Stakeholders disagree over how to reform FDA’s advisory committee system

A broad range of stakeholders have recommended significant changes to the US Food and Drug Administration’s (FDA) advisory committee system and meetings.

Some commenters argued that the agency should increase requirements for participating on the panels and ensure panelists continue voting on key issues such as the safety and efficacy of the products. However, others said the panels are too restrictive – preventing certain experts from participating – and argued for doing away with voting recommendations.

Earlier this summer, FDA held a virtual listening session in June to gauge stakeholder input on how its advisory committees function and potential reforms to the advisory committee system. The committees, which are made up of external experts, advise the agency on some of the most difficult regulatory questions the agency faces, often providing input on products for which the approval decision is not clear cut.

In 2021, FDA granted accelerated approval to Biogen’s Alzheimer's drug Aduhelm (aducanumab-avwa) despite all but one of the experts on the Peripheral and Central Nervous System Drugs Advisory Committee voting that the clinical trial did not demonstrate the drug’s effectiveness. The agency’s decision to approve to the drug against the advice of the committee led to significant criticism and calls to reform the advisory committee process. Several members of the advisory committee also resigned in protest of the decision. Biogen has since announced that it will withdraw the drug and cease its production in November 2024.

FDA Commissioner Robert Califf and other top agency officials have repeatedly stated that while they appreciate the opinions of external experts, they use additional information and reasoning to decide whether to approve a product. The commissioner has also raised issues about the usefulness of asking experts to vote on whether to approve a drug. Ultimately, the agency used the listening sessions and a public docket that closed on 13 August to gauge stakeholder thinking on reforming the advisory committee system.

During the listening session, several speakers raised concerns about potential conflicts of interest that panel members may have based on their previous work with medical manufacturers and the dearth of experts specific to the product or disease. Some complained that FDA's conflict of interest requirements for advisory committees are too narrow, and it is hard to find non-voting patient and consumer advocates to participate on the panels. They also argued that those participating often lack scientific expertise and have industry ties.

Aaron Kesselheim, a Harvard professor of medicine and bioethics and one of the advisory committee members who resigned over the Aduhelm decision, emphasized the need to recruit panelists who are free from financial conflicts of interest. He said there are enough experts out there without conflicts, but FDA should invest resources to find them. While he acknowledged that there is concern about finding experts in rare diseases, he said what's really needed are people with expertise in interpreting data, which comes from experts in related fields. In rare cases where specialized experts are needed, he noted that the agency can use its ability to bring in non-voting experts to participate on the panels.

Kesselheim dismissed concerns that there's too much paperwork associated with participating on the panels and noted that experts deal with paperwork all the time, including when providing documentation on financial interests to journals and academic institutions. He said the panelists don't get enough time to discuss the issues at hand, and only get to debate the specific topics they are asked to discuss during the Q&A portion of the meetings.

"I would recommend restructuring advisory committee meetings to cut down industry presentations since the data are well-described in the meeting materials and increase the time for advisory committee members with the option to have industry answer questions," said Kesselheim.

Kesselheim asked FDA for more guidance on evaluating the mounds of individual patient testimonies the panelists receive because it is difficult to know how to evaluate the testimonies against the data. He also emphasized the importance of allowing panelists to vote.

"It helped crystalize and clarify my perspectives after a day of conversations," Kesselheim said. "I would suggest FDA look into how advisory committee questions are phrased to ensure they are well-designed and illicit the most useful information for the FDA to use, but I would not recommend that the FDA avoid votes."

Sue Peschin, president and CEO of the Alliance for Aging Research had a very different perspective. She said public perception of FDA is largely based on news media, which often gets things wrong. She asked the agency to take steps to improve how they communicate their processes and decisions in the media to avoid public misunderstandings.

Peschin suggested several steps, such as providing journalists with training on the basics of FDA's work in partnership with the Association of Health Care Journalists (AHCJ), directly correcting journalists who make mistakes, and publishing a "just-the-facts" statement an hour after advisory meetings to counteract any errors in the media.

"When there's a negative vote in an advisory committee, this puts political pressure on the FDA to defend itself,” said Peschin. "We'd like to see the FDA develop a public response on reasons for disagreement, especially in cases where advisory committee members go to the press with unfounded accusations against the agency."

Peschin argued that advisory committee members should not vote on approvals or similar questions, such as whether a product has proven to be safe and effective. She said FDA and the Government Services Administration (GSA), which oversees the advisory committee bureaucracy, should reconsider the definition of conflicts of interest to look beyond connections to the medical product industries. She argued that anti-industry funders such as Arnold Ventures had contributed tens of millions of dollars to some academics and advocacy group representatives who spoke at the listening session.

"Those folks are currently saying nothing regarding those ties and they're the ones usually wreaking havoc on the process," said Peschin. She also insinuated that anti-industry advocates may have participated and then resigned from the advisory committee after the Aduhelm decision as a public relations stunt to lambast FDA and the product.

"The ripple effects of their overblown self-importance contributed to multiple press stories and misinformation overload," Peschin added.

Russ Paulsen, chief operating officer of USAgainstAlzheimer's noted that the public does not have much insight into how FDA makes marketing authorization decisions beyond advisory committee meetings.

