Fix three wrongs to make advisory committees right
A prescription for getting FDA the external advice it needs and the public deserves
FDA leadership, medical product developers and patient advocates have known for a long time that the agency’s advisory committee system is broken. Meetings rarely produce valuable advice and all too often they disrupt rather than illuminate the path from science to medicine.
The numbers reflect FDA’s disenchantment with advisory committees. A recent study found that the proportion of new drugs referred to an advisory committee decreased from 59% in 2011 to 6% in 2021.
Advisory committees are achieving the opposite of their intended missions. The dysfunction erodes confidence in regulatory decisions; fuels accusations of regulatory capture; introduces unpredictability at the end of lengthy, expensive product development paths; and limits FDA’s ability to keep up with rapidly advancing science and understand the needs of patients.
FDA is expected to disclose the results of a review of advisory committee procedures next year. Making consequential improvements will take courage.
Fixing advisory committees will require correcting three wrongs: the wrong people are on the committees; meetings are held at the wrong times; and committees are asked the wrong questions.
“Advisory committee meetings have devolved into theatrical performances in which thoughtful debate has been replaced by a thumbs up or down vote on the fate of a product.”
Taking a step back, advisory committees should be embedded in a broader system for providing external scientific and medical advice that can generate consensus along the full continuum of product development. This could be advanced by extending the collaborative communities concept pioneered by the Center for Devices and Radiological Health to drugs and biologics, and by ramping up FDA participation in forums convened by neutral third parties.
Confusion about mission
FDA treats advisory committee meetings as risks that must be managed rather than opportunities to elicit actionable insights. More often than not they are convened to provide political cover or public explanations for decisions the agency has already made.
For example, the Oncology Center of Excellence routinely publishes commentaries detailing its views on issues it brings to the Oncology Drugs Advisory Committee before the committee meets.
At their best, advisory committee meetings are venues for pressure-testing FDA’s and the sponsor’s interpretations of data. They are also opportunities for the agency to lift the curtain on the complexity of its reviews, to air any disputes among its staff, and to provide information that will smooth the path for continued medical progress. They rarely live up to this promise.
Advisory committee meetings have devolved into theatrical performances in which thoughtful debate has been replaced by a thumbs up or down vote on the fate of a product. They are populated by a collection of generalists that may or may not be supplemented by one or two subject matter experts.
These problems stem in part from confusion over mission.
Meetings are portrayed in the media and medical journals as if they are trials, with FDA acting as the prosecution, drug companies as the defense and committee members as the jury. Any common ground between sponsors and regulators is portrayed as collusion, and the agency’s failure to adhere to a committee’s verdict as a miscarriage of justice.
If they were intended to be adversarial proceedings that made binding decisions, it would make sense to eliminate the possibility that committee members could be influenced by financial links, no matter how tenuous, to companies affected by their votes. And it would be reasonable to routinely hold meetings weeks or days before PDUFA deadlines, after all the evidence has been collected and assessed.
The proper role of advisory committees is not, however, to serve as a jury or to substitute snap judgments for FDA reviews.
Advisory committees are necessary because FDA employees cannot have at their fingertips all of the expertise required to make the best decisions. There will always be a need for outside experts to inform the agency’s regulatory decisions, especially for matters involving questions about the best ways to meet the needs of individual patients and of public health.
When organized properly, advisory committee meetings provide transparency that can make medical product development more efficient and increase the confidence of patients, physicians and the public in regulatory decisions.
Putting the right people on committees
The criteria FDA uses to select — and exclude — advisory committee members doesn’t produce the kind of advice FDA needs, and it doesn’t generate confidence among patients and the medical community.
Under pressure from watchdogs who argue that even tangential contact with the private sector indelibly taints an individual’s thinking, FDA has interpreted conflict-of-interest rules in ways that prevent individuals with deep knowledge of a topic from participating on advisory committees.
“We have very stringent conflict-of-interest rules that limit the pool of advisory committee members to a point of frustration at least to me where we have some advisory committees that don’t seem to have experts in the field,” Patrizia Cavazzoni, director of FDA’s Center for Drug Evaluation and Research (CDER), said at the BIO convention in June 2021.
“We need to partner with industry” to find solutions to the COI issue, Cavazzoni said.
Richard Pops, chairman and CEO of Alkermes plc (NASDAQ:ALKS) said at the meeting that BIO had launched an initiative to provide input to FDA on COI and other advisory committee issues.
BIO hasn’t made public its recommendations and FDA hasn’t provided any clues about what changes it is considering. Comments from senior agency officials and industry point to some steps that would make it possible for the committees to serve FDA and the public.
FDA could deepen the pool of expertise by revising conflict-of-interest criteria to apply only to individuals with recent financial ties to a company with a product under consideration or its direct competitors.
The politicians who will object to paring back conflict-of-interest exclusions should look in the mirror and ask a few questions. Do they routinely solicit campaign contributions from companies and interest groups that have a direct interest in legislation? Have they or their colleagues invested in companies that are affected by legislation or welcomed the counsel of corporate lobbyists? When was the last time a member of Congress recused themselves from a vote because of a real or perceived financial conflict of interest?
“If the right people are around the table, a nuanced discussion of the topics on which panelists are experts is generally far more valuable than a count of the votes they cast.”
In many cases, the people who are excluded because of perceived conflict-of interest are exactly the experts who could contribute the most relevant advice.
The problem is particularly acute when committees consider issues involving rare diseases because most scientists and physicians with relevant expertise have participated in industry-funded research on the disease or have served on an industry advisory board. Seasoning a committee of generalists with one or two specialists isn’t sufficient.
