Conceptual Framework from Ethical Issues in Studying the Safety of Approved Drugs: A Letter Report (IOM, 2010a) for Analyzing the Ethics of Postmarketing Randomized Clinical Trials Required by the Food and Drug Administration:
Four Central Classes of Considerations and Recommendations
I. The Public Health Context. The Food and Drug Administration (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—a question that requires a policy decision from FDA.
II. 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.
III. 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 (i) uncertainty about the risk-benefit balance is such that a responsible policy decision cannot be made based either on the existing evidence or on evidence from new observational studies, and (ii) the trial is properly designed and implemented to reduce uncertainty about the benefit–risk balance sufficiently for a responsible policy decision to be made.
IV. Additional Ethical Obligations to Trial Participants. FDA should ensure that the 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.