FDA follows most adcomm recommendations, study says

Although the number of independent advisory committee meetings has decreased over the last decade, the US Food and Drug Administration (FDA) continues to make decisions that align with most advisory committee recommendations when they are in favor of approving a prescription drug, according to a recent study from the Program on Regulation, Therapeutics and Law (PORTAL) published in JAMA Health Forum.

C. Joseph Ross Daval, a postdoctoral research fellow at PORTAL at Brigham and Women's Hospital/Harvard Medical School in Boston, and colleagues found that while FDA was usually aligned with advisory committees when their recommendations were in favor of approving a drug, the agency agreed with the advisory committee less often when they returned a negative vote.

“The FDA more often approved drugs after a negative vote than declined to approve drugs after a positive vote, and it rarely reconvened advisors before approval of drugs that had previously received a negative vote,” Daval and colleagues wrote.

While the FDA is not required to follow the recommendations of its advisory committees, it usually does. Concerns about how and when the agency convenes advisory committees were raised after the agency’s controversial approval of Aduhelm (aducanumab-avwa) to treat Alzheimer's disease after a near-unanimous advisory committee vote against recommending approval (RELATED: FDA approves aducanumab for use in Alzheimer’s disease, Regulatory Focus 07 June 2021).

The researchers identified 409 human drug advisory committee meetings between 2010 and 2021, assessing how the advisory committees voted as well as FDA’s actions following a recommendation up through November 2022. Through a manual review of meeting minutes, the researchers grouped advisory committee meetings based on whether they took a vote for initial approval, supplemental indication, accelerated approval drug withdrawal, safety action, another regulatory action or no vote.

Daval and colleagues found that the Oncologic Drugs Advisory Committee met 78 times (19%), the Endocrinologic and Metabolic Drugs Advisory Committee met 44 times (11%), and the Anesthetic and Analgesic Drug Products Advisory Committee met 41 times (10%). The most common action taken at a meeting was to vote on initial drug approvals (54%) followed by not voting on a regulatory action (20%), voting on a supplemental indication (14%), voting on a safety action (7%), voting on a different regulatory action (3%), and voting on a withdrawal of an accelerated approval drug (2%). Two meetings were closed to the public and the topic of the meeting was not available.

There was a decrease in the number of human drug advisory committee meetings convened over the study period, from 50 meetings in 2012 to 18 meetings in 2020 and 2021. Meetings where the advisory committee voted on an initial approval decreased from 26 in 2012 to 8 in 2021, the greatest decrease compared to other meeting categories.

In 262 of 298 advisory committee votes (88%) for initial approvals, supplemental approvals, withdrawals of approval, and safety actions, FDA followed the advisory committee recommendations, Daval and colleagues said, which included 142 of 147 positive votes (97%) for initial approval and 33 of 36 positive votes (92%) of supplemental indications.

FDA followed the advisory committee recommendation for 40 of 60 negative votes (67%) of initial approvals and 18 of 21 negative votes for supplemental indications (86%). “Many of the negative-vote approvals occurred years after the vote, when new evidence may have emerged in support of approval,” the researchers explained. “For this reason, not all instances of discordance were necessarily equivalent to overruling the advisory committee.”

While the FDA is convening fewer meetings, the agency “continues to follow” the independent expert advice of its advisory committees. “The consistent alignment between advisory votes and FDA action across years and subject areas suggests that these committees play a key role in the FDA’s decision-making process,” Daval and colleagues wrote, adding that “reforms are necessary to clarify the FDA’s commitment to independent expert advice as an integral part of its regulation of prescription drugs.”

FDA’s ‘real question’ to adcomms

The research from Daval and colleagues differed from previous research on the topic, which showed a similar alignment between advisory committees and FDA for both negative and positive votes, according to Genevieve P. Kanter of the Department of Health Policy and Management at the University of Southern California in Los Angeles.

Based on the asymmetry of FDA’s actions following approval and non-approval recommendations, the agency’s real question to its advisory committees appears to be “’What is preventing this drug from being approved right now?’ or perhaps, ‘What are different ways we can get this drug approved?’” Kanter wrote in an invited commentary.

Considering other possibilities – that FDA always or never follows its advisory committee or was more aligned with the advisory committee when it returned a vote for non-approval – the results of the study show “FDA appears to have been looking for reasons to approve drugs,” Kanter said.

“[Pro-approval] bias need not be problematic as long as it reflects the public’s priorities of speedy access to new treatments and high(er) risk tolerance. If, on the other hand, it reflects the influence of pharma, this bias is deeply concerning, especially in light of the political arm twisting, diminished frequency of advisory committee meetings, and abolition of voting,” she explained. “The FDA views itself as an impartial referee, but its recent actions suggest it might also be a myopic one.”

JAMA Health Forum study
JAMA Health Forum invited commentary

FDA follows most adcomm recommendations, study says

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