final FDA... under this routine use may include experts asked to perform statistical, forensic, or other analyses..., the Agency's Chief Scientist and Deputy Commissioner for Science and Public Health, the Agency's...

  10. Seafood Contamination after the BP Gulf Oil Spill and Risks to Vulnerable Populations: A Critique of the FDA Risk Assessment

    PubMed Central

    Wong, Karen K.; Solomon, Gina M.

    2011-01-01

    Background: The BP oil spill of 2010 resulted in contamination of one of the most productive fisheries in the United States by polycyclic aromatic hydrocarbons (PAHs). PAHs, which can accumulate in seafood, are known carcinogens and developmental toxicants. In response to the oil spill, the U.S. Food and Drug Administration (FDA) developed risk criteria and established thresholds for allowable levels [levels of concern (LOCs)] of PAH contaminants in Gulf Coast seafood. Objectives: We evaluated the degree to which the FDA’s risk criteria adequately protect vulnerable Gulf Coast populations from cancer risk associated with PAHs in seafood. Discussion: The FDA LOCs significantly underestimate risk from seafood contaminants among sensitive Gulf Coast populations by failing to a) account for the increased vulnerability of the developing fetus and child; b) use appropriate seafood consumption rates; c) include all relevant health end points; and d) incorporate health-protective estimates of exposure duration and acceptable risk. For benzo[a]pyrene and naphthalene, revised LOCs are between two and four orders of magnitude below the level set by the FDA. Comparison of measured levels of PAHs in Gulf seafood with the revised LOCs revealed that up to 53% of Gulf shrimp samples were above LOCs for pregnant women who are high-end seafood consumers. Conclusions: FDA risk assessment methods should be updated to better reflect current risk assessment practices and to protect vulnerable populations such as pregnant women and children. PMID:21990339

  11. The FDA's decision-making process: isn't it time to temper the principle of protective paternalism?

    PubMed

    Brandt, Lawrence J

    2008-05-01

    The authors conducted a well-designed, multinational, large study of women younger than 65 yr of age with irritable bowel syndrome (IBS) with a mixed pattern of diarrhea and constipation (IBS-M) or constipation (IBS-C) and showed that a statistically greater percentage of patients in each group responded to tegaserod compared with patients treated with placebo. Practicality looms large, however, in that the Food and Drug Administration (FDA) disallowed the continued marketing of tegaserod because of cardiovascular safety concerns, and it now is only available under a restricted access program. The wisdom of this decision aside, it is disturbing that the FDA revealed a zero-tolerance for any significant risk of disease when a drug (e.g., tegaserod) was used for a nonlife-threatening condition; the FDA chose to neglect any potential benefit of significant improvement in quality of life, while at the same time allowing the continued availability of sildenifil for erectile dysfunction and other medications (e.g., rosiglitazone and nonsteroidal anti-inflammatory drugs [NSAIDs]), each with a far greater risk of cardiovascular complications. Whether tegaserod will be re-released and, if so, under what conditions, is yet to be determined, as is the question of whether the FDA will decide to allow a more transparent decision-making process with input from all interested parties affected by their decision.

  12. Delegations of authority and organization; Ryan White Comprehensive AIDS Resources Emergency Act of 1990--FDA. Final rule.

    PubMed

    1991-08-28

    The Food and Drug Administration (FDA) is amending the regulations for delegations of authority by adding a new authority delegated by the Assistant Secretary for Health to the Commissioner of Food and Drugs. The authority being added is under title XXVI of the Public Health Service Act, section 2672, Provisions Relating to Blood Banks, as amended.

  13. 76 FR 24494 - Draft Guidance for Industry and FDA Staff: Processing/Reprocessing Medical Devices in Health Care...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-02

    .../ Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling; Availability AGENCY... Staff: Processing/Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling... ``Draft Guidance for Industry and FDA Staff: Processing/Reprocessing Medical Devices in Health Care...

  14. Research priorities and infrastructure needs of the Family Smoking Prevention and Tobacco Control Act: science to inform FDA policy.

    PubMed

    Leischow, Scott J; Zeller, Mitch; Backinger, Cathy L

    2012-01-01

    A new law in the United States gives the Food and Drug Administration (FDA) wide latitude to regulate tobacco products for the first time. Given the need for science to serve as a foundation for FDA actions, it is critical that a scientific review of the literature relevant to the proposed legislation be undertaken by experts in the field of nicotine and tobacco research in order to develop research priorities. This paper describes an initiative that was implemented to identify research opportunities under "The Family Smoking Prevention and Tobacco Control Act" and summarizes the conclusions and future directions derived from that initiative. Multiple research and surveillance needs were identified, such as characterization of biomarkers and increased analysis of risk perception. It was also recognized that science will play a critical role in policy determinations such as what constitutes "substantial equivalence" and that there will be considerable infrastructure needs (e.g., laboratories for product testing). Science must drive FDA's decision making regarding tobacco regulation. This article provides a summary of research opportunities identified through literature reviews related to various provisions of the new law. However, the science required by the law requires a transdisciplinary approach because of its complexity, so one of the challenges facing the FDA will be to connect the silos of research in recognition that the "system" of tobacco regulation is greater than the sum of its parts.

  15. Awareness and trust of the FDA and CDC: Results from a national sample of US adults and adolescents.

    PubMed

    Kowitt, Sarah D; Schmidt, Allison M; Hannan, Anika; Goldstein, Adam O

    2017-01-01

    Trust in government agencies plays a key role in advancing these organizations' agendas, influencing behaviors, and effectively implementing policies. However, few studies have examined the extent to which individuals are aware of and trust the leading United States agencies devoted to protecting the public's health. Using two national samples of adolescents (N = 1,125) and adults (N = 5,014), we examined demographic factors, with a focus on vulnerable groups, as correlates of awareness of and trust in the Centers for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), and the federal government. From nine different weighted and adjusted logistic regression models, we found high levels of awareness of the existence of the FDA and CDC (ranging from 55.7% for adolescents' awareness of the CDC to 94.3% for adults' awareness of the FDA) and moderate levels of trust (ranging from a low of 41.8% for adults' trust in the federal government and a high of 78.8% for adolescents' trust of the FDA). In the adolescent and adult samples, awareness was higher among non-Hispanic Blacks and respondents with low numeracy. With respect to trust, few consistent demographic differences emerged. Our findings provide novel insights regarding awareness and trust in the federal government and specific United States public health agencies. Our findings suggest groups to whom these agencies may want to selectively communicate to enhance trust and thus facilitate their communication and regulatory agendas.

  16. Regulatory perspectives and research activities at the FDA on the use of phantoms with in vivo diagnostic devices

    NASA Astrophysics Data System (ADS)

    Agrawal, Anant; Gavrielides, Marios A.; Weininger, Sandy; Chakrabarti, Kish; Pfefer, Joshua

    2008-02-01

    For a number of years, phantoms have been used to optimize device parameters and validate performance in the primary medical imaging modalities (CT, MRI, PET/SPECT, ultrasound). Furthermore, the FDA under the Mammography Quality Standards Act (MQSA) requires image quality evaluation of mammography systems using FDA-approved phantoms. The oldest quantitative optical diagnostic technology, pulse oximetry, also benefits from the use of active phantoms known as patient simulators to validate certain performance characteristics under different clinically-relevant conditions. As such, guidance provided by the FDA to its staff and to industry on the contents of pre-market notification and approval submissions includes suggestions on how to incorporate the appropriate phantoms in establishing device effectiveness. Research at the FDA supports regulatory statements on the use of phantoms by investigating how phantoms can be designed, characterized, and utilized to determine critical device performance characteristics. These examples provide a model for how novel techniques in the rapidly growing field of optical diagnostics can use phantoms during pre- and post-market regulatory testing.

  17. 76 FR 53912 - FDA's Public Database of Products With Orphan-Drug Designation: Replacing Non-Informative Code...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-30

    ... HUMAN SERVICES Food and Drug Administration FDA's Public Database of Products With Orphan-Drug... its public database of products that have received orphan-drug designation. The Orphan Drug Act... received orphan designation were published on our public database with non-informative code names....

  18. Scientific and regulatory reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012.

    PubMed

    Sacks, Leonard V; Shamsuddin, Hala H; Yasinskaya, Yuliya I; Bouri, Khaled; Lanthier, Michael L; Sherman, Rachel E

    Some new drug applications fail because of inadequate drug performance and others are not approved because the information submitted to the US Food and Drug Administration (FDA) is unsatisfactory to make that determination. Resubmission of failed applications is costly, delaying marketing approval and the availability of new drugs to patients. To identify the reasons that FDA marketing approval for new drugs was delayed or denied. A retrospective review of FDA documents and extraction of data were performed. We examined all drug applications first submitted to the FDA between 2000 and 2012 for new molecular entities (NMEs), which are active ingredients never before marketed in the United States in any form. Using FDA correspondence and reviews, we investigated the reasons NMEs failed to obtain FDA approval. Reasons for delayed FDA approval or nonapproval of NME applications. Of the 302 identified NME applications, 151 (50%) were approved when first submitted and 222 (73.5%) were ultimately approved. Seventy-one applications required 1 or more resubmissions before approval, with a median delay to approval of 435 days following the first unsuccessful submission. Of the unsuccessful first-time applications, 24 (15.9%) included uncertainties related to dose selection, 20 (13.2%) choice of study end points that failed to adequately reflect a clinically meaningful effect, 20 (13.2%) inconsistent results when different end points were tested, 17 (11.3%) inconsistent results when different trials or study sites were compared, and 20 (13.2%) poor efficacy when compared with the standard of care. The frequency of safety deficiencies was similar among never-approved drugs compared with those with delayed approval (43 of 80 never approved [53.8%] vs 37 of 71 eventually approved [52.1%]; difference, 1.7% [95% CI, -14.86% to 18.05%]; P = .87). However, efficacy deficiencies were significantly more frequent among the never-approved drugs than among those with delayed approvals

  19. Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999–2014

    PubMed Central

    Hatswell, Anthony J; Baio, Gianluca; Berlin, Jesse A; Irs, Alar; Freemantle, Nick

    2016-01-01

    Introduction The efficacy of pharmaceuticals is most often demonstrated by randomised controlled trials (RCTs); however, in some cases, regulatory applications lack RCT evidence. Objective To investigate the number and type of these approvals over the past 15 years by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Methods Drug approval data were downloaded from the EMA website and the ‘Drugs@FDA’ database for all decisions on pharmaceuticals published from 1 January 1999 to 8 May 2014. The details of eligible applications were extracted, including the therapeutic area, type of approval and review period. Results Over the period of the study, 76 unique indications were granted without RCT results (44 by the EMA and 60 by the FDA), demonstrating that a substantial number of treatments reach the market without undergoing an RCT. The majority was for haematological malignancies (34), with the next most common areas being oncology (15) and metabolic conditions (15). Of the applications made to both agencies with a comparable data package, the FDA granted more approvals (43/44 vs 35/44) and took less time to review products (8.7 vs 15.5 months). Products reached the market first in the USA in 30 of 34 cases (mean 13.1 months) due to companies making FDA submission before EMA submissions and faster FDA review time. Discussion Despite the frequency with which approvals are granted without RCT results, there is no systematic monitoring of such treatments to confirm their effectiveness or consistency regarding when this form of evidence is appropriate. We recommend a more open debate on the role of marketing authorisations granted without RCT results, and the development of guidelines on what constitutes an acceptable data package for regulators. PMID:27363818

  20. Disproportionality analysis of buprenorphine transdermal system and cardiac arrhythmia using FDA and WHO postmarketing reporting system data.

