The FDA should ask for randomised, controlled clinical trials on already marketed drugs only where a substantial public health issue has arisen that cannot be resolved through existing evidence or new observational studies, and where questions about the product’s potential risks or risk-benefit ratio “rise to the level of requiring a policy decision”, says the US Institute of Medicine (IoM).

The IoM has published a ‘letter report’ on Ethical Issues in Studying the Safety of Approved Drugs in response to a request from the Food and Drug Administration, as the agency gears up for the 13-14 July joint meeting of its Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Committee on the cardiovascular safety of GlaxoSmithKline’s diabetes drug Avandia (rosiglitazone).

The FDA has come under fire for allowing the TIDE post-marketing trial, currently recruiting patients – and apparently with some difficulty, in light of the safety concerns around Avandia – for a head-to-head comparison of GSK’s drug with Takeda’s Actos (pioglitazone). US Senators Max Baucus and Chuck Grassley recently wrote to FDA Commissioner Margaret Hamburg arguing that “any proposed head-to-head trial of rosiglitazone versus pioglitazone would be unethical and exploitative”.

The IoM’s report addresses the first of five questions that the FDA wants the Institute to explore in a review of the scientific and ethical issues involved in conducting safety studies with already approved drugs.

Specifically, the FDA asked the IoM to convene a special committee to look at the issues and challenges raised by the expanded authority over drugs in the post-marketing phase granted to the agency under the Food and Drug Administration Amendments Act of 2007.

These questions were:

- What are the ethical and informed consent issues that must be considered when designing randomised clinical trials to evaluate potential safety risks?
- What are the strengths and weaknesses of various approaches, such as observational studies (including patient registries), meta-analyses (including patient-level data meta-analyses), and randomised controlled trials, in generating evidence about safety questions?

- Considering the speed, cost and value of the trials concerned, what types of follow-up studies are appropriate to investigate different kinds of signals – whether detected pre- or post-approval – and in what temporal order?
- Under what circumstances should head-to-head randomised clinical trials be required to evaluate safety post-approval?
- How should the FDA factor in different kinds of safety evidence when considering different kinds of regulatory actions?

A more detailed analysis of these issues, together with their implications and effects, will be included in the IoM committee’s final report, scheduled for completion in spring 2011.

The letter report on the ethical issues surrounding post-marketing trials does not enter into the specifics of the Avandia debate, although it does address issues that come into play with that case, the IoM notes. Rather, the committee has come up with a conceptual framework intended to be broadly applicable to post-marketing trials.

The key issues covered in this framework and in the wider report are as follows:

- The Public Health Context. When considering whether a company should start or continue a trial post-approval, 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 – a question that requires a policy decision from FDA”, the committee says.

- Regulatory Science and Public Accountability. The agency should apply regulatory-science principles and practices, including 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”.

- Design Considerations. It is only appropriate for the FDA to ask for a randomised controlled trial to provide additional evidence on an approved drug’s efficacy and safety, the IoM committee believes, 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 risk/benefit balance “sufficiently for a responsible policy decision to be made”.

- Additional Ethical Obligations to Trial Participants. The FDA should ensure that the trial will answer the relevant public health question “with a design that minimises risks to trial participants and involves ongoing monitoring of risks”. These risks should be judged acceptable by appropriate oversight bodies both before and during the trial, and by trial participants “at enrolment and as appropriate during the trial”.

Specifically, the report says, the 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”, as well as any new research findings “relevant to a participant’s willingness to accept the risks associated with the trial”. The FDA and relevant oversight bodies should also ensure that “those conducting the trial convey such changes to participants in a timely and understandable fashion”.

If the FDA does feel a randomised, controlled trial is necessary for it to make a policy decision, the report suggests, then:

_ The evidence gap addressed by the trial should be “clearly present and specifically identified”, while the research question and study design should be precisely crafted to address that gap.

_ The trial should be adequately powered, while the trial procedures and pre-specified analytic plans should be “appropriate to provide answers to the study questions”.
_ The inclusion and exclusion criteria should “reflect the best available knowledge about risks and potential benefits in the population”.

_ A “comprehensive and robust” safety monitoring plan should be in place for the trial, administered by a properly qualified data-safety monitoring board.