Postmarket Surveillance

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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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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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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In order to keep our competitive edge, the Federal Drug Administration (FDA) is placing increased emphasis on strengthening both the field and application of regulatory science relative to pharmaceutical research, development, review, and post-market surveillance.  The FDA also has a mandate to recognize areas of unmet public health need and try to galvanize action to move appropriate new products through the pipeline and into the market.  The FDA has the responsibility, therefore, not just to review and approve products if the data support that decision, but also to follow these products once marketed to answer critical questions about efficacy and safety.  Examination of products across their life cycle enables not only the identification and analysis of emerging safety signals, but also facilitates the continual balancing of risks and benefits.

Research studies, both preclinical and clinical, that form the basis for approval of medical products are increasingly being performed in other countries and often in networks of other countries.   For this reason, international recognition of both the scientific appropriateness and ethical conduct of those studies becomes increasingly important to global regulatory bodies.  A key understanding is that if a safety concern develops for an approved drug, it does not necessarily reflect that a mistake was made.  It may instead reflect new emerging knowledge about that drug in practical use.  Regulatory safety has to be a dynamic process.  The desire is to proactively ensure that the right studies are done so that the best possible decisions result.  However, there isn’t always an absolute, clear decision to be made; resolution, therefore, requires a dynamic balancing of risks and benefits.  Questions need to be asked about whether certain subpopulations of patients may benefit from targeted use of a drug, or whether the safety concerns are sufficient to mean a more active withdrawal of a product from the market.   Advances in science and technology need to be better incorporated into the regulatory process, with a key area being safety science.   To continue to strengthen the science of regulatory safety, the need is to broaden not only the kinds of preclinical and clinical studies that can be done to deepen our understanding of safety, but also to broaden our understanding of how to apply and weight that data to further the science of risk management.

Source: Interview between Dr. Eli Adashi, Professor of Medical Science at Brown University and host of Medscape One-on-One, and Dr. Margaret Hamburg, Commissioner of the US Food and Drug Administration.  MedScape Today.

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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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In the FDA’s effort to make both its decisions and clinical trial data more transparent to the public, Agency decisions have become more available for public debate.  Sophisticated analyses (increasingly by third parties) of publically available data may present to the FDA a more complex picture of drug safety, as not all posted clinical trials fit standard regulatory paradigms, are sufficiently powered, have similar patient selection criteria,  or collect and analyze similar parameters. Changes made in the interest of public health, therefore, may further complicate regulatory assessment of potential changes to drug status.  For these reasons, among others, drug safety decisions are rarely “black and white.”  To its credit, the “new” FDA seems more open to try a middle path (e.g., the diabetes medicine Avandia will remain on the market under a restricted access program [risk evaluation and mitigation strategy, or REMS]).  Even more unusual, however, was public admission by the FDA of disagreement about Avandia within its own scientific ranks.  Furthermore, 3 top FDA officials co-authored a New England Journal of Medicine article explaining their rationale.  Interpretation of clinical trial data, however, is relatively easy compared to analyses of post-market safety data, where patient populations and indications are even more diverse.  It will be interesting to see how public access to evolving data (e.g., the anticipated FDA post-marketing drug safety (public) website) will affect Agency decisions, the timing of those decisions, and how much influence third-party analyses will have on regulatory outcomes.  The upside to the ensuing debate may be heightened public awareness of the importance of risk management, as all drugs have risk.  With the down-spiral of new drugs both coming to and remaining on the market, an outstanding question is whether the public and subsequently the regulatory environment will become more or less risk adverse as our perception of drug safety and risk management evolves.

Source: The New York Times

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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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As of 15 June 2010, the new Food and Drug Administration (FDA) Postmarketing Drug Safety Evaluation website was launched.   The FDA posted postmarket safety evaluations for 26 drugs approved between September 2007 and January 2008 and is reviewing an additional 20 or 30 others. To date, no label changes have been recommended.

