FDA Should Define Role in Protecting Clinical Trial Participants: Report

Researchers are calling for federal regulators to take a new look at the ethics behind post-marketing trials, which often involve the evaluation of a potentially serious side effect associated with a medication, which may not be adequately disclosed to participants.  

An essay published this week in the New England Journal of Medicine highlights the ethical concerns involved in post-market drug trials, focusing on a controversial clinical trial that compared the safety of GlaxoSmithKline’s diabetes drug Avandia to Takeda Pharmaceuticals’ Actos.

Researchers from the Johns Hopkins Berman Institute of Bioethics looked at the fallout from that trial, known as the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE), which some say exposed participants to an unnecessarily high risk of heart attack and death from use of Avandia.

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Post-Marketing Trial Sparked Ethics Debate

The report indicates that the post-marketing trial involving Avandia and Actos, and a subsequent Institute of Medicine (IOM) report released in May of this year, reveal three issues with post-marketing clinical trials that the FDA should address.

First, the researchers said the FDA should set standards for what level of evidence would trigger a post-marketing trial, and at what point such a trial would be considered too dangerous for participants. Second, the researchers determined that the FDA needs to better define its obligations and role in protecting clinical trial participants. Finally, the FDA should look at its relationship with institutional review boards (IRBs) and what role they play in protecting study participants as well.

The TIDE trial sparked a wide debate regarding the efficacy and safety of long-term treatment with Avandia when compared to Actos, in patients with type 2 diabetes. Ultimately, Avandia was severely restricted in the U.S., and has all but disappeared from the market. Actos was later linked to an increased risk of bladder cancer, which has sparked a wave of Actos bladder cancer lawsuits against the manufacturer.

IOM Report Found Deficiences in FDA Drug Oversight

The IOM report, which the essay researchers referenced heavily, found that the agency’s current approach to drug oversight after medications are approved is not sufficient and does not ensure that the benefits and risks of drugs are consistently monitored over the life cycle of the product.

The IOM evaluated the scientific and ethical aspects of conducting safety studies for approved drugs at the FDA’s request, concluding that a regulatory framework should be adopted that could help make the agency’s decision-making process more predictable, transparent and proactive.

Questions have been raised about whether the existing evidence about the risks associated with side effects of Avandia before the trial was enough to deem the study unethical and unjustifiable. The new report references an FDA memorandum from 2008, which described the trial as unethical and exploitive for participants.

In the IOM committee’s report to the FDA, it suggested post-marketing research to occur only under specific conditions in cases where the uncertainty of the benefit-risk balance of a drug is so great that it cannot be regulated without further information. Other factors suggested were the findings of the research to reduce uncertainty in its regulation, sufficient protections to be put into place for participants and the FDA use the findings to make a quick decision regarding its regulation.

The committee also emphasized the process of informed-consent within post-marketing trails, something that was allegedly not done during the TIDE trial. According to a February 2010 letter, Congress alleged that the consent form in the TIDE trail did not provide adequate risk information. The IOM committee recommended offering participants information about the current known risks of the drug prior to consent.

The FDA responded to the IOM’s report regarding the practices and ethics involved in drug safety post-market but did not state whether they would follow any of the recommendations outlined by the IOM.

“FDA is currently engaged in developing a systematic process for assessing and communicating new information about a drug after it is marketed,” the FDA statement said.


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