Healthy Skepticism Library item: 18476

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Publication type: Magazine

Gever J
IOM Panel Frames Issues in Drug Safety Studies
MedPage Today 2010 July 12
http://www.medpagetoday.com/PublicHealthPolicy/ClinicalTrials/21115

Full text:

The FDA is ethically bound to order new randomized trials of marketed drugs when questions about their risk-benefit profile can’t be answered with existing data or observational studies, according to an Institute of Medicine (IOM) committee report requested by the FDA.

The analysis comes on the eve of an FDA advisory committee meeting expected to help determine the fate of the controversial diabetes drug rosiglitazone (Avandia).

In fact, that bit of scheduling prompted FDA Commissioner Margaret Hamburg, MD, to ask that a key portion of the report be submitted this month.

Hamburg had posed five questions to the IOM’s 12-member Committee on Ethical and Scientific Issues in Studying the Safety of Approved Drugs:

What are the ethical and informed consent issues that must be considered when designing randomized clinical trials to evaluate potential safety risks?
What are the strengths and weaknesses of various approaches, including observational studies, including patient registries, meta-analyses, including patient-level data meta-analyses, and randomized controlled trials, to generate evidence about safety questions?
Considering the speed, cost, and value of studies, what types of follow-up studies are appropriate to investigate different kinds of signals (detected preapproval or postmarketing) and in what temporal order?
Under what circumstances should head-to-head randomized clinical trials for safety be required?
How should FDA factor in different kinds of safety evidence in considering different kinds of regulatory actions?
The committee, co-chaired by Ruth Faden, PhD, MPH, and Steven N. Goodman, MD, MHS, PhD, both of Johns Hopkins University, noted in the report that members met only once and performed literature searches that could not be considered a comprehensive review.

Their “letter report” therefore did not address all the questions in detail. The committee promised a fuller report sometime in 2011.

But because Hamburg specifically asked for insight on the first of the five questions in time for the rosiglitazone meeting, the committee submitted an interim analysis late last week.

It indicated that the FDA is legally and morally bound to continue evaluating drugs’ safety and efficacy after their initial approval.

“Ensuring the acceptability of the risk–benefit profile of a drug after it is approved for the U.S. market is no less central to FDA’s public health mission than ensuring the acceptability of the profile before it is permitted to enter the market,” the committee wrote.

To that end, the agency may order new studies — even randomized controlled trials — as long as there is a clear need and such trials can be performed ethically.

Such a trial can be ethical only if the existing evidence, by itself, is insufficient to warrant removing the drug from the market immediately, the report indicated.

It also noted that the public-health questions involving the nature or acceptability of the risk-benefit balance ultimately require a policy decision from the FDA.

That decision requires support from processes with public accountability and transparency, panel members argued.

Input from all stakeholders, as well as technical experts from clinical practice, biologic science, ethics, biostatistics, epidemiology, and research design, is necessary as well, according to the report.

The resulting decision should specify the evidence gap and ensure that trials are “precisely crafted” to address it.

Postmarketing studies must be adequately powered, bearing in mind that patients at high risk of adverse events may have to be excluded because of the ethical mandate to minimize dangers to participants.

“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 report said.

Those “other conditions” must include a data safety and monitoring board to oversee the trial, as well as adequate informed consent.

“When a substantial amount of information indicating that a drug to be studied may involve serious safety risks has already accumulated, there are heightened obligations to ensure that potential participants understand the risks posed by study enrollment,” according to the report.

It noted as well that the ethical requirements may shift while a trial is under way, as new information becomes available, or standard clinical practice changes. In such cases, consent may have to be renewed.