    PubMed

    Sessler, Nelson E; Walker, Ekaterina; Chickballapur, Harsha; Kacholakalayil, James; Coplan, Paul M

    2017-01-01

    Positive-controlled clinical studies have shown a dose dependent effect of buprenorphine transdermal system on QTc interval prolongation. This study provides assessment of the buprenorphine transdermal system and cardiac arrhythmia using US FDA and WHO postmarketing reporting databases. Disproportionality analysis of spontaneously reported adverse events to assess whether the reporting rate of cardiac arrhythmia events was disproportionately elevated relative to expected rates of reporting in both FDA and WHO databases. Cardiac arrhythmia events were identified using the standardized Medical Dictionary for Regulatory Activities query for torsade de pointes and/or QT prolongation (TdP/QTP). The threshold for a signal of disproportionate adverse event reporting was defined as the lower 90% confidence limit ≥ 2 of the Empiric Bayes geometric mean in FDA database and as the lower 95% confidence limit of the Informational Component >0 in WHO database. There were 124 (<1%) and 77 (2%) cardiac arrhythmia event cases associated with buprenorphine transdermal as compared to 3206 (12%) and 2913 (14%) involving methadone in the FDA and WHO databases, respectively. In the FDA database methadone was associated with a signal of disproportionate reporting for TdP/QTP (EB05 3.26); however, buprenorphine transdermal was not (EB05 0.33). In the WHO database methadone was associated with a signal of disproportionate reporting for TdP/QTP (IC025 2.66); however, buprenorphine transdermal was not (IC025 -0.88). Similar trends were observed in sensitivity analyses by age, gender, and specific terms related to ventricular arrhythmia. The signal identified in the transdermal buprenorphine thorough QTc study, which led to a dose limitation in its US label, does not translate into a signal of increased risk for cardiac arrhythmia in real world use, as assessed by this method of analyzing post-market surveillance data.

  1. The 2014 FDA assessment of commercial fish: practical considerations for improved dietary guidance.

    PubMed

    McGuire, Jennifer; Kaplan, Jason; Lapolla, John; Kleiner, Rima

    2016-07-13

    The U.S. Food and Drug Administration (FDA) recently released its report: A Quantitative Assessment of the Net Effects on Fetal Neurodevelopment from Eating Commercial Fish (As Measured by IQ and also by Early Age Verbal Development in Children). By evaluating the benefits and potential concerns of eating fish during pregnancy and breastfeeding, the analysis suggests that pregnant women consuming two seafood meals (8-12 oz) per week could provide their child with an additional 3.3 IQ points by age 9. Recent insights from behavioral economics research indicate that other factors, such as concerns about price and methylmercury (MeHg) exposure, appear to reduce fish consumption in many individuals.To assess the net effects of eating commercial fish during pregnancy, we compared the consumption of select fish species necessary to achieve IQ benefits with the amount necessary to have adverse developmental effects due to MeHg exposure. For the species or market types evaluated, the number of servings necessary to reach MeHg exposure to observe an adverse effect was at least twice that the amount estimated to achieve peak developmental benefit. We then reported average costs of fresh and canned or pouched fish, and calculated the cost per week for pregnant women to achieve maximum IQ benefits for their gestating child. Canned light tuna was the least expensive option at $1.83 per week to achieve maximum IQ benefit.Due to their relatively low cost, canned and pouched fish products eaten with enough regularity are likely to provide peak cognitive benefits. Because of its popularity, canned and pouched tuna could provide some of the largest cognitive benefits from fish consumption in the U.S. Future FDA consumer advice and related educational initiatives could benefit from a broader perspective that highlights the importance of affordable and accessible fish choices. These observations underscore the importance of clear public health messaging that address both health

  2. Proton pump inhibitor-associated hypomagnesemia: what do FDA data tell us?

    PubMed

    Luk, Chee Phun; Parsons, Richard; Lee, Ya Ping; Hughes, Jeffery David

    2013-06-01

    Proton pump inhibitors (PPIs) are a class of medications indicated for the treatment of gastric acid-related diseases. Hypomagnesemia is a rare but serious adverse effect of PPIs. To address the association between the use of different PPIs and hypomagnesemia by examining the frequency of occurrence of hypo magnesemia among the reported adverse drug reactions from the Food and Drug Administration (FDA) Adverse Event Reporting System database. We conducted a cross-sectional study of PPI-associated adverse effect cases reported to the FDA between November 1, 1997, and April 1, 2012. Logistic regression was used to examine the association of sex, age, and different PPIs with hypomagnesemia. χ² analysis was conducted to investigate the association of PPI-associated hypomagnesemia with hypocalcemia and hypokalemia. Among 66,102 subjects identified as experiencing 1 or more adverse effects while taking a PPI, 1.0% (n = 693) were reported to have hypomagnesemia. The mean (SD) age of PPI users presenting with hypomagnesemia was 64.4 (12.9) years. Results from logistic regression indicated that, compared with esomeprazole, all other PPIs had a higher rate of hypomagnesemia, with pantoprazole having the highest rate (OR 4.3; 95% CI 3.3-5.7; p < 0.001). The risk of female subjects having hypo magnesemia (OR 0.83; 95% CI 0.71-0.97; p = 0.016) was significantly lower than that of males. Elderly subjects (age >65 years) were at increased risk of PPI-associated hypomagnesemia (OR 1.5; 95% CI 1.2-1.7; p < 0.001). χ² analysis showed strong association between hypomagnesemia and both hypocalcemia (p < 0.001) and hypokalemia (p < 0.001). All PPIs were associated with hypomagnesemia, with esomeprazole having the lowest risk and pantoprazole having the highest risk. The risk of PPI-associated hypomagnesemia was higher in males and the elderly population. Hypocalcemia and hypokalemia commonly coexisted with PPI-associated hypomagnesemia.

  3. An Algorithm to Identify Generic Drugs in the FDA Adverse Event Reporting System.

    PubMed

    Iyer, Geetha; Marimuthu, Sathiya Priya; Segal, Jodi B; Singh, Sonal

    2017-06-07

    Although generic drugs constitute approximately 88% of drugs prescribed in the US, there are no reliable methods to identify generic drugs in the US FDA Adverse Event Reporting System (FAERS). The aim of this study was to develop an algorithm for identifying generic drugs in the FAERS. We used 1237 adverse event reports for tamsulosin, levothyroxine, and amphetamine/dextroamphetamine from the publicly available FAERS from 2011-2013, and 277 source case narratives obtained from the FDA. Two reviewers independently and in duplicate used a three-item algorithm including the following criteria: manufacturer name, New Drug Application (NDA) number/abbreviated NDA (ANDA), and specific use of the term 'generic' or 'brand' to classify the focal drug of each case report as definitely generic (two of three criteria), probably generic (one of three criteria), brand, and cannot be assessed. Inter-rater reliability was estimated using kappa coefficients, and internal consistency was estimated using Cronbach's alpha. We compared the classification of the drugs as generic versus non-generic in publicly available FAERS compared with the original case reports (reference). The focal drug was classified as generic (definite or probable) in 15.8% (39/234), 9% (67/742), and 16.7% (42/261) of tamsulosin, levothyroxine and amphetamine/dextroamphetamine cases, respectively (overall kappa 0.89, 95% confidence interval 0.85-0.93), while 37% of reports could not be classified due to incomplete information. Among the drugs classified as generics using the publicly available FAERS, we categorized 95.3% as generic drugs using the original case reports. Among those drugs that did not meet the algorithm-based definition of generic in the publicly available data, 20.9% were reclassified as generics using the original case reports. The algorithm demonstrated high inter-rater reliability with moderate internal consistency for identifying generic drugs in the FAERS, in our sample. Future efforts

  4. Nanoparticle therapeutics: FDA approval, clinical trials, regulatory pathways, and case study.

    PubMed

    Eifler, Aaron C; Thaxton, C Shad

    2011-01-01

    The approval of drugs for human use by the US Food and Drug Administration (FDA) through the Center for Drug Evaluation and Research (CDER) is a time-consuming and expensive process, and approval rates are low (DiMasi et al., J Health Econ 22:151-185, 2003; Marchetti and Schellens, Br J Cancer 97:577-581, 2007). In general, the FDA drug approval process can be separated into preclinical, clinical, and postmarketing phases. At each step from the point of discovery through demonstration of safety and efficacy in humans, drug candidates are closely scrutinized. Advances in nanotechnology are being applied in the development of novel therapeutics that may address a number of shortcomings of conventional small molecule drugs and may facilitate the realization of personalized medicine (Ferrari, Curr Opin Chem Biol 9:343-346, 2005; Ferrari, Nat Rev Cancer 5:161-171, 2005; Ferrari and Downing, BioDrugs 19:203-210, 2005). Appealingly, nanoparticle drug candidates often represent multiplexed formulations (e.g., drug, targeting moiety, and nanoparticle scaffold material). By tailoring the chemistry and identity of variable nanoparticle constituents, it is possible to achieve targeted delivery, reduce side effects, and prepare formulations of unstable (e.g., siRNA) and/or highly toxic drugs (Ferrari, Curr Opin Chem Biol 9:343-346, 2005; Ferrari, Nat Rev Cancer 5:161-171, 2005; Ferrari and Downing, BioDrugs 19:203-210, 2005). With these benefits arise new challenges in all aspects of regulated drug development and testing.This chapter distils the drug development and approval process with an emphasis on special considerations for nanotherapeutics. The chapter concludes with a case study focused on a nanoparticle therapeutic, CALAA-01, currently in human clinical trials, that embodies many of the potential benefits of nanoparticle therapeutics (Davis, Mol Pharm 6:659-668, 2009). By choosing CALAA-01, reference is made to the infancy of the therapeutic nanoparticle field; in 2008

  5. The impact of FDA and EMEA guidelines on drug development in relation to Phase 0 trials.

    PubMed

    Marchetti, S; Schellens, J H M

    2007-09-03

    An increase in the number of identified therapeutic cancer targets achieved through recent biomedical research has resulted in the generation of a large number of molecules that need to be tested further. Current development of (anticancer) drugs is a rather inefficient process that for an average new molecule takes around 10-15 years. It is also a challenging process as it is associated with high costs and a low rate of approval. It is known that less than 10% of new molecular entities entering clinical Phase I testing progress beyond the investigational programme and reach the market; this probability is even lower for anticancer agents. In 2003, the US Food and Drug Administration (US FDA) declared the urgent need for new toolkits to improve the critical development path that leads from scientific discovery to the patient. In this scenario, Phase 0 (zero) trials should allow an early evaluation in humans of pharmacokinetic and pharmacodynamic profiles of test compounds through administration of sub-pharmacological doses and for a short time period to a low number of humans. Typically, Phase 0 studies have no therapeutic or diagnostic intent. Owing to the low doses administered and the low risk of toxicity, shorter preclinical packages to support these studies are required. Phase 0 trials have been proposed to help in making an early selection of promising candidates for further evaluation in Phase I-III trials, providing a potentially useful instrument for drug discovery, particularly in the field of oncology. Phase 0 studies are expected to reduce costs of drug development, and to limit the preclinical in vitro and in vivo testing and the time period of drug development. However, there are also concerns about the utility and feasibility of Phase 0 studies. In January 2006, guidelines on exploratory investigational new drug studies in humans have been published by the US FDA, and currently a Phase 0 programme is ongoing at the National Cancer Institute to

  6. Complete Genome Sequence of West Nile Virus Strains Used for the Formulation of CBER/FDA RNA Reference Reagents and Lot Release Panels for Nucleic Acid Testing

    PubMed Central

    Añez, Germán

    2014-01-01

    We report the complete sequences of two West Nile virus strains (FDA-Hu02 and NY99) used for the formulation of CBER/FDA RNA reference reagents and lot release panels for use with nucleic acid technology testing. PMID:25359905

  7. Implementing the Biopharmaceutics Classification System in Drug Development: Reconciling Similarities, Differences, and Shared Challenges in the EMA and US-FDA-Recommended Approaches.