"That whole structure of it being the only window [into the drug approval process] inherently puts focus on the advisory committee meeting and the votes there," he said.

Paulsen agreed there needs to be reforms ensuring the right expertise is available on panels, the structure of the committees, and more diversity on the panels. But he said such issues can't be fixed with just more communication. Instead, he urged stakeholders to think about the advisory committee meetings as just one piece of how FDA makes decisions and consider how to transparently better communicate with advocacy groups so they can better explain the process to patients and find ways for FDA to engage with the groups beyond the advisory committee setting so they can update the agency on patient perspectives.

"The entire structure of decision-making has no real place for the voice of the patients to be heard other than potential personal stories in this open public hearing and that segregated portion of the meeting often feels completely disconnected from the rest of the meeting," said Paulsen. "There's no opportunity for dialogue and it may not include stories that are broadly representative of the patient experience."

The drug lobby group PhRMA wrote to FDA, raising concerns about the lack of expertise on advisory committees, especially in areas such as rare diseases, clinical trial innovation, and emerging technologies. They said that experts are often available but not eligible to participate in the panels.

"Considering these restraints, PhRMA encourages FDA to exercise flexibility, when possible, to allow qualified individuals to serve on [advisory committees] as ad-hoc advisors, notwithstanding potential ties to industry," said PhRMA. "In general, PhRMA believes that disclosure of potential conflicts of interest can promote transparency and mitigate concerns while also allowing for participation by those with appropriate scientific expertise."

"In the meantime, to assist FDA in the recruitment of appropriate experts on [advisory committees], we encourage FDA to continue the development of and share with other Centers the educational reference guide developed by CDER on recruiting experts," the group added. "To encourage the widest participation possible, the Open Public Hearing (OPH) process should be consistent across [advisory committees], with every effort made to extend the OPH time to provide ample speaking opportunities for registrants."

PhRMA also said that direct and transparent communication of administrative requirements and processes could help address issues of special government employees (SGE) participating on advisory committees. More specifically, the group recommended the agency offer training on the drug development process and medical regulations. It also recommended requiring more concise briefing documents to help panelists better prepare for the meetings.

The Biotechnology Innovation Organization (BIO) raised similar issues about FDA's conflict of interest requirements for experts to participate on the committees. The group said it is concerned the current policies could prevent "key thought-leading scientists, physicians, and medical experts" from participating.

BIO also noted that FDA appoints additional advisors on advisory committees on an ad hoc basis when their expertise is needed, and said it is crucial to balance potential conflicts of interest against the agency's need to get feedback from true experts.

"With respect to ad hoc advisors, we believe they should be selected based on specific expertise that is directly relevant to the product being discussed," said BIO. "Preference should not be given to ad hoc advisors simply because they have experience serving on a previous advisory committee and have general expertise in the disease or technology area."

BIO recommended that FDA provide a summary of docket comments to advisory committee members before they meet so they can succinctly grasp the views of a broad range of stakeholders, and the agency should encourage those submitting docket entries to provide a short summary at the time of submission. The group also called for more patient-representative participation in the panels. It also noted that there is no standard for how many patient representatives can participate, and that oftentimes, panels don't have a lot of patient representative participation.

"We recommend patients with relevant diseases be included in advisory committee meetings, as well as individuals from representative patient advocacy groups," said BIO. "We should also broaden patient representation – not have the same voices every time – to help ensure that both the advisory committee and FDA are hearing from many voices."

"Additionally, as it is critical for FDA to reconsider its COI policies with respect to clinical experts, FDA should similarly revisit COI policies related to the patient representative and patient advocacy groups," the group said. "Patient advocacy groups frequently receive much-needed support from industry partners in their specific disease area."

Robert Steinbrook, director of Public Citizen, a consumer advocacy group, also wrote to FDA and echoed many of his previous comments during the listening session. He raised concerns that statements made by FDA officials indicate the agency plans to take fewer votes from advisory committee experts on key questions such as whether a product has proven safe and effective and whether the benefits outweigh the risks.

"Although we understand that a committee vote may be mistakenly viewed as an agency decision, it is the FDA’s responsibility to explain as needed that advisory committees, as the name indicates, are advisory, and the agency makes the final decision," said Steinbrook. "Discussion questions and voting questions complement each other. Voting is an integral part of the process, because it allows committee members to record their overall view after a long and detailed discussion of the pluses and minuses of
a drug or device."

"Importantly, without a vote, it would be easier for the FDA or the sponsor of a marketing application to spin the discussion as they wish and to disregard the committee’s advice," he added. "Moreover, a vote, particularly in instances when the FDA does not follow the committee’s recommendations, increases the chances that the agency will clearly and publicly state why it reached a different decision."

Steinbrook also asked FDA and the sponsor to publish their briefing documents at least five to seven business days before an advisory committee meeting instead of two days, which is the current practice, to allow panelists and the public in general to scrutinize the documents. He also said that FDA has become overly reliant on using waivers to allow experts with financial conflicts to participate on panels due to a lack of expert volunteers.

"Reducing to zero, with rare exceptions, the number of voting members of advisory committees who are granted waivers to participate would be an important step forward for the integrity of the advisory committee process," said Steinbrook.

Listening session part one

Listening session part two

Stakeholder comments

Stakeholders disagree over how to reform FDA’s advisory committee system

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