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

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

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

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

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.

The U.S. Food and Drug Administration announced (30 Sept 2009) the availability of the first draft guidance for industry on Risk Evaluation and Mitigation Strategies (REMS), which are required for certain drugs or biologics.

The Food and Drug Administration Amendments Act of 2007 (FDAAA) granted the FDA the authority to require the submission and implementation of a REMS if the FDA determines that a REMS is necessary to ensure that a drug’s benefit outweighs its risks.

An approved REMS that is voluntarily submitted is subject to the same requirements and enforcement as a REMS that was originally submitted as a required proposed REMS.  If an applicant voluntarily submits a proposed REMS, it will not be approved as a REMS until the FDA determines that it is required to ensure that the benefits of the drug outweigh the risks and that it meets the FDAAA criteria.  Proposed REMS that are not approved are not subject to the requirements and enforcement of an approved REMS.  FDA will notify applicants who voluntarily submit a proposed REMS whether the REMS will be required.  If the FDA determines that a REMS is not required, an applicant may undertake voluntary risk management measures that would be performed outside of a REMS.

Differentiation between a REMS and the earlier (i.e., prior to FDAAA) risk minimization action plans (RiskMAPs) is addressed.

Source: FDA Draft Guidance