Controversies have battered the FDA’s credibility around drug approvals in recent years, and the agency is mulling reforms that reflect changing times.
The revamp is a project of commissioner Dr. Robert Califf has lobbied for over the past few years, arguing that adcomms could do away with voting on approval recommendations to help eliminate confusion about their role in the regulatory process. Earlier this summer, the FDA held a listening session seeking input from stakeholders about how the agency can improve the committees’ processes and procedures in general.
Adcomm members have since weighed in. 3D Communications, a consultancy firm with clients who appear before adcomms, independently queried 400 former and current committee members regarding recommendations that came out of the listening session.
The survey made it clear that adcomm members see value in continuing to vote on recommendations to determine a product's benefits and risks ahead of approval — 95% said the FDA should continue to have a voting question.
The FDA has 50 technical and scientific adcomms that review drugs before regulators perform the final review. The subject matter experts review drug information and vote on the ultimate recommendation. Although the vote is non-binding, the FDA is aligned with their decisions around 80% of the time, according to a study published in 2019.
Committee controversy
The reform talks come in the wake of the FDA’s Aduhelm approval, Biogen and Esai’s Alzheimer’s disease treatment that’s been surrounded by controversy and was pulled from the market earlier this year. The FDA approved the treatment in 2021 following a mixed adcomm vote, but doctors were skeptical of Aduhelm’s efficacy, and Medicare refused to cover it.
Aduhelm’s road to approval under the accelerated pathway was irregular, with the FDA failing to record meetings and interactions with Biogen, and the company giving an unusual presentation to FDA reviewers with an outsized price tag, according to a Congressional report.
The FDA’s credibility has taken a hit in the years since the debacle, and three experts resigned from their adcomm roles in 2021 after disagreeing with the FDA’s decision to approve Aduhelm.
“[The three resignees] were very vocal in the press, and it brought into question the utility of the advisory committee meetings,” said Jim DiBiasi, co-founder of 3D Communications.
One of the FDA’s aims during the listening session was to discuss how it could reverse the “misconception” that adcomm votes are binding on the agency’s decisions, as well as work on ways to improve the public's understanding of how the committees work.
“Although all decisions are made by FDA staff, the discussions that take place at advisory committee meetings are important pieces that are considered as part of the FDA’s decision-making,” FDA principal deputy commissioner Namandjé Bumpus, said in an April statement.
However, some experts believe the FDA is not making full use of adcomms to meet these goals, with the agency frequently failing “to note the advisory committee recommendation and how this may have contributed to the final decision” in some 2020 and 2021 drug approvals, according to Dr. Reshma Ramachandran, assistant professor at the Yale University School of Medicine and first author of an analysis of the FDA’s June listening session.
“We believe this failure to acknowledge or explain such a key part of the agency’s decision-making process represents a missed opportunity to build and maintain trust,” Ramachandran wrote.
Califf also believes that not all circumstances are appropriate for an adcomm vote, and that the recommendations to the agency could instead be gathered through the committee’s discussion.
Reform questions
Beyond the voting issue, addressing conflicts of interest among adcomm members has long been part of reform talks, with concerns that the current rules block the top experts from participating in reviews. The FDA currently avoids using experts who have financial conflicts of interest with drug sponsors, although the agency issues waivers to bring in more members.
In the survey, 90% of adcomm members agreed that subject matter experts who have conflicts of interest should be allowed to participate in meetings, although most also agreed they should do so as a non-voting member. And some members responded that the conflicts should be looked at on a case-by-case basis.
“Especially in the area of rare diseases and ultra-rare diseases where there might be 10 subject matter experts in the world, and for a sponsor to walk into an advisory committee meeting and not have any subject matter experts because they're all conflicted. … It's really a disservice [to] public health,” said DiBiasi.
Industry groups agree the rules should be loosened around conflicts of interest to ensure the top experts are evaluating new drugs. Flexibility and transparency around these conflicts could strengthen adcomms and the FDA’s image by hearing recommendations from the best scientists in specific areas, they attest.
“Despite recent expansions in the number of [advisory committee] members, there remains a shortage of experts in areas such as rare disease, clinical trial innovation and emerging technologies who are either available or considered eligible to participate in [a committee],” PhRMA wrote in its comments to the FDA in August.
Lykos Therapeutics, which recently received adcomm and FDA rejections for its MDMA-assisted therapy for PTSD, also commented that adcomms should include at least one patient or caregiver representing the disease — separate from the consumer representative — to speak on the lived experience of the disease.
As the FDA reflects on its adcomm processes, some changes are likely to come in the future, according to Dibiasi, who also spoke at the listening session and sees the FDA’s efforts as a public health interest.
“To the FDA’s credit, they’re listening,” DiBiasi said.