Rare disease advocates are calling for the establishment of a standing advisory committee staffed with experts on topics that typically arise in reviews of Orphan drugs, such as the science of small trials, researching patient preferences, and the interpretation of real-world data. The new committee could meet jointly with advisory committees with expertise in the relevant area of medicine.
Getting the right people in the room also applies to the public comment portion of advisory committee meetings.
At the 2021 BIO meeting, Cavazzoni expressed concern about the public comment portion of the meetings, suggesting that that FDA should find ways to tone down the emotional content of meetings. “These are really important decisions, scientific decisions, and we have seen in very recent advisory committees how advisory committees can be swayed by emotion in the face of very hard facts to the contrary.”
Internal FDA memos released about the review of Sarepta’s Exondys 51 characterized an advisory committee meeting on the NDA as "emotional," and suggested that the committee members who voted to recommend approval were overwhelmed by that emotion, while those who recommended against approval were hewing to science.
In addition to complaints that emotion may be inappropriately swaying advisory committee members, concerns have been expressed for decades that patient advocates may be tainted by undisclosed biopharma industry funding. The concern is supposed to be mitigated by voluntary disclosures at meetings about industry funding, but the disclosures are not always reliable.
For example, in 2016 BioCentury reported that individuals representing 13 patient or physician organizations testified at a meeting of FDA’s Arthritis Advisory Committee. Everyone who presented on behalf of a patient or physician group said they had no conflicts. However, websites for 11 of the groups showed that each of them received funding from companies with a direct financial interest in the meeting outcome.
Asking the right questions
FDA often asks committee members to vote on questions that are so ambiguous or convoluted that they aren’t certain what they are voting for or against. It isn’t uncommon for committee members to explain after voting that they have discordant views about the meaning of a question.
FDA also frequently demands yes/no votes that committee members and the public interpret as recommendations about approving or rejecting a product application.
It makes little sense for FDA to ask advisory committees if a product meets the legal requirements for approval, and if it does, which regulatory pathway is most appropriate. Those are questions that require expertise and access to data and analyses that only FDA possesses.
Patient representatives, physicians and scientists are well-positioned, however, to provide advice that can be crucial to approval decisions. Often they fill in one piece of a complex puzzle.
A scientist with a deep understanding of the application of Bayesian statistics to trial design and interpretation, for example, or an expert on off-target effects of gene therapies, could provide valuable advice. But they may not be the best people to determine if the benefits of a drug outweigh its risks, or if FDA should approve a product.
If the right people are around the table, a nuanced discussion of the topics on which panelists are experts is generally far more valuable than a count of the votes they cast.
Deemphasizing votes and prioritizing discussion could also reduce concerns about potential conflict of interest.
Advisory committee debates and recommendations are particularly important if an application raises unprecedented issues. These could include the first application for a new modality, reliance on novel methods of generating evidence, or uncertainty about the effects a regulatory decision could have on individual patients or public health.
In every case, FDA should do a better job of putting the issues in context than it typically does. This includes describing how it has approached similar issues in the past, including the standards and flexibilities it has applied.
Why and when should meetings be convened?
Decisions about why and when advisory committee meetings are held are at least as important as the composition of the committees.
FDA’s reticence to expose decisions to advisory committee debate could become a matter of public concern in the coming months.
CDC has suggested that clinicians could treat monkeypox with Tembexa brincidofovir from Chimerix Inc. (NASDAQ:CMRX), an antiviral that FDA approved in June 2021 for treatment of smallpox based on animal data.
“To get the advice FDA needs and the public demands, the process must be changed to ask the right people the right questions at the right times.”
The agency did not hold an advisory committee meeting about the application, so there was no public probing of data indicating that long-term administration for another indication was associated with increased mortality. The label calls for two weekly doses to treat smallpox and carries a black box warning of “increased risk for mortality when used for longer duration.”
The Tembexa application raised precisely the kind of questions that an advisory committee could have addressed.
Meetings should be held when external scientific or medical advice will lead to better decisions, or if there is a need for transparency.
FDA should promulgate clear criteria describing the circumstances that trigger an advisory committee meeting. For meetings about product applications, criteria could include new technologies, endpoints or types of evidence, or the need to understand impacts on patients or on public health.
Asking the right questions at the right time is critical. External advice and consensus building is often most valuable if it comes long before applications are submitted to FDA, when there is still time for the agency and product developers to change course.
Patients, FDA and the biopharma industry would have been well-served if the agency had undertaken a public process that included its Peripheral and Central Nervous System Drugs Advisory Committee to develop a consensus about approval endpoints for Alzheimer’s disease before Biogen Inc. (NASDAQ:BIIB) submitted a BLA for Aduhelm aducanumab-avwa. FDA was well aware of the controversy, and it could and should have publicly discussed its views and solicited external advice prior to approving an Alzheimer’s therapy based on reductions in β-amyloid deposits.
There is ample precedent. FDA’s Oncology Center of Excellence, for example, spends considerable time and resources developing scientific consensus on endpoints, including new surrogate endpoints, independent of reviews of specific products.
Reviving the advisory committee system will be increasingly important in the coming years as FDA races to keep up with scientific advances and society grapples with increasing skepticism over government regulation of medicine.
The mantra of precision medicine — the right drug for the right patient at the right time — can be adapted for advisory committees. To get the advice FDA needs and the public demands, the process must be changed to ask the right people the right questions at the right times.
Signed commentaries do not necessarily reflect the views of BioCentury.
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