According to a commentary by former Institute of Medicine (IOM) committee members, published this week in the New England Journal of Medicine, increased “fast-tracking” of drug approvals (i.e., for medical conditions with no effective treatment) necessitates a counterbalance of enhanced postmarket surveillance and ethical governance throughout the lifecycle of a drug.  The authors of the report argue that the FDA, when requiring that a postmarked study be initiated, has a unique ethical obligation to research participants, which “cannot be handed off to contractors or the industry sponsor.”  Furthermore, “because some postmarked trials are required specifically to address mounting concerns that the drug’s risks may outweigh its benefits, there are heightened obligations to ensure that potential research participants understand the risks of enrollment.”  Because the volume of postmarked studies is increasing – due not only to FDA-mandated research, but also to increased emphasis on comparative-effectiveness – the benefit-risk balance for comparable study designs can vary depending upon the purpose for which a specific study is being conducted.  The challenges, therefore, for ensuring truly informed consent by study participants can vary widely.

Source:  Science Codex

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The FDA has published an updated Guidance Agenda – new and revised draft guidances CDER is planning to publish during calendar year 2012.   Guidances of particular interest to nonclinical pharmaceutical toxicologists may include:


• Endocrine Disruption Potential of Drugs: Non Clinical Evaluation

• Integrated Summary of Safety


• Food-Effect Bioavailability and Fed Bioequivalence Studies—Bioavailability and Bioequivalence Studies for Orally Administered Drug Products Submitted in New Drug Applications General Consideration

Electronic Submissions
• Providing Regulatory Submissions in Electronic Format – General Considerations
• Providing Regulatory Submissions in Electronic Format – Study Data
• Providing Regulatory Submissions in Electronic Format – Standardized Study Data


SourceU.S. Food and Drug Administration

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Off-label Drug Use: Fact vs. Fiction

Posted by cdavenport on Friday Aug 17, 2012 Under Drug Promotion, Drug Safety, FDA

The authors – CM Wittich, CM Burkle, and WL Lanier – offer a concise review of the topic of off-label drug use including its definition, prevalence, and implications for drug safety.   The article format addresses 10 common questions and their answers about off-label drug use.  The breadth of application, its acceptance, and the liabilities of off-label use are explored.  A history of FDA regulations surrounding the practice is presented, which helps to put its evolution into proper perspective.  Off-label use, which occurs in every medical specialty, is more common in patient populations not likely to be included in clinical trials (e.g., pediatric, pregnant, or psychiatric patients).  Once a medication is marketed, the FDA does not limit or control how the medication is prescribed by physicians. The pros and cons of the distribution of information regarding the off-label use of medications by pharmaceutical companies, the use of informed consent, and the liability of prescribing physicians are discussed.

SourceMayo Clinic Proceedings  – pdf of full article.

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Linguamatics, the leader in natural language processing (NLP)-based text mining, announced that the Federal Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) has licensed its 12E text mining platform as a discovery and decision support tool to supplement laboratory research efforts on drug safety.  The FDA will use the platform to review published literature and drug product labels to address key biomedical issues, including mechanisms of drug toxicity and disease processes.  In addition to document retrieval, the 12E platform can identify, extract, synthesize, and analyze relevant facts and relationships (e.g., between genes and diseases, drugs and side effects).  Customers include top tier commercial, academic, and governmental organizations, including 9 of the top 10 global pharmaceutical companies.  The 12E platform is available both as an in-house or cloud-based system.

Typical applications in pharmaceutical, biotechnology, and healthcare include:
•    Mapping gene-disease relationships and identifying potentially novel therapeutic targets
•    Biomarker discovery
•    Drug repurposing
•    Drug safety
•    Patent analysis
•    Clinical trial site selection and study design
•    Mining electronic medical records to improve prediction of health outcomes
•    Translational medicine
•    Competitive intelligence
•    Social media mining
•    Subjective data mining (sentiment analysis, key opinion mining)

SourcesBioSpace and Business Weekly

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Analysis and overview of new drug reviews from 1993 through present by an over 20-year-active FDA veteran of drug approvals, Dr. John Jenkins (Director, Office of New Drugs, Center for Drug Evaluation and Research).  The presentation includes review times and comparison to global approvals.  Of note, median approval times for New Molecular Entities (NME) applications are 10 months, a 47% reduction from calendar year 1993.  A status update on CDER compliance with past PDUFA goals is given, with information on forward planning to comply with PDUFA V goals.  In accordance with the enhanced emphasis on benefit-risk analysis in PDUFA V, discussion of the anticipated framework and balance of stakeholder concerns is detailed.   The PDUFA V program for NME review is presented, with key elements and projected timelines detailed.

This slide presentation gives excellent perspective of past and future trends for the global pharmaceutical market, with emphasis on FDA approvals of NME.