    PubMed

    Cardot, J-M; Garcia Arieta, A; Paixao, P; Tasevska, I; Davit, B

    2016-07-01

    The US-FDA recently posted a draft guideline for industry recommending procedures necessary to obtain a biowaiver for immediate-release oral dosage forms based on the Biopharmaceutics Classification System (BCS). This review compares the present FDA BCS biowaiver approach, with the existing European Medicines Agency (EMA) approach, with an emphasis on similarities, difficulties, and shared challenges. Some specifics of the current EMA BCS guideline are compared with those in the recently published draft US-FDA BCS guideline. In particular, similarities and differences in the EMA versus US-FDA approaches to establishing drug solubility, permeability, dissolution, and formulation suitability for BCS biowaiver are critically reviewed. Several case studies are presented to illustrate the (i) challenges of applying for BCS biowaivers for global registration in the face of differences in the EMA and US-FDA BCS biowaiver criteria, as well as (ii) challenges inherent in applying for BCS class I or III designation and common to both jurisdictions.

  8. Too fast or not too fast: the FDA's approval of Merck's HPV vaccine Gardasil.

    PubMed

    Tomljenovic, Lucija; Shaw, Christopher A

    2012-01-01

    There are not many public health issues where views are as extremely polarized as those concerning vaccines, and Merck's HPV vaccine Gardasil is a case in point. Ever since gaining the FDA's approval in 2006, Merck has been heavily criticized for their overly aggressive marketing strategies and lobbying campaigns aimed at promoting Gardasil as a mandatory vaccine. Subsequently, questions have been raised as to whether it was appropriate for vaccine manufacturers to partake in public health policies when their conflicts of interests are so obvious. Some of their advertising campaign slogans, such as "cervical cancer kills x women per year" and "your daughter could become one less life affected by cervical cancer," seemed more designed to promote fear rather than evidence-based decision making about the potential benefits of the vaccine. Although, conflicts of interests do not necessarily mean that the product itself is faulty, marketing claims should be carefully examined against factual science data. Currently Gardasil vaccination is strongly recommended by the U.S. and other health authorities while public concerns about safety and efficacy of the vaccine appear to be increasing. This discrepancy leads to some important questions that need to be resolved. The current review examines key issues of this debate in light of currently available research evidence.

  9. FDA-Approved Selective Estrogen Receptor Modulators Inhibit Ebola Virus Infection

    PubMed Central

    Johansen, Lisa M.; Brannan, Jennifer M.; Delos, Sue E.; Shoemaker, Charles J.; Stossel, Andrea; Lear, Calli; Hoffstrom, Benjamin G.; DeWald, Lisa Evans; Schornberg, Kathryn L.; Scully, Corinne; Lehár, Joseph; Hensley, Lisa E.; White, Judith M.; Olinger, Gene G.

    2014-01-01

    Ebola viruses remain a substantial threat to both civilian and military populations as bioweapons, during sporadic outbreaks, and from the possibility of accidental importation from endemic regions by infected individuals. Currently, no approved therapeutics exist to treat or prevent infection by Ebola viruses. Therefore, we performed an in vitro screen of Food and Drug Administration (FDA)– and ex–US-approved drugs and selected molecular probes to identify drugs with antiviral activity against the type species Zaire ebolavirus (EBOV). From this screen, we identified a set of selective estrogen receptor modulators (SERMs), including clomiphene and toremifene, which act as potent inhibitors of EBOV infection. Anti-EBOV activity was confirmed for both of these SERMs in an in vivo mouse infection model. This anti-EBOV activity occurred even in the absence of detectable estrogen receptor expression, and both SERMs inhibited virus entry after internalization, suggesting that clomiphene and toremifene are not working through classical pathways associated with the estrogen receptor. Instead, the response appeared to be an off-target effect where the compounds interfere with a step late in viral entry and likely affect the triggering of fusion. These data support the screening of readily available approved drugs to identify therapeutics for the Ebola viruses and other infectious diseases. The SERM compounds described in this report are an immediately actionable class of approved drugs that can be repurposed for treatment of filovirus infections. PMID:23785035

  10. The analysis of the market success of FDA approvals by probing top 100 bestselling drugs.

    PubMed

    Polanski, Jaroslaw; Bogocz, Jacek; Tkocz, Aleksandra

    2016-05-01

    Target-oriented drug discovery is the main research paradigm of contemporary drug discovery. In target-oriented approaches, we attempt to maximize in vitro drug potency by finding the optimal fit to the target. This can result in a higher molecular complexity, in particular, the higher molecular weight (MW) of the drugs. However, a comparison of the successful developments of pharmaceuticals with the general trends that can be observed in medicinal chemistry resulted in the conclusion that the so-called molecular obesity is an important reason for the attrition rate of drugs. When analyzing the list of top 100 drug bestsellers versus all of the FDA approvals, we discovered that on average lower-complexity (MW, ADMET score) drugs are winners of the top 100 list in terms of numbers but that, especially, up to some optimal MW value, a higher molecular complexity can pay off with higher incomes. This indicates that slim drugs are doing better but that fat drugs are bigger fishes to catch.

  11. Review of embryo-fetal developmental toxicity studies performed for recent FDA-approved pharmaceuticals.

    PubMed

    Ishihara-Hattori, Kana; Barrow, Paul

    2016-09-01

    Details of embryo-fetal development (EFD) studies were compiled from published FDA approval documents for 43 small molecule drugs (2014-2015) and 37 monoclonal antibodies (mAbs, 2002-2015). Anti-cancer agents were analyzed separately. Rats and rabbits were the species used for EFD studies on 93% of small molecule drugs. Overall, the rat and rabbit were equally sensitive to maternal and fetal toxicity (including teratogenicity). Dosages equivalent to more than 50-times the human exposure (or 10-times for mAbs) were frequently used, but were unnecessary for 90% of drugs. EFD studies were not required for several recently approved mAbs owing to pre-existing scientific knowledge. The cynomolgus monkey was used for developmental toxicity testing of 75% of mAbs, frequently using an ePPND study design. Studies in pregnant rodents using homologous murine antibodies supplemented or replaced monkey studies under some circumstances. Most anti-cancer small molecules and mAbs were tested for developmental toxicity in at least one species. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. The analysis of the market success of FDA approvals by probing top 100 bestselling drugs

    NASA Astrophysics Data System (ADS)

    Polanski, Jaroslaw; Bogocz, Jacek; Tkocz, Aleksandra

    2016-05-01

    Target-oriented drug discovery is the main research paradigm of contemporary drug discovery. In target-oriented approaches, we attempt to maximize in vitro drug potency by finding the optimal fit to the target. This can result in a higher molecular complexity, in particular, the higher molecular weight (MW) of the drugs. However, a comparison of the successful developments of pharmaceuticals with the general trends that can be observed in medicinal chemistry resulted in the conclusion that the so-called molecular obesity is an important reason for the attrition rate of drugs. When analyzing the list of top 100 drug bestsellers versus all of the FDA approvals, we discovered that on average lower-complexity (MW, ADMET score) drugs are winners of the top 100 list in terms of numbers but that, especially, up to some optimal MW value, a higher molecular complexity can pay off with higher incomes. This indicates that slim drugs are doing better but that fat drugs are bigger fishes to catch.

  13. Combining Molecular Scaffolds from FDA Approved Drugs: Application to Drug Discovery.

    PubMed

    Taylor, Richard D; MacCoss, Malcolm; Lawson, Alastair D G

    2017-03-09

    We have enumerated all linear combinations of ring systems from FDA approved drugs, up to three rings in length and up to four bonds linkers to give an in silico database of approximately 14 million molecules. This virtual library was compared with molecular databases of published and commercially available compounds to assess the prevalence of drug ring combinations in modern medicinal chemistry and to identify areas of under-represented, but clinically validated, chemical space. From the 10 trillion molecular comparisons, we found that less than 1% of the possible combinations of drug ring systems appear in commercially available libraries. This key observation highlights significant opportunities to design new fragment-like and lead-like libraries aimed at improving success rates and reducing risk in small molecule drug discovery, as, based on our previous analysis ( Taylor J. Med. Chem. 2014 , 57 , 5845 - 5849 ), approximately 70% of all new drugs are made up of only ring systems that have been used in existing drugs.

  14. Towards a Computational Analysis of Status and Leadership Styles on FDA Panels

    NASA Astrophysics Data System (ADS)

    Broniatowski, David A.; Magee, Christopher L.

    Decisions by committees of technical experts are increasingly impacting society. These decision-makers are typically embedded within a web of social relations. Taken as a whole, these relations define an implicit social structure which can influence the decision outcome. Aspects of this structure are founded on interpersonal affinity between parties to the negotiation, on assigned roles, and on the recognition of status characteristics, such as relevant domain expertise. This paper build upon a methodology aimed at extracting an explicit representation of such social structures using meeting transcripts as a data source. Whereas earlier results demonstrated that the method presented here can identify groups of decision-makers with a contextual affinity (i.e., membership in a given medical specialty or voting clique), we now can extract meaningful status hierarchies, and can identify differing facilitation styles among committee chairs. Use of this method is demonstrated on the transcripts of U.S. Food and Drug Administration (FDA) advisory panel meeting transcripts; nevertheless, the approach presented here is extensible to other domains and requires only a meeting transcript as input.

  15. Nonclinical aspects of biopharmaceutical development: discussion of case studies at a PhRMA-FDA workshop.

    PubMed

    Buckley, L A; Benson, K; Davis-Bruno, K; Dempster, M; Finch, G L; Harlow, P; Haggerty, H G; Hart, T; Kinter, L; Leighton, J K; McNulty, J; Roskos, L; Saber, H; Stauber, A; Tabrizi, M

    2008-01-01

    Robust assessments of the nonclinical safety profile of biopharmaceuticals are best developed on a scientifically justified, case-by-case basis, with consideration of the therapeutic molecule, molecular target, and differences/similarities between nonclinical species and humans (ICH S6). Significant experience has been gained in the 10 years ensuing since publication of the ICH S6 guidance. In a PhRMA-FDA-sponsored workshop, "Nonclinical Aspects of Biopharmaceutical Development," industry and US regulatory representatives engaged in exploration of current scientific and regulatory issues relating to the nonclinical development of biopharmaceuticals in order to share scientific learning and experience and to work towards establishing consistency in application of general principles and approaches. The proceedings and discussions of this workshop confirm general alignment of strategy and tactics in development of biopharmaceuticals with regard to such areas as species selection, selection of high doses in toxicology studies, selection of clinical doses, the conduct of developmental and reproductive toxicity (DART) studies, and assessment of carcinogenic potential. However, several important aspects, including, for example, appropriate use of homologues, nonhuman primates, and/or in vitro models in the assessment of risk for potential developmental and carcinogenic effects, were identified as requiring further scientific exploration and discussion.

