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.

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

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

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

Prior to drug approval, a potential new drug is usually subjected to the scrutiny of an expert advisory panel, selected by the FDA, who recommend whether or not the product should be marketed.   These recommendations are non-binding.  Industry analysts looked at product-specific decisions, a total of 120 votes, made by advisory committees to the FDA from 2007 through 2010.  The FDA followed its committees’ advice 74% of the time.  Significantly, only 3 times did the FDA overrule a “no” vote from the committee: Tarceva (lung cancer), Avastin (breast cancer), and Micardis (hypertension).  In other words, a “no” vote from an advisory panel is likely to meet acceptance, but a “yes” vote does not mean that the product will be approved.  All of the recent hype over obesity drugs aside, it is important to understand current events in light of historical precedence.  It also highlights the importance of risk management, particularly when dealing with drugs that have blockbuster potential.

Source: Forbes

Although the Food and Drug Administration (FDA) routinely reviews the safety and effectiveness of all prescription drugs prior to approval, some side effects become evident only after the drugs are taken by millions of patients – far more than it is possible to test in clinical trials.  A drug’s side-effect profile becomes better characterized, therefore, with greater exposure and use.  Additionally, once marketed, many drugs are prescribed for alternate disease states with new target populations; unanticipated safety issues may arise in new target populations.  For this reason, the new on-line quarterly reports (launched 15 June 2010) will  address safety risks that were not identified during a drug’s development or prior to FDA approval.  These reports are targeted to appear within roughly 2 years of a new drug’s approval (back to 27 September 2007) or, for drugs that have Risk Evaluation and Mitigation Strategies (REMS), since the REMS was required or last assessed.  REMS ensure that the benefits of a drug or biological product outweigh its risks.

Quarterly safety summaries incorporate potential signals of serious risks/new safety information identified by the Adverse Event Reporting System (AERS) as well as by FDA-initiated research.  When a potential signal of a serious risk is identified from AERS data, it is entered as a safety issue into the Center for Drug Evaluation and Research (CDER) Document Archiving, Reporting, and Regulatory Tracking System (DARRTS) or into the Center for Biologics Evaluation and Research (CBER) Therapeutics and Blood Safety Branch Safety Signal Tracking (SST) system.  Although potential signals of serious risks are usually based upon groups of AERS reports, a single AERS report could initiate the evaluation of a potential safety issue.  FDA posts each potential signal of a serious risk in the quarter in which it is first identified.  If additional safety information is developed concerning a potential signal that has already been posted, it is addressed by FDA in new safety communications/updates, but does not appear again as a new quarterly posting.  Listing does not necessarily imply a causal relationship between the drug and the identified risk.  The FDA is requiring REMS formulation as well as posting of  quarterly drug safety reports in accordance with Title IX, Section 921 of the FDA Amendments Act (FDAAA) of 2007 (see insert).

Source: The Herald Sun

Relevant References: Mass Tort Defense,  FDA Law Blog, FDA Transparency Blog

Despite greater emphasis on safety as a result of attrition, the application of toxicology (~6% of the total R&D budget) to the preclinical drug development process has remained largely unchanged for over 30 years!  For this reason, the impetus to reduce safety risks early has been slow to evolve, with limited resources specifically dedicated to this endeavor. Revolutionizing  the way that toxicology is applied, such as moving from a hazard  identification and risk assessment preclinical paradigm to one that reduces or  eliminates risk prior to major expenditures,  may provide a means of narrowing the productivity gap within the biopharmaceutical industry.  This paper suggests a strategy for the integration of toxicology into early drug development (discovery phase) through identification of potential safety issues related to therapeutic use, target selection, and compound selection, with a primary emphasis on new chemical entities. Information gained may also guide the appropriate selection of the toxicological species used to support clinical trials.  Assays predictive of target organ effects (insufficiently discussed, in my opinion, in the present article) vs. assays designed to look at specific mechanisms of drug-induced toxicities at the intracellular level are presented relative to the need for development of high throughput safety screens.

In conclusion, the preclinical toxicology strategy needs to accommodate the unique attributes of the target, the compound, and the therapeutic application, along with assays that are “fit-for-purpose” for that specific project. This paper provides an overview of safety issues for initial exploration and cites possible techniques available to address them in the preclinical space.

Source:  Pharmaceutical Outsourcing

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

As of 2007, the FDA has the  authority to require a Risk Evaluation and Mitigation Strategy (REMS) for certain drugs and biological products, to ensure that the benefits of such products outweighed the risks.  Although the FDA mandated risk-management plan applies only to prescription drugs and biologicals, the effect of a REMS extends down the supply chain to affect which physicians may prescribe and how pharmacies dispense medication, even though the FDA has no regulatory authority beyond manufacturers.  Ned Milenkovich (Modern Medicine, 8 Oct 2009) poses the question, therefore, whether Congress and the FDA are exceeding their authority by indirectly regulating professions that traditionally have been governed by the various states?  This article gives a good overview of the status and use of REMS by the FDA and Industry and considers the indirect effects.