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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New Hypersensitivity Screen for Drugs

Posted by cdavenport on Friday Jun 22, 2012 Under Drug Safety, Immunogenicity, Preclinical, toxicity, Toxicology

Many drug hypersensitivity reactions are HLA-linked, meaning that they will occur much more often or even exclusively in individuals who have certain variants of the HLA gene.  A new study elucidates the specific mechanism leading to HLA gene-linked hypersensitivity to the drug abacavir.  These findings are applicable to other drugs and related hypersensitivity reactions.

The findings are discussed in the paper “Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire,” published last week in the scientific journal Proceedings of the National Academy of Sciences.

An interview with the authors is published in the Source cited below.

Source:  Clinical Toxicology

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Transgenic and genetically modified animal models are increasingly being used in the study of disease and for the safety assessment of new compounds.  Use of these models enhances understanding of the role that specific genes play in biological pathways.   The primary uses of transgenic mouse models in toxicology have mainly been to screen for genotoxicity and carcinogenicity and to understand the mechanisms of toxicity.   These mouse models can reliably predict the carcinogenic potential of compounds and significantly reduce the number of false positives.  When applied as single assays, however, transgenic models are unable to identify all known human carcinogens.  Use of a short-term transgenic mouse assay in combination with a two-year rat chronic study could eliminate the occurrence of false negatives and increase the overall accuracy of detecting carcinogens and non-carcinogens.  Additional bonuses for use of transgenic assays include reduced duration, conservative use of animals, and decreased cost relative to a traditional two-year rodent chronic toxicity study.

Source:  Life Science Leader

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The increased requirement for combined chronic toxicity and fertility assessment of biologics has led to greater use of sexually mature non-human primates.  Older animals have different needs compared to the younger, adolescent animals with which we are used to working.  In addition, the establishment of sexual maturity requires additional parameter measurements, such as assessment of menstrual cycling, hormone analyses, and seminology.  Changes in caging are required to reflect the social hierarchy inherent with the interaction of older primates, especially since subordinate animals mature later than their dominant peers.  Provision of complex environmental stimuli also becomes a greater necessity.  Due to the increased size and weight of older primates, handling becomes more of a potential source of stress and injury, to both animals and their handlers.  Differential criteria for assessment of sexual maturity in primates are discussed.

Source:  Developments in Life Sciences

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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.


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Both pharmaceutical industry and regulatory professionals acknowledge the importance of balancing timely access to new medicines with the need for thorough review of drug safety and efficacy data.  A new study, funded by the Pew Charitable Trusts (to be published in the New England Journal of Medicine), reviewed drug approval decisions of the Food and Drug Administration (FDA), the Canadian drug regulator -Health Canada, and the European Medicines Agency (EMA) between 2001 and 2010.  Yale and Mayo Clinic researchers studied each regulator’s database of drug approvals to identify novel therapeutics and timing of key regulatory events, thereby allowing regulatory review speed to be calculated.  The study found that the FDA approves 80% of all the applications it receives.  The median time for novel drug reviews by the FDA was 322 days (10.5 months).  That was 45 to 70 days ahead of Europe and Canada, which typically completed their novel drug reviews after 12 and 13 months, respectively.  Over the same 10-year time frame, the FDA reviewed 225 novel drug applications, 40 more than Europe and nearly 125 more than Canada.  Among novel drugs approved in both the U.S. and Europe, 64% were first approved by the FDA.  For novel drugs approved in both the U.S. and Canada, 86% were first approved by the FDA.

Release of study results may be too late to impact upcoming drug user fee Congressional legislation.  This legislation will reauthorize user fees the FDA collects from companies that make prescription drugs and medical devices.   In return for a 6% increase in user fees, the FDA has already agreed to accelerate novel drug approvals even further.  The standing Senate bill (approved by the White House) supports a new user fee for the review of generic drugs and adds provisions that address some challenges of globalization by enhancing the safety of the drug supply chain, increase incentives for the development of new antibiotics, renew and enhance mechanisms to ensure that children’s medicines are appropriately tested and labeled, and that expedite the development and review of certain drugs for treatment of serious or life-threatening diseases and conditions (e.g., by allowing conduct of smaller, shorter clinical trials).

SourcesHuffPost Health, Modern, R&D Magazine, and The Hill.

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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

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An Institute of Medicine (IOM) committee report, recommends that the FDA take proactive steps to continue monitoring drug safety after initial approval and throughout the market lifecycle.   Post-market evidence is far greater than what the FDA has when deciding upon initial approval.  The IOM recommendation is that the initial approval is viewed as just one early step in a process that requires continuous, long-term monitoring (the “lifecycle approach”).  The report makes recommendations about how post-market research should be conducted.  The committee found that while randomized controlled trials remain the gold standard for studying drug effectiveness, observational studies have ethical and practical benefits over clinical trials post-approval.  Safety results can be obtained more quickly, therefore regulatory action can be initiated earlier.  One of the key report recommendations is that upon approval, each drug will have a single, publicly available Benefit and Risk Assessment Management Plan (BRAMP) to serve as a central, evolving repository of side effects and other information.  As a centralized comprehensive record, the BRAMP will include a description, a benefit/risk assessment of any safety questions that exist when a drug is approved as well as any that emerge over the course of its market lifecycle, and details on any regulatory actions taken and their results.  Furthermore, it was recommended that the FDA’s drug surveillance systems could be improved through use of various technological and methodological advances (e.g., use of natural language processing for review of electronic medical records).  The possibility was also raised that with a more robust post-approval monitoring process, the more flexible regulatory authorities could be in the pre-approval stage.

SourceMedical News Today, and

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In the next 2-5 years, large pharmaceutical companies plan to increase outsourcing of preclinical work, with emphasis on Discovery and non-GLP Toxicology.  This trend is driven by the reductions in internal preclinical capability within Big Pharma.  In an apparent reversal of the current trend towards use of a limited number of preferred providers, capacity will necessitate increasing the number of contract research organizations (CRO) involved.  An offshore trend is anticipated despite the rapidly narrowing price differentials between Chinese and Western CROs for nonclinical work.  A survey suggested that the offshore CROs best positioned to secure the early-stage drug development business from large pharmaceutical companies are Covance, WuXi, BioDuro, and ShangPharma.   As an example, ShangPharma recently opened a new facility to accommodate a multi-year contract with Eli Lilly, with emphasis on in vivo pharmacology, oncology, and metabolic disease work.

Sources: 11 Jan 201217 Apr 2012, 19 Apr 2012

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