  16. Monitoring Antimicrobial Resistance in the Food Supply Chain and Its Implications for FDA Policy Initiatives

    PubMed Central

    Zawack, Kelson; Li, Min; Booth, James G.; Love, Will; Lanzas, Cristina

    2016-01-01

    In response to concerning increases in antimicrobial resistance (AMR), the Food and Drug Administration (FDA) has decided to increase veterinary oversight requirements for antimicrobials and restrict their use in growth promotion. Given the high stakes of this policy for the food supply, economy, and human and veterinary health, it is important to rigorously assess the effects of this policy. We have undertaken a detailed analysis of data provided by the National Antimicrobial Resistance Monitoring System (NARMS). We examined the trends in both AMR proportion and MIC between 2004 and 2012 at slaughter and retail stages. We investigated the makeup of variation in these data and estimated the sample and effect size requirements necessary to distinguish an effect of the policy change. Finally, we applied our approach to take a detailed look at the 2005 withdrawal of approval for the fluoroquinolone enrofloxacin in poultry water. Slaughter and retail showed similar trends. Both AMR proportion and MIC were valuable in assessing AMR, capturing different information. Most variation was within years, not between years, and accounting for geographic location explained little additional variation. At current rates of data collection, a 1-fold change in MIC should be detectable in 5 years and a 6% decrease in percent resistance could be detected in 6 years following establishment of a new resistance rate. Analysis of the enrofloxacin policy change showed the complexities of the AMR policy with no statistically significant change in resistance of both Campylobacter jejuni and Campylobacter coli to ciprofloxacin, another second-generation fluoroquinolone. PMID:27324772

  17. Tamoxifen: an FDA approved drug with neuroprotective effects for spinal cord injury recovery

    PubMed Central

    Colón, Jennifer M.; Miranda, Jorge D.

    2016-01-01

    Spinal cord injury (SCI) is a condition without a cure, affecting sensory and/or motor functions. The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration. Among these complex set of events are damage of the blood-brain barrier, edema formation, inflammation, oxidative stress, demyelination, reactive gliosis and apoptosis. The multiple events activated after SCI require a multi-active drug that could target most of these events and produce a permissive environment for cell survival, regeneration, vascular reorganization and synaptic formation. Tamoxifen, a selective estrogen receptor modulator, is an FDA approved drug with several neuroprotective properties that should be considered for the treatment of this devastating condition. Various investigators using different animal models and injury parameters have demonstrated the beneficial effects of this drug to improve functional locomotor recovery after SCI. Results suggest that the mechanism of action of Tamoxifen administration is to modulate anti-oxidant, anti-inflammatory and anti-gliotic responses. A gap of knowledge exists regarding the sex differences in response to Tamoxifen and the therapeutic window available to administer this treatment. In addition, the effects of Tamoxifen in axonal outgrowth or synapse formation needs to be investigated. This review will address some of the mechanisms activated by Tamoxifen after SCI and the results recently published by investigators in the field. PMID:27651756

  18. Media Coverage of FDA Drug Safety Communications about Zolpidem: A Quantitative and Qualitative Analysis.

    PubMed

    Woloshin, Steve; Schwartz, Lisa M; Dejene, Sara; Rausch, Paula; Dal Pan, Gerald J; Zhou, Esther H; Kesselheim, Aaron S

    2017-05-01

    FDA issues Drug Safety Communications (DSCs) to alert health care professionals and the public about emerging safety information affecting prescription and over-the-counter drugs. News media may amplify DSCs, but it is unclear how DSC messaging is transmitted through the media. We conducted a content analysis of the lay media coverage reaching the broadest audience to characterize the amount and content of media coverage of two zolpidem DSCs from 2013. After the first DSC, zolpidem news stories increased from 19 stories/week in the preceding 3 months to 153 following its release. Most (81%) appeared in the lay media, and 64% focused on the DSC content. After the second DSC, news stories increased from 24 stories/week in the preceding 3 months to 39 following. Among the 100 unique lay media news stories, at least half correctly reported three key DSC messages: next-day impairment and drowsiness as common safety hazards, lower doses for some but not all zolpidem products, and women's higher risk for impairment. Other DSC messages were reported in fewer than one-third of stories, such as the warning that impairment can happen even when people feel fully awake. The first-but not the second-zolpidem DSC generated high-profile news coverage. The finding that some messages were widely reported but others were not emphasizes the importance of ensuring translation of key DSC content.

  19. Repurposing the FDA-Approved Pinworm Drug Pyrvinium as a Novel Chemotherapeutic Agent for Intestinal Polyposis

    PubMed Central

    Giambelli, Camilla; Fei, Dennis Liang; Han, Lu; Hang, Brian I.; Bai, Feng; Pei, Xin-Hai; Nose, Vania; Burlingame, Oname; Capobianco, Anthony J.; Orton, Darren; Lee, Ethan; Robbins, David J.

    2014-01-01

    Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes. PMID:25003333

  20. Inhibition of Aβ42 oligomerization in yeast by a PICALM ortholog and certain FDA approved drugs

    PubMed Central

    Park, Sei-Kyoung; Ratia, Kiira; Ba, Mariam; Valencik, Maria; Liebman, Susan W.

    2016-01-01

    The formation of small Aβ42 oligomers has been implicated as a toxic species in Alzheimer disease (AD). In strong support of this hypothesis we found that overexpression of Yap1802, the yeast ortholog of the human AD risk factor, phosphatidylinositol binding clathrin assembly protein (PICALM), reduced oligomerization of Aβ42 fused to a reporter in yeast. Thus we used the Aβ42-reporter system to identify drugs that could be developed into therapies that prevent or arrest AD. From a screen of 1,200 FDA approved drugs and drug-like small compounds we identified 7 drugs that reduce Aβ42 oligomerization in yeast: 3 antipsychotics (bromperidol, haloperidol and azaperone), 2 anesthetics (pramoxine HCl and dyclonine HCl), tamoxifen citrate, and minocycline HCl. Also, all 7 drugs caused Aβ42 to be less toxic to PC12 cells and to relieve toxicity of another yeast AD model in which Aβ42 aggregates targeted to the secretory pathway are toxic. Our results identify drugs that inhibit Aβ42 oligomers from forming in yeast. It remains to be determined if these drugs inhibit Aβ42 oligomerization in mammals and could be developed as a therapeutic treatment for AD. PMID:28357335

  1. A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection.

    PubMed

    Barrows, Nicholas J; Campos, Rafael K; Powell, Steven T; Prasanth, K Reddisiva; Schott-Lerner, Geraldine; Soto-Acosta, Ruben; Galarza-Muñoz, Gaddiel; McGrath, Erica L; Urrabaz-Garza, Rheanna; Gao, Junling; Wu, Ping; Menon, Ramkumar; Saade, George; Fernandez-Salas, Ildefonso; Rossi, Shannan L; Vasilakis, Nikos; Routh, Andrew; Bradrick, Shelton S; Garcia-Blanco, Mariano A

    2016-08-10

    Currently there are no approved vaccines or specific therapies to prevent or treat Zika virus (ZIKV) infection. We interrogated a library of FDA-approved drugs for their ability to block infection of human HuH-7 cells by a newly isolated ZIKV strain (ZIKV MEX_I_7). More than 20 out of 774 tested compounds decreased ZIKV infection in our in vitro screening assay. Selected compounds were further validated for inhibition of ZIKV infection in human cervical, placental, and neural stem cell lines, as well as primary human amnion cells. Established anti-flaviviral drugs (e.g., bortezomib and mycophenolic acid) and others that had no previously known antiviral activity (e.g., daptomycin) were identified as inhibitors of ZIKV infection. Several drugs reduced ZIKV infection across multiple cell types. This study identifies drugs that could be tested in clinical studies of ZIKV infection and provides a resource of small molecules to study ZIKV pathogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B

    PubMed Central

    Li, Xiang; Li, Haitao; Li, Shengqing; Zhu, Feng; Dong, Zigang

    2012-01-01

    Ceftriaxone, an FDA-approved third-generation cephalosporin antibiotic, has antimicrobial activity against both gram-positive and gram-negative organisms. Generally, ceftriaxone is used for a variety of infections such as community-acquired pneumonia, meningitis and gonorrhea. Its primary molecular targets are the penicillin-binding proteins. However, other activities of ceftriaxone remain unknown. Herein, we report for the first time that ceftriaxone has antitumor activity in vitro and in vivo. Kinase profiling results predicted that Aurora B might be a potential ‘off’ target of ceftriaxone. Pull-down assay data confirmed that ceftriaxone could bind with Aurora B in vitro and in A549 cells. Furthermore, ceftriaxone (500 µM) suppressed anchorage-independent cell growth by targeting Aurora B in A549, H520 and H1650 lung cancer cells. Importantly, in vivo xenograft animal model results showed that ceftriaxone effectively suppressed A549 and H520 lung tumor growth by inhibiting Aurora B. These data suggest the anticancer efficacy of ceftriaxone for the treatment of lung cancers through its inhibition of Aurora B. PMID:22962305

  3. Monitoring Antimicrobial Resistance in the Food Supply Chain and Its Implications for FDA Policy Initiatives.

    PubMed

    Zawack, Kelson; Li, Min; Booth, James G; Love, Will; Lanzas, Cristina; Gröhn, Yrjö T

    2016-09-01

    In response to concerning increases in antimicrobial resistance (AMR), the Food and Drug Administration (FDA) has decided to increase veterinary oversight requirements for antimicrobials and restrict their use in growth promotion. Given the high stakes of this policy for the food supply, economy, and human and veterinary health, it is important to rigorously assess the effects of this policy. We have undertaken a detailed analysis of data provided by the National Antimicrobial Resistance Monitoring System (NARMS). We examined the trends in both AMR proportion and MIC between 2004 and 2012 at slaughter and retail stages. We investigated the makeup of variation in these data and estimated the sample and effect size requirements necessary to distinguish an effect of the policy change. Finally, we applied our approach to take a detailed look at the 2005 withdrawal of approval for the fluoroquinolone enrofloxacin in poultry water. Slaughter and retail showed similar trends. Both AMR proportion and MIC were valuable in assessing AMR, capturing different information. Most variation was within years, not between years, and accounting for geographic location explained little additional variation. At current rates of data collection, a 1-fold change in MIC should be detectable in 5 years and a 6% decrease in percent resistance could be detected in 6 years following establishment of a new resistance rate. Analysis of the enrofloxacin policy change showed the complexities of the AMR policy with no statistically significant change in resistance of both Campylobacter jejuni and Campylobacter coli to ciprofloxacin, another second-generation fluoroquinolone.

  4. The informational turn in food politics: The US FDA's nutrition label as information infrastructure.

    PubMed

    Frohlich, Xaq

    2017-04-01

    This article traces the history of the US FDA regulation of nutrition labeling, identifying an 'informational turn' in the evolving politics of food, diet and health in America. Before nutrition labeling was introduced, regulators actively sought to segregate food markets from drug markets by largely prohibiting health information on food labels, believing such information would 'confuse' the ordinary food consumer. Nutrition labeling's emergence, first in the 1970s as consumer empowerment and then later in the 1990s as a solution to information overload, reflected the belief that it was better to manage markets indirectly through consumer information than directly through command-and-control regulatory architecture. By studying product labels as 'information infrastructure', rather than a 'knowledge fix', the article shows how labels are situated at the center of a legally constructed terrain of inter-textual references, both educational and promotional, that reflects a mix of market pragmatism and evolving legal thought about mass versus niche markets. A change to the label reaches out across a wide informational environment representing food and has direct material consequences for how food is produced, distributed, and consumed. One legacy of this informational turn has been an increasing focus by policymakers, industry, and arguably consumers on the politics of information in place of the politics of the food itself.

