Editor's note: On June 11, a third FDA advisory panel member, Aaron Kesselheim, MD, a professor of medicine at Harvard Medical School in Boston, also resigned, Reuters reports.
Two members of the US Food and Drug Administration's (FDA's) Peripheral and Central Nervous System Drugs Advisory Committee have resigned following the agency's approval of the controversial Alzheimer's drug aducanumab (Aduhelm, Biogen/Eisai), against the committee's recommendation.
One of the advisory panel members is David Knopman, MD, a clinical neurologist from the Mayo Clinic in Rochester, Minnesota, who was excluded from participating on the committee for the aducanumab meeting because of his involvement in clinical trials of the drug, and who is a known critic of aducanumab.
"I have been previously honored to serve on the committee as I believed the FDA Advisory committees provided valuable input to the FDA and to the public," Knopman told Medscape Medical News.
"I understand that the advisory committees are just that — advisory — but, the whole saga of the approval of aducanumab, from the biased questions posed to the committee on Nov 6, 2020 at the public hearing to the announcement of the accelerated approval 2 days ago, was deeply disrespectful to the committee members and denigrated their role.
"I don't wish to be part of an advisory committee in the future and be treated as my colleagues were who served on the aducanumab advisory committee," he added.
In a paper published late last year in the journal Alzheimer’s & Dementia, a group led by Knopman concluded that "aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes."
Earlier today, it was reported that Joel Perlmutter, MD, professor of neurology at Washington University School of Medicine in St Louis, Missouri, also had resigned because the drug's approval had come without additional consultation with the advisory committee.
The FDA approved aducanumab for the treatment of Alzheimer's earlier this week. But last November, the Peripheral and Central Nervous System Drugs Advisory Committee voted 8-1 against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.
Two phase 3 clinical trials (ENGAGE and EMERGE) evaluating the drug, an antiamyloid-beta human monoclonal antibody, were stopped in early 2019 because of futility. Biogen said at the time that the studies were unlikely to meet their primary endpoints.
However, a few months later, Biogen and Eisai announced that a new analysis showed that the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial. Although ENGAGE still didn't meet its primary endpoint, data from its new analysis "supported" the EMERGE findings, the drug companies said.
However, the FDA's advisory panel were not impressed with the data, voting against approval.
As reported by Medscape Medical News, three members of the committee elaborated on their decision in a Viewpoint published in JAMA saying there was "no persuasive evidence to support approval of aducanumab at this time."
"There is no reason to favor the trial with the positive signal in 1 of 2 treatment groups over the trial with the negative outcome in both treatment groups," they noted.
"As an advisory committee member, I am extraordinarily disappointed that our unbiased advisory committee review was not valued," Perlmutter told Medscape Medical News.
Perlmutter said he did not believe the evidence supporting efficacy of aducanumab in the treatment of Alzheimer's was convincing; in addition, he had concerns about potential adverse effects with the drug, as well as the cost and the possible delays to the development of other therapies that this approval may cause.
"For these reasons, I resigned my membership on this committee," he stated.
No Votes for Approval
The FDA approved aducanumab under its accelerated approval pathway, which can be used to fast-track a drug that provides a meaningful therapeutic advantage over existing treatments for a serious or life-threatening illness.
However, under this pathway, the FDA requires Biogen to conduct a new randomized, controlled clinical trial to verify the drug's clinical benefit.
The FDA said the approval was based on three separate double-blind, randomized, dose-ranging studies in a total of 3382 patients with Alzheimer's, in which those receiving the active drug had a significant dose- and time-dependent reduction of beta amyloid plaque, while those in the control group had no reduction in amyloid.
In a statement, the FDA said that accelerated approval can be based on the drug's effect on a surrogate endpoint that is "reasonably likely to predict a clinical benefit to patients."
Perlmutter explained that following the early termination of the ENGAGE and EMERGE trials for futility, a subsequent retrospective review of the data was done, and Biogen proposed that EMERGE was positive, and that although ENGAGE was not, the EMERGE data was sufficient for FDA approval.
"The advisory committee reviewed all of the data and voted on whether the data from EMERGE was sufficient as primary evidence for treatment of Alzheimer's. Ten on the committee voted no, 1 voted uncertain, and nobody voted yes," he said. "Nevertheless, without additional data presented to the advisory committee, the FDA granted accelerated approval of aducanumab."
Perlmutter noted that retrospective analyses of clinical trial data are fraught with statistical bias but can be reasonable approaches for designing new prospective studies. "They are, however, not good ways to determine the effectiveness of a new therapy."
Insufficient Evidence of Efficacy
He also pointed out that Biogen used a surrogate endpoint — clearance of amyloid-beta in the brain as measured by PET — in the new analysis, but there is insufficient evidence that amyloid-beta clearance predicts clinical benefit.
"Many studies evaluating investigative drugs designed to clear abnormal amyloid-beta from the brain in people with sporadic forms of Alzheimer's have failed to show a benefit. This is a major problem," said Perlmutter.
He also has concerns about potential side effects of the drug.
"Infusion of aducanumab frequently causes amyloid-related imaging abnormalities (ARIA) — abnormal small, scattered lesions in the brain, as occurred in many study participants. There is controversy as to whether this causes neurologic abnormalities," he added.
In addition, Perlmutter is worried about the impact of the aducanumab approval on the development of other therapies for Alzheimer's.
Approval of a drug that is not effective has serious potential to impair future research into new treatments that may be effective for treating Alzheimer's, he said.
"Alzheimer's treatment is a huge, urgent, unmet need, but I also think if we approve something where the data is not strong, we have a risk of delaying good treatment. For example, new Alzheimer's studies may be required to no longer compare an investigational drug to placebo — as would be the standard — but rather may have to compare to aducanumab.
"Enthusiasm, from either potential volunteer participants or funders, for new treatments may wane due to thinking that we already have an effective treatment, when in fact we do not. These are potentially very serious issues for helping all of these people and families affected by Alzheimer's," Perlmutter said.
He also pointed out that aducanumab therapy will potentially cost billions of dollars, which could be better spent in either developing stronger evidence for aducanumab or other therapeutic interventions.
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Cite this: Two FDA Panel Members Resign Over Alzheimer's Drug Approval - Medscape - Jun 09, 2021.
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