Source Slide Show (pdf hyperlink):  FDA

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FDA Pharamacogenomic Biomarker Database

Posted by cdavenport on Thursday Jul 5, 2012 Under Databases, Drug Safety, FDA, Genetic Toxicology, Regulatory

Pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose. Drug labels may contain information on genomic biomarkers and can describe:

    • Drug exposure and clinical response variability
    • Risk for adverse events
    • Genotype-specific dosing
    • Mechanisms of drug action
    • Polymorphic drug target and disposition genes

This resource table lists FDA-approved drugs with pharmacogenomic information / biomarkers in their labels.

Source:  FDA

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PDUFA V: Risk – Benefit Emphasis New

Posted by cdavenport on Friday Jun 29, 2012 Under Drug Safety, FDA, Risk Management

What is new about PDUFA V?   Congress, the media, and the public have a history of boiling down the issue to whether drugs are safe or not safe.  In reality the issue is benefit versus risk.   In addition, this judgement needs to be aligned with that of the patients who take the medication.  Emphasis on this risk-benefit framework is a landmark difference in the pending PDUFA V legislation.

Source:  Nature

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FDA Resource for Approved Drug Information

Posted by cdavenport on Monday Jun 25, 2012 Under Databases, FDA, Preclinical, Regulatory

Ever wanted to know the ins and outs of almost every drug approved by the Food and Drug Administration since 1939?

By using the Drugs@FDA database, you can search for information about FDA-approved brand name and generic drugs and therapeutic biological products.  The database includes most of the drug products approved since 1939 and has drug labels, patient information, approval letters, and other information for most drug products approved since 1998.

Source:  FDA

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Drug Safety: Tip of the Iceberg

Posted by cdavenport on Thursday Jun 7, 2012 Under Drug Safety, FDA, Post-market Surveillance, Risk Management, toxicity

The 10 drugs with the largest numbers of reports sent directly to the FDA by healthcare practitioners and consumers in 2011 in order of frequency are Pradaxa, Coumadin, Levaquin, Carboplatin, Zestril, Cisplatin, Zocor, Cymbalta, Cipro and Bactrim.  It is interesting to note that just two of these drugs were first introduced in the last decade (Pradaxa and Cymbalta), and only one in the previous year (Pradaxa), suggesting that major drug safety issues are not confined to recently approved drugs.  On one hand, this shows that FDA and manufacturer safety surveillance programs have identified these significant safety risks. On the other, it illustrates that placing warnings in product information only begins the process of managing drug safety risks.   Relative rates vs. report expectations are detailed.

These data come from QuarterWatch™ an Institute for Safe Medication Practices surveillance program that monitors all serious and fatal adverse drug events (ADEs) reported to the Food and Drug Administration through MedWatch, its adverse event reporting system.  The goal is to identify signals that may represent important new drug safety issues.

Source:  Philly.com/Health

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Potential Academic Contributions to Drug Development

Posted by cdavenport on Monday May 14, 2012 Under Drug Safety, FDA, Techniques

Dr. Janet Woodcock (CDER, FDA) stated that for every 10 drugs that enter Phase I clinical trials, only 1 drug is approved.  The cost of bringing an innovative drug to market often requires a decade and a billion dollars of investment.  The paradigm where pharmaceutical companies invest heavily in research and development yet garner few drug approvals is unsustainable.

Woodcock suggests that academic researchers can contribute better methods and technologies to enable faster/better preclinical and clinical decisions to be made during drug development.  Recommendations given include:

  • Development of biomarkers that help identify not only safety risks but also identify patients most likely to benefit from a new, targeted therapy
  • Greater emphasis on applied science (e.g., drug manufacturing and scale-up enhancements)
  • Identification of biochemical pathways causal to disease states
  • Identification of proof-of-concept/surrogate endpoints
  • Enhanced understanding of how the body handles a drug
  • Take a lead on developing orphan drugs, which have historically not been a priority for pharmaceutical companies
  • Develop and implement new ways to conduct clinical trials (e.g., use of early biomarker identification to guide patient selection) with the goal of developing faster, better, smaller clinical studies to gain critical information more quickly ( e.g., work being done at Stanford University)
  • To extend clinical trials into the community and region surrounding academic medical centers to facilitate patient access, recruitment, and to enhance compliance

The public has a decreased tolerance for risk, as evidenced by increased regulatory requirements for premarket evaluation of drug safety and efficacy.  The hope is that academic researchers can drive changes in the required testing paradigms (nonclinical and clinical) to enable faster, better, and cheaper drug approvals.

Sources:  Lecture by Dr. Janet Woodcock at the California Institute for Quantitative Biosciences (qb3), UCSF and HealthCanal.com.

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