  5. In Vitro Screening of an FDA-Approved Library Against ESKAPE Pathogens.

    PubMed

    Younis, Waleed; AbdelKhalek, Ahmed; Mayhoub, Abdelrahman S; Seleem, Mohamed N

    2017-01-01

    Bacterial resistance to conventional antibiotics is an increasingly serious threat to public health worldwide that requires immediate exploration and the development of novel antimicrobial compounds. Drug repurposing is an inexpensive and untapped source of new antimicrobial leads, and it holds many attractive features warranting further attention for antimicrobial drug discovery. In an effort to repurpose drugs and explore new leads in the field of antimicrobial drug discovery, we performed a whole-cell screening assay of 1,600 Food and Drug Administration (FDA) approved drugs against Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae (ESKAPE) pathogens. The in vitro screening identified 49 non-antimicrobial drugs that were active against at least one species of ESKAPE pathogen. Although some of these drugs were known to have antibacterial activity, many have never been reported before. In particular, sulfonamide-containing structures represent a novel drug scaffold that should be investigated further. The characteristics of these drugs as antimicrobial agents may offer a safe, effective, and quick supplement to current approaches to treating bacterial infections. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. The Unintended Consequences of an FDA Warning: The Case of Power Morcellation in Myoma Surgery.

    PubMed

    Po, Leslie; Lee, Patricia E

    2016-01-01

    To study patients' perspectives regarding the risks and benefits of the use of power morcellation. Cross-sectional survey (Canadian Task Force classification II-3). Academic tertiary referral hospital. Women waiting in gynecology waiting rooms. Not applicable. Of the 321 women invited, 310 (97%) responded to the survey; 19% of the participants had myomas requiring treatment, and the other 81% did not. Women with myomas were more likely to be aware of the risks of morcellation (32% vs 14%; p < .001); 29% obtained their information directly from their physicians, while 71% obtained it from other resources. After reading about the risks and benefits of open and MIS approaches to myoma removal, 65% would choose an MIS approach if the risk of cancer spread was up to 0.3% (1 in 350). The majority of women (75%) felt that the government should not have a role in surgical decision making, but should provide information to help patients make decisions. Women have different risk tolerances. Most women would be willing to take the 1 in 350 (0.3%) risk of undiagnosed sarcoma spread to benefit from MIS approaches. FDA warnings may have unintended consequences by limiting the acceptable medical choices available for patients. Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.

  7. Pharmacogenomic Biomarkers: an FDA Perspective on Utilization in Biological Product Labeling.

    PubMed

    Schuck, Robert N; Grillo, Joseph A

    2016-05-01

    Precision medicine promises to improve both the efficacy and safety of therapeutic products by better informing why some patients respond well to a drug, and some experience adverse reactions, while others do not. Pharmacogenomics is a key component of precision medicine and can be utilized to select optimal doses for patients, more precisely identify individuals who will respond to a treatment and avoid serious drug-related toxicities. Since pharmacogenomic biomarker information can help inform drug dosing, efficacy, and safety, pharmacogenomic data are critically reviewed by FDA staff to ensure effective use of pharmacogenomic strategies in drug development and appropriate incorporation into product labels. Pharmacogenomic information may be provided in drug or biological product labeling to inform health care providers about the impact of genotype on response to a drug through description of relevant genomic markers, functional effects of genomic variants, dosing recommendations based on genotype, and other applicable genomic information. The format and content of labeling for biologic drugs will generally follow that of small molecule drugs; however, there are notable differences in pharmacogenomic information that might be considered useful for biologic drugs in comparison to small molecule drugs. Furthermore, the rapid entry of biologic drugs for treatment of rare genetic diseases and molecularly defined subsets of common diseases will likely lead to increased use of pharmacogenomic information in biologic drug labels in the near future. In this review, we outline the general principles of therapeutic product labeling and discuss the utilization of pharmacogenomic information in biologic drug labels.

  8. Repurposing the FDA-approved pinworm drug pyrvinium as a novel chemotherapeutic agent for intestinal polyposis.

    PubMed

    Li, Bin; Flaveny, Colin A; Giambelli, Camilla; Fei, Dennis Liang; Han, Lu; Hang, Brian I; Bai, Feng; Pei, Xin-Hai; Nose, Vania; Burlingame, Oname; Capobianco, Anthony J; Orton, Darren; Lee, Ethan; Robbins, David J

    2014-01-01

    Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes.

  9. Security and privacy qualities of medical devices: an analysis of FDA postmarket surveillance.

    PubMed

    Kramer, Daniel B; Baker, Matthew; Ransford, Benjamin; Molina-Markham, Andres; Stewart, Quinn; Fu, Kevin; Reynolds, Matthew R

    2012-01-01

    Medical devices increasingly depend on computing functions such as wireless communication and Internet connectivity for software-based control of therapies and network-based transmission of patients' stored medical information. These computing capabilities introduce security and privacy risks, yet little is known about the prevalence of such risks within the clinical setting. We used three comprehensive, publicly available databases maintained by the Food and Drug Administration (FDA) to evaluate recalls and adverse events related to security and privacy risks of medical devices. Review of weekly enforcement reports identified 1,845 recalls; 605 (32.8%) of these included computers, 35 (1.9%) stored patient data, and 31 (1.7%) were capable of wireless communication. Searches of databases specific to recalls and adverse events identified only one event with a specific connection to security or privacy. Software-related recalls were relatively common, and most (81.8%) mentioned the possibility of upgrades, though only half of these provided specific instructions for the update mechanism. Our review of recalls and adverse events from federal government databases reveals sharp inconsistencies with databases at individual providers with respect to security and privacy risks. Recalls related to software may increase security risks because of unprotected update and correction mechanisms. To detect signals of security and privacy problems that adversely affect public health, federal postmarket surveillance strategies should rethink how to effectively and efficiently collect data on security and privacy problems in devices that increasingly depend on computing systems susceptible to malware.

  10. Cloned animal products in the human food chain: FDA should protect American consumers.

    PubMed

    Butler, Jennifer E F

    2009-01-01

    Animal cloning is "complex process that lets one exactly copy the genetic, or inherited, traits of an animal." In 1997, Dolly the sheep was the first animal cloned and since then "scientists have used animal cloning to breed dairy cows, beef cattle, poultry, hogs and other species of livestock." Cloned animals are highly attractive to livestock breeders because "cloning essentially produces an identical copy of an animal with superior traits." The main purpose of cloning livestock is "more focused on efficiency and economic benefits of the producer rather than the overall effect of cloning on an animal's physical and mental welfare." The focus of this article is threefold. First, the science behind animal cloning is explained and some potential uses and risks of this technology are explored. Second, FDA's historical evolution, current regulatory authority, and limitations of that authority, is described. Lastly, a new regulatory vision recognizes the realities of 21st century global markets and the dynamic evolution of scientific discovery and technology.

  11. FDA-approved drugs selected using virtual screening bind specifically to G-quadruplex DNA.

    PubMed

    Castillo-González, Dáimel; Pérez-Machado, Gisselle; Guédin, Aurore; Mergny, Jean-Louis; Cabrera-Pérez, Miguel-Angel

    2013-01-01

    Guanine-rich sequences found in telomeres and oncogene promoters have the ability to form G-quadruplex structures. In this paper we describe the use of a virtual screening assay to search a database of FDA-approved compounds for compounds with the potential to bind G-quadruplex DNA. More than 750 telomerase inhibitors were identified in a literature search as acting through G-quadruplex stabilization, and from evaluation of these compounds, theoretical models capable of discriminating new compounds that bind G-quadruplex DNA were developed. Six compounds predicted to bind to the G-quadruplex structure were tested for their ability to bind to the human telomeric DNA sequence. Prochloroperazine, promazine, and chlorpromazine stabilized the G-quadruplex structure as determined by fluorescence resonance energy transfer techniques. These compounds also bound to promoter sequences of oncogenes such as c-myc and K-ras. Amitriptyline, imipramine, and loxapine were less stabilizing but did bind to the G-quadruplex. The ability of prochloroperazine, promazine, and chlorpromazine to recognize G-quadruplex structures was confirmed using a fluorescent intercalator displacement assay, in which displacement of thiazole orange from G-quadruplex structures was demonstrated. Interestingly, these compounds exhibited selectivity for the G-quadruplex structure as all had poor affinity for the duplex sequence.

  12. Challenges and opportunities in RSV vaccine development: Meeting report from FDA/NIH workshop.

    PubMed

    Roberts, Jeffrey N; Graham, Barney S; Karron, Ruth A; Munoz, Flor M; Falsey, Ann R; Anderson, Larry J; Marshall, V; Kim, Sonnie; Beeler, Judy A

    2016-09-22

    Respiratory syncytial virus (RSV) is the most common cause of serious acute lower respiratory illness in infants and young children and a significant cause of disease burden in the elderly and immunocompromised. There are no licensed RSV vaccines to address this significant public health need. While advances in vaccine technologies have led to a recent resurgence in RSV vaccine development, the immune correlates of protection against RSV and the immunology of vaccine-associated enhanced respiratory disease (ERD) remain poorly understood. FDA's Center for Biologics Evaluation and Research (CBER) and NIH's National Institute of Allergy and Infectious Diseases (NIAID) organized and co-sponsored an RSV Vaccines Workshop in Bethesda, Maryland on June 1 and 2, 2015. The goal of the conference was to convene scientists, regulators, and industry stakeholders to discuss approaches to RSV vaccine development within the context of three target populations - infants and children, pregnant women, and individuals >60years of age. The agenda included topics related to RSV vaccine development in general, as well as considerations specific to each target population, such as clinical and serological endpoints. The meeting focused on vaccine development for high income countries (HIC), because issues relevant to vaccine development for low and middle income countries (LMIC) have been discussed in other forums. This manuscript summarizes the discussion of clinical, scientific, and regulatory perspectives, research gaps, and lessons learned.

  13. Tamoxifen: an FDA approved drug with neuroprotective effects for spinal cord injury recovery.

    PubMed

    Colón, Jennifer M; Miranda, Jorge D

    2016-08-01

    Spinal cord injury (SCI) is a condition without a cure, affecting sensory and/or motor functions. The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration. Among these complex set of events are damage of the blood-brain barrier, edema formation, inflammation, oxidative stress, demyelination, reactive gliosis and apoptosis. The multiple events activated after SCI require a multi-active drug that could target most of these events and produce a permissive environment for cell survival, regeneration, vascular reorganization and synaptic formation. Tamoxifen, a selective estrogen receptor modulator, is an FDA approved drug with several neuroprotective properties that should be considered for the treatment of this devastating condition. Various investigators using different animal models and injury parameters have demonstrated the beneficial effects of this drug to improve functional locomotor recovery after SCI. Results suggest that the mechanism of action of Tamoxifen administration is to modulate anti-oxidant, anti-inflammatory and anti-gliotic responses. A gap of knowledge exists regarding the sex differences in response to Tamoxifen and the therapeutic window available to administer this treatment. In addition, the effects of Tamoxifen in axonal outgrowth or synapse formation needs to be investigated. This review will address some of the mechanisms activated by Tamoxifen after SCI and the results recently published by investigators in the field.

  14. A History of the Sonocare CST-100: The First FDA-approved HIFU Device

    NASA Astrophysics Data System (ADS)

    Muratore, Robert

    2006-05-01

    The Sonocare CST-100 Therapeutic Ultrasound System, designed for the treatment of glaucoma, was developed in the 1980s and became the first high intensity focused ultrasound (HIFU) device to receive Food and Drug Administration approval. The system arose from studies done by F.L. Lizzi, Eng.Sc.D., of Riverside Research Institute and D.J. Coleman, M.D., of Cornell Medical Center/New York Hospital on the safety of ultrasound diagnosis of the eye. As safety limits were probed, therapeutic regimes were discovered. Optimization of operational parameters, clinical experience, and engineering design came together through a spin-off company, Sonocare, Inc., formed to produce and market the ophthalmic device. Various precedents were set during the approval process, including the acceptance by the FDA of radiation momentum imparted to an absorber as a measure of acoustic power. Many devices were sold, but the laser industry, grandfathered into the therapeutic field, eventually out-marketed Sonocare. The CST-100 remains as a model of elegant industrial design, and existing units are used daily in HIFU laboratory experiments.

