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ISPOR Panelists: Can the FDA Advisory Committee Process Be Strengthened?

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Panelists at the leading health economics and outcomes conference discuss whether the FDA's process for allowing outside experts to weigh in on drug approvals needs changes.

The share of drugs receiving scrutiny from an FDA advisory committee prior to approval is smaller than it was 15 years ago, and it’s not clear why that’s happened, according to a panelist taking part in a symposium at ISPOR—The Professional Society for Health Economics and Outcomes Research meeting in Atlanta, Georgia.

The symposium, “Strengthening FDA Expert Advice and the Use of FDA Advisory Committees,” examined the role of these expert panels, which offer guidance on drug approvals or expanded indications that regulators are not bound to accept.

David Howard, PhD | Image Credit: Emory University

David Howard, PhD | Image Credit: Emory University

Sunday’s symposium closed out a day of short courses held ahead of the main conference, which opens today. Moderated by David Howard, PhD, professor of health policy and management, Emory University, the panel included these experts:

  • Joseph Daval, JD, currently with the FDA Office of Chief Counsel, spoke in his capacity as a former fellow in the Program on Regulation, Therapeutics, and Law (PORTAL) at Harvard University; Daval’s research included the analysis on how frequently drugs were evaluated by an advisory committee prior to approval
  • Genevieve Kanter, PhD, associate professor of public policy, University of Southern California
  • Sean Tunis, MD, MSc, principal, Rubix Health, a former official with the FDA and CMS

The session was sponsored by Arnold Ventures.

Joseph Daval, JD | Image Credit: FDA Office of Chief Counsel

Joseph Daval, JD | Image Credit: FDA Office of Chief Counsel

Daval’s research arose from the controversy over the FDA’s approval of the Alzheimer drug aducanumab (Aduhelm; Biogen), over objections of the FDA advisory committee that reviewed the drug. “Basically, we were wondering, how often does that happen? And the answer is about once a year, from 2010 to 2021,” he said.

But the more interesting finding was the decline in how many drugs go before an advisory committee. In 2010, about half received such a review; by 2021, it was just 6%, Daval said. A follow-up paper showed the number of advisory committee meetings fell from 50 in 2012 to 8 in 2021.

However, “Even as the FDA was convening fewer advisory committees, it generally followed their advice, and quite consistently,” he said.

Daval’s group then scrutinized alignment between advisory committee recommendations and FDA actions and found a high degree of agreement—a year after committee votes, there was 86% alignment on both new approvals and supplemental approvals. "And the FDA declined to approve 67% of the drugs following a negative vote," he said.

Daval said despite the decline in the number of meetings, advisory committees matter greatly; he outlined the limited cases where the FDA must state why it has not convened an advisory committee.

“Reporters live tweet these meetings like they’re the State of the Union,” he said. “And then there is a broader vision…which is that there is inherent value in engaging in transparent, public-facing deliberation with experts, who are independent from the political umbrella under which the agency operates, that it adds credibility and legitimacy to its decisions.

“If we're considering this in the public health context, where there is a need for trust in government for trust in science, there is then value in using advisory committees, even if the FDA doesn't always follow the advice. And that value lies in forcing the agency to make its reasoning plain and engaging the expert public in form of the advisors, and the nonexpert public in the process.”

Conflicts of Interest

Genevieve Kanter, PhD | Image Credit: University of Southern California

Genevieve Kanter, PhD | Image Credit: University of Southern California

Kanter’s research interest is conflicts of interest, and she presented data based on following advisory committee members for 15 years, which showed that overall, members of advisory committees with a financial tie to a sponsor may be more likely to vote in favor of a drug’s approval by 10 percentage points. However, the type of financial tie matters, she said.

An advisory committee member who did research for multiple competitors within the same drug class did not vote any differently from a person with no financial ties. But if the member was on an advisory committee for the sponsor “or had some kind of financial or ownership stake, then it went from 50% to 85%, which is a very, very strong effect,” Kanter said.

What are the key takeaways? Kanter sees 2 things: “One is that conflicts of interest can be a big deal, and so they shouldn't be just generally dismissed. The second is just the existence of a financial tie is not something to get criminally outraged about; we have to look at the nature of the tie.”

The presence of patient and consumer representatives on boards matters, she said, but as reporting has shown, drug company support for patient advocacy groups has raised questions about their independence.

Kanter said the FDA should view the opportunity to gain external advice from experts through advisory committees “as a way to build public trust, instead of just viewing it as a barrier that the agency or the drug companies have to overcome.”

Fewer Meetings, Less Scrutiny?

Sean Tunis, MD, MSc | Image Credit: Rubix Health

Sean Tunis, MD, MSc | Image Credit: Rubix Health

Tunis’ prior work in the public sector covered time not only at the FDA, giving him familiarity with the advisory committee process, but also with CMS’ Medicare Evidence Development and Coverage Advisory Committee (MEDCAC), which he said also meets far less frequently than it once did. Many reasons have been offered—such as redeployment of staff following implementation of the Affordable Care Act—but Tunis speculates there are other reasons.

The charter that created MEDCAC in 1999 stated that the committee should be convened “when the evidence is controversial or complex,” Tunis noted, yet since 2012 it has gone from 4 to 6 meetings per year to 1 to 2 per year, at a time of enormous innovation in drug development and challenging decisions in coverage.

“The agency, very notably, did not convene a Medicare Advisory Committee on the Alzheimer disease drugs, which is probably the most consequential and controversial decision that they've made in the past 10 years at least,” Tunis said. “I doubt it was resources.”

Medicare’s standards for decisions on payment are based on what is “reasonable and necessary,” and are different from theFDA’s standards of “safe and effective.” Due to the population it serves, Medicare is interested in what drugs are appropriate for older adults who may have comorbidities, and “they tend to focus a little bit more on some of the more definitive end points of patient functional status, and quality of life.”

An early challenge, Tunis said, was that experts were willing to speak privately about concerns with evidence for some drugs, but almost no one was willing to come to a microphone and state concerns in public. So, eventually the phrasing of the voting questions shifted to a rating system.

“What that did very significantly was, it didn't back us into a corner,” Tunis said, because the group was making an assessment but not a decision.

Framing FDA advisory committee questions is more challenging than people realize, he said. In the case of aducanumab, for example, the agency recognized the questions about the evidence, he said, but what justified the decision was, “there was massive unmet need, and there hadn’t been a new drug in 17 years.” Thus, even though the evidence was limited, the agency believed, on the whole, the approval was justified.

However, the FDA was criticized for approving the Alzheimer disease therapy without going back to the advisory committee, and Medicare declined to cover it except for patients already on the clinical trial. Congress decided to investigate the agency’s process, and Biogen ultimately pulled the drug from the market.

“One of the things that I think is a problem with both advisory committee members and the public's understanding of advisory committees, is they mistakenly think that it's the evidence—that is all you need to know to make a decision when it's really the evidence placed into the context of judgment,” Tunis said.

“There's a lot of debate in the context of FDA Advisory Committee reforms of whether they should do away with voting,” Tunis said. Some stakeholders believe that votes by committee members tend to “box you in,” he said, while the real value of the process, both to the public and to the regulators, is the discussion and the analysis of the evidence.

Reforming the process, he said, would involve more explicit explanations of all the factors that go into a decision, not simply referring to “the strengths and the weaknesses of the evidence that went into the decision.”

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