What are the ethical issues the FDA faces when requiring a drugmaker to run a randomized clinical trial for an approved drug when a safety issue exists? The agency is confronting this dilemma as it evaluates the Avandia diabetes pill, which was linked to heart attacks and strokes in two large observational studies (see here and here) and will be the subject of a contentious FDA advisory committee meeting next week.

To gain some guidance and political cover, FDA commish Margaret Hamburg recently asked an Institute of Medicine committee to explore this question - and four others concerning ethical and scientific issues in studying approved drugs, which will be answered in a more detailed analysis next spring. Given the Avandia debate, Glaxo is having trouble recruiting patients (see this). So the IOM will make a brief presentation during the meeting next week, but released a preliminary response to the first question this morning.

So what did the committee say? Basically, the IOM committee offered guidelines, but not specific recommendations for the Avandia trial itself. “A trial in which the risks to participants are not outweighed by the prospect of direct medical benefits to participants may be justifiable if a question of pressing public health importance cannot be properly answered without the conduct of the trial and if other conditions intended to safeguard the rights and interests of participants are satisfied,” the committee writes. And so the trick for the FDA is gauge the extent to which nailing down the Avandia safety risks overshadows the risk posed to trial participants. Some say the trial is not worth the risk (see here).

In general, the committee says the FDA should only allow a drug to remain on the market if benefit outweighs the risk; allowing a trial to continue would be unethical if new evidence is so compelling that a decision can’t wait for additional new info; before starting a new trial, the agency should be certain no other research or way of gathering info - such as an observational study - can reduce the uncertainy about a risk-benefit profile; and the FDA can require a trial if the existing evidence is insufficient to determine causality or the risk-benefit profile.

The IOM goes on to say that: “All observational studies and meta-analyses of randomized trials may be affected by confounding or bias. If the estimated relative risks are small, selection bias, confounding, and measurement error may be alternative explanations for associations found in an observational study. But small relative risks of serious outcomes associated with widely used agents can have substantial public health consequences. Under such circumstances, if there is substantial uncertainty about a safety signal, a well-designed and well-conducted postmarketing randomized clinical trial is the best approach for characterizing the risk–benefit profile. The opportunity to evaluate both risks and benefits in the same study is an important advantage of randomized trials.”

If a randomized controlled trial is deemed necessary for an FDA-policy decision, its characteristics should include the following:

1. The evidence gap should be clearly present and specifically identified, and the research question and study design should be precisely crafted to address the gap.

2. The trial should be adequately powered, and the trial procedures and the prespecifiee analytic plans should be appropriate to provide answers to the study questions.

3. The inclusion and exclusion criteria should reflect the best available knowledge about risks and potential benefits in the population. (It is never ethically justified to include in a postmarketing trial participants for whom the drug is contraindicated by the currently approved product label unless their involvement is necessary to answer a specific question and the risks to them posed by participation are acceptable).

4. A comprehensive and robust safety-monitoring plan should be in place.