  15. Phase 0 clinical trials in cancer drug development: from FDA guidance to clinical practice.

    PubMed

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

    2007-12-01

    The Food and Drug Administration (FDA) recently introduced the Exploratory Investigational New Drug Guidance to expedite the clinical evaluation of new therapeutic and imaging agents. Early clinical studies performed under the auspices of this guidance, so-called "Phase 0" trials, have been initiated at the National Cancer Institute to integrate qualified pharmacodynamic biomarker assays into first-in-human cancer clinical trials of molecularly targeted agents. The goal of this integration is to perform molecular proof-of-concept investigations at the earliest stage of cancer drug development. Phase 0 trials do not offer any possibility of patient benefit; instead, intensive, real-time pharmacodynamic and pharmacokinetic analyses of patient tumor samples and/or surrogate tissues are performed to inform subsequent trials. Phase 0 studies do not replace formal Phase I drug safety testing and require a substantial investment of resources in assay development early on; however, they offer the promise of more rational selection of agents for further, large-scale development as well as the molecular identification of potential therapeutic failures early in the development process.

  16. Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir?

    PubMed Central

    Zaidi, Asifa; Meng, Qinglai; Popkin, Daniel

    2016-01-01

    Current anti-retroviral treatment (ART) for HIV is effective in maintaining HIV at undetectable levels. However, cessation of ART results in immediate and brisk rebound of viremia to high levels. This rebound is driven by an HIV reservoir mainly enriched in memory CD4+ T cells. In order to provide any form of functional HIV Cure, elimination of this viral reservoir has become the focus of current HIV cure strategies. Alefacept was initially developed for the treatment of chronic plaque psoriasis. Alefacept is a chimeric fusion protein consisting of the CD2-binding portion of human leukocyte function antigen-3 (LFA3) linked to the Fc region of human IgG1 (LFA3-Fc). Alefacept was designed to inhibit memory T cell activation that contributes to the chronic autoimmune disease psoriasis by blocking the CD2 coreceptor. However, it was found to deplete memory T cells that express high levels of CD2 via NK cell-mediated antibody dependent cell cytotoxicity (ADCC) in vivo. Phase II and phase III clinical trials of alefacept with psoriasis patients demonstrated promising results and an excellent safety profile. Subsequently, alefacept has been successfully repurposed for other memory T cell-mediated autoimmune diseases including skin diseases other than psoriasis, organ transplantation and type I diabetes (T1D). Herein, we review our specific strategy to repurpose the FDA approved biologic alefacept to decrease and hopefully someday eliminate the HIV reservoir, for which CD2hi memory CD4+ T cells are a significant contributor. PMID:27110598

  17. Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni

    PubMed Central

    Panic, Gordana; Vargas, Mireille; Scandale, Ivan; Keiser, Jennifer

    2015-01-01

    Background As plans to expand mass drug treatment campaigns to fight schistosomiasis form, worries about reliance on praziquantel as the sole available treatment motivate the investigation for novel antischistosomal compounds. Drug repurposing might be an inexpensive and effective source of novel antischistosomal leads. Methodology 1600 FDA approved compounds were first assayed against Schistosoma mansoni schistosomula at a concentration of 10 µM. Active compounds identified from this screen were advanced to the adult worm screen at 33.33 µM, followed by hit characterization. Leads with complementary pharmacokinetic and toxicity profiles were then selected for in vivo studies. Principal Findings The in vitro screen identified 121 and 36 compounds active against the schistosomula and adult stage, respectively. Further, in vitro characterization and comparison with already available pharmacokinetic and toxicity data identified 11 in vivo candidates. Doramectin (10 mg/kg) and clofazimine (400 mg/kg) were found to be active in vivo with worm burden reductions of 60.1% and 82.7%, respectively. Conclusions/Significance The work presented here expands the knowledge of antischistosomal properties of already approved compounds and underscores variations observed between target-based and phenotypic approaches and among laboratories. The two in vivo-active drugs identified in this study, doramectin and clofazimine are widely available and present as novel drug classes as starting points for further investigation. PMID:26230921

  18. Spin in RCTs of anxiety medication with a positive primary outcome: a comparison of concerns expressed by the US FDA and in the published literature

    PubMed Central

    Beijers, Lian; Jeronimus, Bertus F; Turner, Erick H; de Jonge, Peter; Roest, Annelieke M

    2017-01-01

    Objectives This study aimed to determine the presence of spin in papers on positive randomised clinical trials (RCTs) of antidepressant medication for anxiety disorders by comparing concerns expressed in the Food and Drug Administration (FDA) reviews with those expressed in the published paper. Methods For every positive anxiety medication trial with a matching publication (n=41), two independent reviewers identified the concerns raised in the US FDA reviews and those in the published literature. Spin was identified when concerns or limitations were expressed by the FDA (about the efficacy of the study drug) but not in the corresponding published paper. Concerns mentioned in the papers but not by the FDA were scored as ‘non-FDA’ concerns. Findings Only six out of 35 (17%) of the FDA concerns pertaining to drug efficacy were reported in the papers. Two papers mentioned a concern that fit the FDA categories, but was not mentioned in the corresponding FDA review. Eighty-seven non-FDA concerns were counted, which often reflected general concerns or concerns related to the study design. Conclusions Results indicate the presence of substantial spin in the clinical trial literature on drugs for anxiety disorders. In papers describing RCTs on anxiety medication, the concerns raised by the authors differed from those raised by the FDA. Published papers mentioned a large number of generic concerns about RCTs, such as a lack of long-term research and limited generalisability, while they mentioned few concerns about drug efficacy. These results warrant the promotion of independent statistical review, reporting of patient-level data, more study of spin, and an increased expectation that authors report FDA concerns. PMID:28360236

  19. FDA adverse Event Problem Codes: standardizing the classification of device and patient problems associated with medical device use.

    PubMed

    Reed, Terrie L; Kaufman-Rivi, Diana

    2010-01-01

    The broad array of medical devices and the potential for device failures, malfunctions, and other adverse events associated with each device creates a challenge for public health device surveillance programs. Coding reported events by type of device problem provides one method for identifying a potential signal of a larger device issue. The Food and Drug Administration's (FDA) Center for Devices and Radiological Health (CDRH) Event Problem Codes that are used to report adverse events previously lacked a structured set of controls for code development and maintenance. Over time this led to inconsistent, ambiguous, and duplicative concepts being added to the code set on an ad-hoc basis. Recognizing the limitation of its coding system the FDA set out to update the system to improve its usefulness within FDA and as a basis of a global standard to identify important patient and device outcomes throughout the medical community. In 2004, FDA and the National Cancer Institute (NCI) signed a Memorandum of Understanding (MOU) whereby NCI agreed to provide terminology development and maintenance services to all FDA Centers. Under this MOU, CDRH's Office of Surveillance and Biometrics (OSB) convened a cross-Center workgroup and collaborated with staff at NCI Enterprise Vocabulary Service (EVS) to streamline the Patient and Device Problem Codes and integrate them into the NCI Thesaurus and Meta-Thesaurus. This initiative included many enhancements to the Event Problem Codes aimed at improving code selection as well as improving adverse event report analysis. LIMITATIONS & RECOMMENDATIONS: Staff resources, database concerns, and limited collaboration with external groups in the initial phases of the project are discussed. Adverse events associated with medical device use can be better understood when they are reported using a consistent and well-defined code set. This FDA initiative was an attempt to improve the structure and add control mechanisms to an existing code set

  20. Awareness of the role of science in the FDA regulatory submission process: a survey of the TERMIS-Americas membership.

    PubMed

    Johnson, Peter C; Bertram, Tim A; Carty, Neal R; Hellman, Kiki B; Tawil, Bill J; Van Dyke, Mark

    2014-06-01

    The Industry Committee of the Tissue Engineering Regenerative Medicine International Society, Americas Chapter (TERMIS-AM) administered a survey to its membership in 2013 to assess the awareness of science requirements in the U.S. Food and Drug Administration (FDA) regulatory process. One hundred forty-four members responded to the survey. Their occupational and geographical representation was representative of the TERMIS-AM membership as a whole. The survey elicited basic demographic information, the degree to which members were involved in tissue engineering technology development, and their plans for future involvement in such development. The survey then assessed the awareness of general FDA scientific practices as well as specific science requirements for regulatory submissions to the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), the Center for Devices and Radiological Health (CDRH), and the Office of Combination Projects (OCP). The FDA-specific questions in the survey were culled from guidance documents posted on the FDA web site ( www.fda.gov ). One of the answer options was an opt-out clause that enabled survey respondents to claim a lack of sufficient awareness of the topic to answer the question. This enabled the stratification of respondents on the basis of confidence in the topic. Results indicate that across all occupational groups (academic, business, and government) that are represented in the TERMIS-AM membership, the awareness of FDA science requirements varies markedly. Those who performed best were for-profit company employees, consultants, and government employees; while students, professors, and respondents from outside the USA performed least well. Confidence in question topics was associated with increased correctness in responses across all groups, though the association between confidence and the ability to answer correctly was poorest among students and professors. Though 80% of

  1. An experimental investigation of masking in the US FDA adverse event reporting system database.

    PubMed

    Wang, Hsin-wei; Hochberg, Alan M; Pearson, Ronald K; Hauben, Manfred

    2010-12-01

    A phenomenon of 'masking' or 'cloaking' in pharmacovigilance data mining has been described, which can potentially cause signals of disproportionate reporting (SDRs) to be missed, particularly in pharmaceutical company databases. Masking has been predicted theoretically, observed anecdotally or studied to a limited extent in both pharmaceutical company and health authority databases, but no previous publication systematically assesses its occurrence in a large health authority database. To explore the nature, extent and possible consequences of masking in the US FDA Adverse Event Reporting System (AERS) database by applying various experimental unmasking protocols to a set of drugs and events representing realistic pharmacovigilance analysis conditions. This study employed AERS data from 2001 through 2005. For a set of 63 Medical Dictionary for Regulatory Activities (MedDRA®) Preferred Terms (PTs), disproportionality analysis was carried out with respect to all drugs included in the AERS database, using a previously described urn-model-based algorithm. We specifically sought masking in which drug removal induced an increase in the statistical representation of a drug-event combination (DEC) that resulted in the emergence of a new SDR. We performed a series of unmasking experiments selecting drugs for removal using rational statistical decision rules based on the requirement of a reporting ratio (RR) >1, top-ranked statistical unexpectedness (SU) and relatedness as reflected in the WHO Anatomical Therapeutic Chemical level 4 (ATC4) grouping. In order to assess the possible extent of residual masking we performed two supplemental purely empirical analyses on a limited subset of data. This entailed testing every drug and drug group to determine which was most influential in uncovering masked SDRs. We assessed the strength of external evidence for a causal association for a small number of masked SDRs involving a subset of 29 drugs for which level of evidence

  2. The liberal state and the rogue agency: FDA's regulation of drugs for mood disorders, 1950s-1970s.

    PubMed

    Shorter, Edward

    2008-01-01

    The theory of the liberal state does not generally contemplate the possibility that regulatory agencies will turn into "rogues," regulating against the interests of their clients and, indeed, the public interest. In the years between circa 1955 and 1975 this seems to have happened to one of the prime regulatory agencies of the US federal government: the Food and Drug Administration (FDA). Intent upon transforming itself from a traditional "cop" agency to a regulatory giant, the FDA campaigned systematically to bring down some safe and effective drugs. This article concentrates on hearings in the area of psychopharmacology regarding several antianxiety drugs, namely meprobamate (Miltown), chlordiazepoxide (Librium) and diazepam (Valium). In addition, from 1967 to 1973 this regulatory vengefulness occurred on a broad scale in the Drug Efficacy Study Implementation (DESI), an administrative exercise that removed from the market almost half of the psychopharmacopoeia. The article explores possible bureaucratic motives for these actions.