In accordance with the Food and Drug Administration Amendments Act of 2007 (FDAAA), the FDA now summarizes information about ongoing and completed postmarketing safety evaluations of serious adverse events (SAE) submitted to the FDA for New Drug Applications (NDAs) and Biologic License Applications (BLAs) that have been approved since 27 September 2007.   These evaluations are completed to determine if there are any new SAE not previously identified during product development, known side effects reported in unusual number, or potential new safety concerns identified post approval.  These postmarketing evaluations will be performed no later than 18 months following approval (i.e., early in the product’s marketed life cycle) or after its use by 10,000 individuals, whichever is later.

To develop these postmarketing safety evaluations the FDA assesses several data sources including:
• The product’s pre-approval safety profile
• The product’s current FDA-approved label
• Reports made to FDA’s Adverse Event Reporting System (AERS)
• Reports made to the Vaccine Adverse Event Reporting System (VAERS)
• Manufacturer-submitted periodic safety reports
• Medical literature
• Drug utilization databases
• Data from post-approval clinical trials and other studies, when applicable

FDA analyses for the safety evaluations include:
• Data mining analysis of all adverse event reports in the AERS or VAERS databases
• Review serious adverse event reports
• Medication error analysis
• Product utilization analysis
• Risk management review
• Analysis of post-approval safety data from clinical trials and other studies, when applicable

Summaries of FDA safety analyses on recently approved products will now be prepared quarterly and posted on FDA’s website along with a brief discussion of the steps FDA is taking to address any identified safety issues.

Related posts:

New On-line Quarterly Drug Safety Summary and REMS are Complimentary Efforts
Postmarket Drug Safety: Institute of Medicine Recommendations to FDA

Sources:

FDA-1,   FDA-2,   Resource Shelf,   USA Today,   World Pharma News

To share this post easily, cut and paste:  New FDA Postmarketing Drug Safety Evaluation Website   http://bit.ly/b79Fqs

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How can we better execute postmarket drug surveillance?  A recent study proposes formation of a detailed, publicly available database that could be continually updated and aggregated with new information as new clinical study results are published.  This essentially real-time balance sheet of a drug’s risks and benefits would be open to external review.  Using the Vioxx litigation data as an example, study results suggest that cardiovascular risk could have been identified earlier using this type of sequential cumulative analysis, although this finding is disputed by Merck.

A historical overview of FDA’s postmarket drug safety surveillance system was detailed in a previous post.  Since Vioxx was pulled from the market, the FDA has instituted several postmarket surveillance initiatives: additional staff members in all divisions to monitor drug safety, strengthening of the Office of Surveillance and Epidemiology,  and formation of a new postmarket safety tracking system for new drugs.  Dr. Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research, stated that when a potential health concern is noted, that the Agency conducts its own meta-analyses of the data.  Following a Congressional amendment in 2007, the FDA can require: risk management programs for certain drugs, postmarket safety studies, drug label updates, and the publication of clinical trial results.

Source:  The New York Times

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This US Government Accountability Office’s (GAO) current report (2007) gives a brief history and overview of the 2 FDA branches – Office of New Drugs (OND), and the Office of Drug Safety (ODS) –  mandated to oversee postmarketed drug safety.   OND’s primary responsibility is to review new drug applications, but it is also involved in monitoring the safety of marketed drugs.  ODS (now called the Office of Surveillance and Epidemiology) is focused primarily on postmarket drug safety issues.   In its March 2006 report, the GAO found that the FDA lacked clear and effective processes for making decisions about, and providing management oversight of, postmarket drug safety issues.  Updates on FDA’s progress on a variety of initiatives to improve its postmarket drug safety decision-making process, including the establishment of the Drug Safety Oversight Board, is reviewed.  This article, which is the most recent update posted on the GAO website, gives a historical perspective on why ongoing initiatives were enacted.

Source:  Government Accountability Office.

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