IOM – Ethical Issues in Studying Safety of Approved Drugs

Just as an FDA Advisory Committee is mixing a batch of Avandia soup at a hearing held today to discuss and review the post-marketing safety of the drug, the Institute of Medicine (IOM) has issued a letter report on the ethical issues involved in the study of safety in drugs that are already approved and on the market.  

Coincidence?  Nope.  In fact, according to the cover letter, the FDA asked the IOM to respond to five different questions about the ethical and scientific issues associated with this topic.  In light of the Avandia meetings held this week, the IOM letter is a response to the first of five questions posed.  You can download the free report here.  A final report that addresses all five of the questions is due out next year.  

By way of background, when it became law in 2007, the Food and Drug Administration Amendments Act gave the FDA new authority over drug safety once they are on the market, including the ability to require clinical trials on safety.  Naturally, the conduct of such trials raises some ethical considerations – specifically what kind of informed consent would be appropriate?  To that end, the IOM issued the letter report to answer the first of FDA's five questions:

What are the ethical and informed consent issues that must be considered when designing randomized clinical trials to evaluate potential safety risks?  

Is a new post-marketing clinical trial on safety an option here?  It is not one of the questions being posed by the FDA to the AdComm.  Members are asked, however, that "[i]f Avandia (rosiglitazone) is recommended to stay on the market, should the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial be continued in order to provide further data on the comparative CV safety of rosliglitazone, pioglitazone, and standard-of-care management of type 2 diabetes…"

Here is where the IOM netted out – with four primary conclusions:

  1. The Public Health Context - The FDA should determine that there is a substantial public health question about the nature or acceptability of the risks, or the risk-benefit profile, of a marketed drug …"  
  2. Regulatory Science and Public Accountability - FDA should use regulatory science principles and practices that include processes of public accountability and transparency to determine the need for a policy decision, the need for new knowledge to support a policy decision, and the policy decision based on the new knowledge.  
  3. Design Considerations – It is appropriate for FDA to require that a randomized controlled trial be conducted to provide additional evidence about an approved drug's efficacy and safety only when (1) uncertainty about the risk-benefit balance is such that a responsible policy decision cannot be made based on either existing evidence or on evidence from new observational studies, and (ii) the trial is properly designed and implemented to reduce uncertainty about the risk-benefit balance sufficiently for a responsible policy decision to be made.
  4. Additional Ethical Obligations to Trial Participants – FDA should ensure that he trial will answer the public health question with a design that minimizes risks to trial participants and involves ongoing monitoring of risks.  The risks should be judged to be acceptable by appropriate oversight bodies before and during the trial and by trial participants at enrollment and as appropriate during the trial.  Specifically, FDA and appropriate oversight bodies should ensure that the trial includes a comprehensive and meaningful informed consent process that continues during the trial and that takes into account any substantial changes in clinical practice and professional standards and any new research findings relevant to a participant's willingness to accept the risks associated with the trial.  The FDA and appropriate oversight bodies should ensure that those conducting the trial convey such changes to participants in a timely and understandable fashion.

All in all, good common sense, though it is unclear what, if any, impact this IOM letter might have on the current circumstances.  I'm also not sure that these standards should be applied to any clinical trial performed, not just ones for post-marketing safety.  


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