  3. State-of-the-Art in Design Rules for Drug Delivery Platforms: Lessons from FDA-approved Nanomedicines

    PubMed Central

    Dawidczyk, Charlene M.; Kim, Chloe; Park, Jea Ho; Russell, Luisa M.; Lee, Kwan Hyi; Pomper, Martin G.; Searson, Peter C.

    2014-01-01

    The ability to efficiently deliver a drug to a tumor site is dependent on a wide range of physiologically imposed design constraints. Nanotechnology provides the possibility of creating delivery vehicles where these design constraints can be decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing targeting efficiency and efficacy. Here we review the design strategies of the two FDA-approved antibody-drug conjugates (Brentuximab vedotin and Trastuzumab emtansine) and the four FDA-approved nanoparticle-based drug delivery platforms (Doxil, DaunoXome, Marqibo, and Abraxane) in the context of the challenges associated with systemic targeted delivery of a drug to a solid tumor. The lessons learned from these nanomedicines provide important insight into the key challenges associated with the development of new platforms for systemic delivery of anti-cancer drugs. PMID:24874289

  4. The first FDA marketing authorizations of next-generation sequencing technology and tests: challenges, solutions and impact for future assays.

    PubMed

    Bijwaard, Karen; Dickey, Jennifer S; Kelm, Kellie; Težak, Živana

    2015-01-01

    The rapid emergence and clinical translation of novel high-throughput sequencing technologies created a need to clarify the regulatory pathway for the evaluation and authorization of these unique technologies. Recently, the US FDA authorized for marketing four next generation sequencing (NGS)-based diagnostic devices which consisted of two heritable disease-specific assays, library preparation reagents and a NGS platform that are intended for human germline targeted sequencing from whole blood. These first authorizations can serve as a case study in how different types of NGS-based technology are reviewed by the FDA. In this manuscript we describe challenges associated with the evaluation of these novel technologies and provide an overview of what was reviewed. Besides making validated NGS-based devices available for in vitro diagnostic use, these first authorizations create a regulatory path for similar future instruments and assays.

  5. FDA-EPA Public Health Guidance on Fish Consumption: A Case Study on Informal Interagency Cooperation in "Shared Regulatory Space".

    PubMed

    Holden, Mark

    2015-01-01

    This article is a case study on how administrative agencies interact with each other in cases of shared regulatory jurisdiction. The theoretical literature on the topic of overlapping jurisdiction both (1) makes predictions about how agencies are expected to behave when they share jurisdiction, and (2) in recent iterations argues that overlapping jurisdiction can confer unique policymaking benefits. Through the lens of that theoretical literature, this article examines the relations between the Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA) regarding the public health risks posed by mercury in fish. It concludes that the FDA-EPA case study (1) corroborates the extant theoretical accounts of how agencies behave in cases of overlapping jurisdiction, (2) supports the conclusion of the recent scholarship that overlapping jurisdiction can confer unique policy benefits, and (3) reveals a few wrinkles not given adequate treatment in the extant literature.

  6. State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines.

    PubMed

    Dawidczyk, Charlene M; Kim, Chloe; Park, Jea Ho; Russell, Luisa M; Lee, Kwan Hyi; Pomper, Martin G; Searson, Peter C

    2014-08-10

    The ability to efficiently deliver a drug to a tumor site is dependent on a wide range of physiologically imposed design constraints. Nanotechnology provides the possibility of creating delivery vehicles where these design constraints can be decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing targeting efficiency and efficacy. Here we review the design strategies of the two FDA-approved antibody-drug conjugates (Brentuximab vedotin and Trastuzumab emtansine) and the four FDA-approved nanoparticle-based drug delivery platforms (Doxil, DaunoXome, Marqibo, and Abraxane) in the context of the challenges associated with systemic targeted delivery of a drug to a solid tumor. The lessons learned from these nanomedicines provide an important insight into the key challenges associated with the development of new platforms for systemic delivery of anti-cancer drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Evaluating oversight of human drugs and medical devices: a case study of the FDA and implications for nanobiotechnology.

    PubMed

    Paradise, Jordan; Tisdale, Alison W; Hall, Ralph F; Kokkoli, Efrosini

    2009-01-01

    This article evaluates the oversight of drugs and medical devices by the U.S. Food and Drug Administration (FDA) using an integration of public policy, law, and bioethics approaches and employing multiple assessment criteria, including economic, social, safety, and technological. Criteria assessment and expert elicitation are combined with existing literature, case law, and regulations in an integrative historical case studies approach. We then use our findings as a tool to explore possibilities for effective oversight and regulatory mechanisms for nanobiotechnology. Section I describes oversight mechanisms for human drugs and medical devices and presents current nanotechnology products. Section II describes the results of expert elicitation research. Section III highlights key criteria and relates them to the literature and larger debate. We conclude with broad lessons for the oversight of nanobiotechnology informed by Sections I-III in order to provide useful analysis from multiple disciplines and perspectives to guide discussions regarding appropriate FDA oversight.

  8. Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library.

    PubMed

    Feng, Jie; Weitner, Megan; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Zhang, Ying

    2015-09-16

    Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2-4 week antibiotic treatment, 10%-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive

  9. FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma.

    PubMed

    Barone, Amy; Hazarika, Maitreyee; Theoret, Marc R; Mishra-Kalyani, Pallavi; Chen, Huanyu; He, Kun; Sridhara, Rajeshwari; Subramaniam, Sriram; Pfuma, Elimika; Wang, Yaning; Li, Hongshan; Zhao, Hong; Zirkelbach, Jeanne Fourie; Keegan, Patricia; Pazdur, Richard

    2017-10-01

    On December 18, 2015, the FDA granted regular approval to pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma based on results of two randomized, open-label, active-controlled clinical trials. In trial PN006, 834 patients with ipilimumab-naïve metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 or 3 weeks until disease progression or ipilimumab 3 mg/kg every 3 weeks for up to four doses. In trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg i.v. every 3 weeks or to investigator's choice of chemotherapy. In trial PN006, patients randomized to pembrolizumab demonstrated a statistically significant improvement in overall survival compared with ipilimumab [every-2-week arm: hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.47-0.83; P < 0.001; every-3-week arm: HR = 0.69; 95% CI, 0.52-0.90; P = 0.004]. In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (≥2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of tumor response-based endpoints using RECIST or immune-related RECIST. Clin Cancer Res; 23(19); 5661-5. ©2017 AACR. ©2017 American Association for Cancer Research.

  10. The Dangers of Dental Devices as reported in the FDA MAUDE Database

    PubMed Central

    Hebballi, Nutan B; Ramoni, Rachel; Kalenderian, Elsbeth; Delattre, Veronique F.; Stewart, Denice C.L.; Kent, Karla; White, Joel M; Vaderhobli, Ram; Walji, Muhammad F

    2014-01-01

    Objectives To determine the frequency and type of adverse events (AEs) associated with dental devices reported to Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. Methods We downloaded and thoroughly reviewed the dental device-related AEs reported to MAUDE from January 01, 1996 – December 31, 2011. Results MAUDE received a total of 1,978,056 reports between January 01, 1996 and December 31, 2011. Among these reports, 28,046 (1.4 percent) AEs reports were associated with dental devices. Within the dental AE reports that had event type information, 17,261 reported injuries, 7,777 reported device malfunctions, and 66 reported deaths. Among the 66 entries classified as death reports, 52 actually reported a death in the description; the remaining were either misclassified or lacked sufficient information in the report to determine whether a death had occurred. 53.5 percent of the dental device associated AEs pertained to endosseous implants. Conclusion There is a plethora of devices used in dental care, and to achieve Element 1 of AHRQ’s Patient Safety Initiative, we must be able to monitor the safety of dental devices. While MAUDE is essentially the single source of this valuable information, our investigations led us to conclude that it currently has major limitations that prevent it from being the broad-based patient safety sentinel the profession requires. Practical Implications As potential contributors to MAUDE, dental care teams play a key role in improving the profession’s access to information about the safety of dental devices. PMID:25637208

  11. Assessing the Quality of Economic Evaluations of FDA Novel Drug Approvals: A Systematic Review.

    PubMed

    Woersching, Alex L; Borrego, Matthew E; Raisch, Dennis W

    2016-12-01

    To systematically review and assess the quality of the novel drugs' economic evaluation literature in print during the drugs' early commercial availability following US regulatory approval. MEDLINE and the United Kingdom National Health Service Economic Evaluation Database were searched from 1946 through December 2011 for economic evaluations of the 50 novel drugs approved by the FDA in 2008 and 2009. The inclusion criteria were English-language, peer-reviewed, original economic evaluations (cost-utility, cost-effectiveness, cost-minimization, and cost-benefit analyses). We extracted and analyzed data from 36 articles considering 19 of the 50 drugs. Two reviewers assessed each publication's quality using the Quality of Health Economic Studies (QHES) instrument and summarized study quality on a 100-point scale. Study quality had a mean of 70.0 ± 16.2 QHES points. The only study characteristics associated with QHES score (with P < 0.05) were having used modeling or advanced statistics, 75.1 versus 61.9 without; using quality-adjusted life years as an outcome, 75.9 versus 64.7 without; and cost-utility versus cost-minimization analysis, 75.9 versus 58.7. Studies most often satisfied quality aspects about stating study design choices and least often satisfied aspects about justifying design choices. The reviewed literature considered a minority of the 2008-2009 novel drugs and had mixed study quality. Cost-effectiveness stakeholders might benefit from efforts to improve the quality and quantity of literature examining novel drugs. Editors and reviewers may support quality improvement by stringently imposing economic evaluation guidelines about justifying study design choices. © The Author(s) 2016.

  12. Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library

    PubMed Central

    Feng, Jie; Weitner, Megan; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Zhang, Ying

    2015-01-01

    Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2–4 week antibiotic treatment, 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and

  13. Security and Privacy Qualities of Medical Devices: An Analysis of FDA Postmarket Surveillance

    PubMed Central

    Kramer, Daniel B.; Baker, Matthew; Ransford, Benjamin; Molina-Markham, Andres; Stewart, Quinn; Fu, Kevin; Reynolds, Matthew R.

