risk management

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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Assessing Safety Earlier in Drug Development

Posted by cdavenport on Wednesday Aug 1, 2012 Under Biomarker, Drug Safety, Preclinical, Risk Management

The objective of a recent survey by Cambridge Health Associates was to identify trends in safety biomarkers and their utilization in drug development.  Regardless of company size, recurrent themes for assessing drug safety in early preclinical development were noted.

  • Greater knowledge of safety biomarkers improved mechanistic understanding and helped to determine the relevance of nonclinical findings for clinical risk assessment.
  • Preclinical inclusion of systems or pathway modeling was deemed important for the selection and interpretation of biomarkers of organ toxicity.
  • Physical chemical prediction software or other forms of genetic or developmental and reproductive toxicity (DART) prediction software (e.g., DEREK, M-CASE, Leadscope) were being incorporated into early preclinical development by most companies.  All 3 software companies have Cooperative Research and Development Agreements (CRADA) with the FDA.
  • For cellular parameter screens, most companies are using image-based multi-parametric approaches of cellular analysis and cytotoxicity at the single-cell and subcellular level (via High Content Analysis [HCA])
  • Off-target screening (usually a CEREP panel) was performed by most companies early in preclinical development.

As might be expected to “slow the burn,” smaller companies ran fewer preclinical screens to predict drug safety and  performed these screens later in the drug development process.  Given that larger companies expect to have this information sooner than later, companies wanting to partner and/or be acquired may consider including more screens for drug safety earlier in their preclinical development programs.

 

SourceDSEC Drug Safety Executive Blog

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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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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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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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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 HealthCanal.com

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Adverse Preclinical Events – Now What?

Posted by cdavenport on Thursday Aug 4, 2011 Under Drug Safety, TigerU

Drug development is a complicated, often convoluted process.  The ability to predict drug toxicity in humans from nonclinical data remains a major challenge.  Since you can’t “erase” an adverse event, optimization of preclinical dose selection is essential.  This presentation outlines the process for dealing with adverse preclinical / nonclinical events in order to 1) optimize the chances of successful drug development, or 2) to create a scientific basis for early termination of drug development.  Conclusion: Experience counts!  There is no single answer for all problems.  Use of sound scientific and business judgement generally yields the best outcome.

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Drug Labels: Toxicity or Information Overload?

Posted by cdavenport on Saturday May 28, 2011 Under Drug Safety, Risk Management, toxicity

Side effect overload on drug labels has less to do with true toxicity and drug safety than with manufacturer liability.  Examination of more than 5600 drug labels yielded over half a million side effects.  An average drug label and the more commonly prescribed drugs averaged 70 and 100 side effects, respectively.  The upper range in a single label was 525 reactions.  Information overload can overwhelm physicians, who must weigh the risks and benefits when prescribing a medication.  The Food and Drug Administration discourages such ‘over warning,’ but information overload is presently the rule rather than the exception.  Not surprisingly, medications typically used by psychiatrists and neurologists had the most complex labels, while drugs used by dermatologists and ophthalmologists had the least.  Although providing drug safety information more efficiently to both health care providers and the public is warranted, drug manufacturer liability concerns must also be addressed.

Source: Drug Discovery and Development

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All medical products pose risks and postmarketing surveillance is critical to expanding the limited evidence base that exists when new drug products are approved.  Through initiation of the Sentinel Initiative (May 2008), the Food and Drug Administration (FDA) is developing the capacity for actively monitoring the safety/toxicity of approved medical products using the electronic health information in claims systems, inpatient and outpatient medical records, and patient registries.   The pilot program, Mini-Sentinel, uses a distributed data network (rather than a centralized database) of health plans and other organizations to create data files in a standard format while maintaining physical and operational control over their own patient-level data, thus ensuring patient privacy.   Laying the groundwork for that system has required input from both public and private organizations.  These data partners can obtain full-text medical records, when necessary, to confirm diagnoses or exposures and to determine the existence or severity of risk factors.

The initial focus of Mini-Sentinel has been on developing the ability to use medical claims data.  Over the next year, laboratory-test results and vital signs will be added.  The FDA will soon begin to actively monitor the data, seeking answers to specific questions (e.g., frequency of myocardial infarction among users of oral hypoglycemic agents).  Using the Mini-Sentinel system, the FDA will also be able to obtain rapid responses to new questions about medical products and, eventually, to evaluate the health effects of its regulatory actions.

Source: New England Journal of Medicine

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Drug safety may be underestimated for chronic-use drugs.  The FDA has placed more resources and requirements in evaluating drugs premarket than it does in monitoring what happens to patients after years of taking a medication.  Drugs that have recently underscored the potential dangers of chronic use are Avandia (diabetes; enhanced cardiovascular risk) and bisphosphonates (e.g., Fosamax, Actonel, and Boniva;  enhanced bone fracture/degeneration risks).  Although one proposed solution is the development of a national database that would track drug use and complications, this does not necessarily address duration of use, presence/duration of concomitant medications/supplements, patient age and medical history, genetic predisposition, etc.   Predominant trends will likely be noted using the proposed methodology, but a more multifaceted analysis will still be necessary to optimize the risk/benefit for individual patients.

Source: FairWarning

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