    2012-01-01

    Background Medical devices increasingly depend on computing functions such as wireless communication and Internet connectivity for software-based control of therapies and network-based transmission of patients’ stored medical information. These computing capabilities introduce security and privacy risks, yet little is known about the prevalence of such risks within the clinical setting. Methods We used three comprehensive, publicly available databases maintained by the Food and Drug Administration (FDA) to evaluate recalls and adverse events related to security and privacy risks of medical devices. Results Review of weekly enforcement reports identified 1,845 recalls; 605 (32.8%) of these included computers, 35 (1.9%) stored patient data, and 31 (1.7%) were capable of wireless communication. Searches of databases specific to recalls and adverse events identified only one event with a specific connection to security or privacy. Software-related recalls were relatively common, and most (81.8%) mentioned the possibility of upgrades, though only half of these provided specific instructions for the update mechanism. Conclusions Our review of recalls and adverse events from federal government databases reveals sharp inconsistencies with databases at individual providers with respect to security and privacy risks. Recalls related to software may increase security risks because of unprotected update and correction mechanisms. To detect signals of security and privacy problems that adversely affect public health, federal postmarket surveillance strategies should rethink how to effectively and efficiently collect data on security and privacy problems in devices that increasingly depend on computing systems susceptible to malware. PMID:22829874

  14. FDA drug prescribing warnings: is the black box half empty or half full?

    PubMed

    Wagner, Anita K; Chan, K Arnold; Dashevsky, Inna; Raebel, Marsha A; Andrade, Susan E; Lafata, Jennifer Elston; Davis, Robert L; Gurwitz, Jerry H; Soumerai, Stephen B; Platt, Richard

    2006-06-01

    Black box warnings (BBWs) are the Food and Drug Administration's (FDA) strongest labeling requirements for high-risk medicines. It is unknown how frequently physicians prescribe BBW drugs and whether they do so in compliance with the warnings. The purpose of the present study was to assess the frequency of use of BBW medications in ambulatory care and prescribing compliance with BBW recommendations. This retrospective study used automated claims data of 929 958 enrollees in 10 geographically diverse health plans in the United States to estimate frequency of use in ambulatory care of 216 BBW drugs/drug groups between 1/1/99 and 31/6/01. We assessed dispensing compliance with the BBW requirements for selected drugs. During a 30-month period, more than 40% of enrollees received at least one medication that carried a BBW that could potentially apply to them. We found few instances of prescribing during pregnancy of BBW drugs absolutely contra-indicated in pregnancy. There was almost no co-prescribing of contra-indicated drugs with the two QT-interval-prolonging BBW drugs evaluated. Most non-compliance occurred with recommendations for baseline laboratory monitoring (49.6% of all therapy initiations that should have been accompanied by baseline laboratory monitoring were not). Many individuals receive drugs considered to carry the potential for serious risk. For some of these drugs, use is largely consistent with their BBW, while for others it is not. Since it will not be possible to avoid certain drug- associated risks, it will be important to develop effective methods to use BBWs and other methods to minimize risks.

  15. Recommendations from the iSBTc-SITC/FDA/NCI Workshop on Immunotherapy Biomarkers

    PubMed Central

    Butterfield, Lisa H.; Palucka, A. Karolina; Britten, Cedrik M.; Dhodapkar, Madhav V.; Håkansson, Leif; Janetzki, Sylvia; Kawakami, Yutaka; Kleen, Thomas-Oliver; Lee, Peter P.; Maccalli, Cristina; Maecker, Holden T.; Maino, Vernon C.; Maio, Michele; Malyguine, Anatoli; Masucci, Giuseppe; Pawelec, Graham; Potter, Douglas M.; Rivoltini, Licia; Salazar, Lupe G.; Schendel, Dolores J.; Slingluff, Craig L.; Song, Wenru; Stroncek, David F.; Tahara, Hideaki; Thurin, Magdalena; Trinchieri, Giorgio; van Der Burg, Sjoerd H.; Whiteside, Theresa L.; Wigginton, Jon M.; Marincola, Francesco; Khleif, Samir; Fox, Bernard A.; Disis, Mary L.

    2011-01-01

    Purpose To facilitate development of innovative immunotherapy approaches, especially for treatment concepts exploiting the potential benefits of personalized therapy, there is a need to develop and validate tools to identify patients who can benefit from immunotherapy. Despite substantial effort, we do not yet know which parameters of anti-tumor immunity to measure and which assays are optimal for those measurements. Experimental Design The iSBTc-SITC, FDA and NCI partnered to address these issues for immunotherapy of cancer. Here, we review the major challenges, give examples of approaches and solutions and present our recommendations. Results and Conclusions While specific immune parameters and assays are not yet validated, we recommend following standardized (accurate, precise and reproducible) protocols and use of functional assays for the primary immunologic readouts of a trial; consideration of central laboratories for immune monitoring of large, multi-institutional trials; and standardized testing of several phenotypic and functional potential potency assays specific to any cellular product. When reporting results, the full QA/QC performed, selected examples of truly representative raw data and assay performance characteristics should be included. Lastly, to promote broader analysis of multiple aspects of immunity, and gather data on variability, we recommend that in addition to cells and serum, that RNA and DNA samples be banked (under standardized conditions) for later testing. We also recommend that sufficient blood be drawn to allow for planned testing of the primary hypothesis being addressed in the trial, and that additional baseline and post-treatment blood is banked for testing novel hypotheses (or generating new hypotheses) that arise in the field. PMID:21558394

  16. A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents

    PubMed Central

    Madrid, Peter B.; Chopra, Sidharth; Manger, Ian D.; Gilfillan, Lynne; Keepers, Tiffany R.; Shurtleff, Amy C.; Green, Carol E.; Iyer, Lalitha V.; Dilks, Holli Hutcheson; Davey, Robert A.; Kolokoltsov, Andrey A.; Carrion, Ricardo; Patterson, Jean L.; Bavari, Sina; Panchal, Rekha G.; Warren, Travis K.; Wells, Jay B.; Moos, Walter H.; Burke, RaeLyn L.; Tanga, Mary J.

    2013-01-01

    Background The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. Methodology/Principal Findings A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. Conclusions/Significance The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses. PMID:23577127

  17. Antipsychotics and torsadogenic risk: signals emerging from the US FDA Adverse Event Reporting System database.

    PubMed

    Poluzzi, Elisabetta; Raschi, Emanuel; Koci, Ariola; Moretti, Ugo; Spina, Edoardo; Behr, Elijah R; Sturkenboom, Miriam; De Ponti, Fabrizio

    2013-06-01

    Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden. As part of the FP7 ARITMO (Arrhythmogenic Potential of Drugs) project, we explored the publicly available US FDA Adverse Event Reporting System (FAERS) database to detect signals of torsadogenicity for antipsychotics (APs). Four groups of events in decreasing order of drug-attributable risk were identified: (1) TdP, (2) QT-interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. The reporting odds ratio (ROR) with 95 % confidence interval (CI) was calculated through a cumulative analysis from group 1 to 4. For groups 1+2, ROR was adjusted for age, gender, and concomitant drugs (e.g., antiarrhythmics) and stratified for AZCERT drugs, lists I and II (http://www.azcert.org , as of June 2011). A potential signal of torsadogenicity was defined if a drug met all the following criteria: (a) four or more cases in group 1+2; (b) significant ROR in group 1+2 that persists through the cumulative approach; (c) significant adjusted ROR for group 1+2 in the stratum without AZCERT drugs; (d) not included in AZCERT lists (as of June 2011). Over the 7-year period, 37 APs were reported in 4,794 cases of arrhythmia: 140 (group 1), 883 (group 2), 1,651 (group 3), and 2,120 (group 4). Based on our criteria, the following potential signals of torsadogenicity were found: amisulpride (25 cases; adjusted ROR in the stratum without AZCERT drugs = 43.94, 95 % CI 22.82-84.60), cyamemazine (11; 15.48, 6.87-34.91), and olanzapine (189; 7.74, 6.45-9.30). This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk.

  18. Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library.

    PubMed

    Feng, Jie; Wang, Ting; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G; Zhang, Ying

    2014-07-01

    Although antibiotic treatment for Lyme disease is effective in the majority of cases, especially during the early phase of the disease, a minority of patients suffer from post-treatment Lyme disease syndrome (PTLDS). It is unclear what mechanisms drive this problem, and although slow or ineffective killing of Borrelia burgdorferi has been suggested as an explanation, there is a lack of evidence that viable organisms are present in PTLDS. Although not a clinical surrogate, insight may be gained by examining stationary-phase in vitro Borrelia burgdorferi persisters that survive treatment with the antibiotics doxycycline and amoxicillin. To identify drug candidates that can eliminate B. burgdorferi persisters more effectively, we screened an Food and Drug Administration (FDA)-approved drug library consisting of 1524 compounds against stationary-phase B. burgdorferi by using a newly developed high throughput SYBR Green I/propidium iodide (PI) assay. We identified 165 agents approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters. The top 27 drug candidates from the 165 hits were confirmed to have higher anti-persister activity than the current frontline antibiotics. Among the top 27 confirmed drug candidates from the 165 hits, daptomycin, clofazimine, carbomycin, sulfa drugs (e.g., sulfamethoxazole), and certain cephalosporins (e.g. cefoperazone) had the highest anti-persister activity. In addition, some drug candidates, such as daptomycin and clofazimine (which had the highest activity against non-growing persisters), had relatively poor activity or a high minimal inhibitory concentration (MIC) against growing B. burgdorferi. Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients.

  19. Evaluation of the proposed FDA pilot dose-response methodology for topical corticosteroid bioequivalence testing.

    PubMed

    Demana, P H; Smith, E W; Walker, R B; Haigh, J M; Kanfer, I

    1997-03-01

    The American FDA has recently released a Guidance document for topical corticosteroid bioequivalence testing. The purpose of this study was to evaluate the recommendations of this document for appropriateness. The new specifications require a dose-vasoconstriction response estimation by the use of a Minolta chromameter in a preliminary pilot study to determine the parameters for use in a pivotal bioequivalence study. The visually-assessed human skin balancing assay methodology routinely practiced in our laboratories was modified to comply with the requirements of the pilot study so that visual and chromameter data could be compared. Two different cream formulations, each containing 0.12% betamethasone 17-valerate, were used for this comparison. Visual data showed the expected rank order of AUC values for most dose durations whereas the chromameter data did not show similar results. The expected rank order of AUC values for both chromameter and visual data was not observed at very short dose durations. In fitting the data to pharmacodynamic models, equivalent goodness of fit criteria were obtained when several different parameter estimates were used in the model definition, however the visual data were best described by the sigmoid Emax model while the chromameter data were best described by the simple Emax model. The Emax values predicted by the models were close to the observed values for both data sets and in addition, excellent correlation between the AUC values and the maximum blanching response (Rmax) (r > 0.95) was noted for both methods of assessment. The chromameter ED50 values determined in this study were approximately 2 hours for both preparations. At this dose duration the instrument would not be sensitive enough to distinguish between weak blanching responses and normal skin for bioequivalence assessment purposes.

  20. Multilaboratory study of flow-induced hemolysis using the FDA benchmark nozzle model.

    PubMed

    Herbertson, Luke H; Olia, Salim E; Daly, Amanda; Noatch, Christopher P; Smith, William A; Kameneva, Marina V; Malinauskas, Richard A

    2015-03-01

    Multilaboratory in vitro blood damage testing was performed on a simple nozzle model to determine how different flow parameters and blood properties affect device-induced hemolysis and to generate data for comparison with computational fluid dynamics-based predictions of blood damage as part of an FDA initiative for assessing medical device safety. Three independent laboratories evaluated hemolysis as a function of nozzle entrance geometry, flow rate, and blood properties. Bovine blood anticoagulated with acid citrate dextrose solution (2-80 h post-draw) was recirculated through nozzle-containing and paired nozzle-free control loops for 2 h. Controlled parameters included hematocrit (36 ± 1.5%), temperature (25 °C), blood volume, flow rate, and pressure. Three nozzle test conditions were evaluated (n = 26-36 trials each): (i) sudden contraction at the entrance with a blood flow rate of 5 L/min, (ii) gradual cone at the entrance with a 6-L/min blood flow rate, and (iii) sudden-contraction inlet at 6 L/min. The blood damage caused only by the nozzle model was calculated by subtracting the hemolysis generated by the paired control loop test. Despite high intralaboratory variability, significant differences among the three test conditions were observed, with the sharp nozzle entrance causing the most hemolysis. Modified index of hemolysis (MIHnozzle ) values were 0.292 ± 0.249, 0.021 ± 0.128, and 1.239 ± 0.667 for conditions i-iii, respectively. Porcine blood generated hemolysis results similar to those obtained with bovine blood. Although the interlaboratory hemolysis results are only applicable for the specific blood parameters and nozzle model used here, these empirical data may help to advance computational fluid dynamics models for predicting blood damage. Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.