2 Advisory Panel Members Resign Over Alzheimer’s Approval
[Report by David McFarland and Jim Dickinson] In the wake of FDA’s controversial decision to approve Biogen’s Alzheimer’s drug, two members of the advisory committee that reviewed data and voted against approving the therapy have resigned in protest. Mayo Clinic (Rochester, MN) professor David Knopman and Washington University School of Medicine professor Joel Perlmutter turned in their resignations from the agency’s Peripheral and Central Nervous System Drugs Advisory Committee due to irregularities with the panel process, according to a Washington Post article.
Knopman told the Post that he did not “wish to be part of a sham process” that led to the agency’s 6/7 approval of Aduhelm (aducanumab). In an email to FDA, he said: “The whole saga of the approval of aducanumab … made a mockery of the [advisory] committee’s consultative process. While I realize that the committee is advisory, the approval of aducanumab appears [to] have been foreordained.” Perlmutter told Stat News in an email that he resigned “due to this ruling by the FDA without further discussion with our advisory committee.” Another panel member, Harvard Medical School professor Aaron Kesselheim, was critical of the approval and posted on Twitter: “Accelerated approval is not supposed to be the backup that you use when your clinical trial data are not good enough for regular approval.”
The resignations are the latest uproar (see earlier story) facing FDA as it defends itself in approving the Alzheimer’s drug. FDA watchers are reacting vigorously, with many pointing to the unusual turn to accelerated approval following FDA’s 11/2020 advisory committee meeting that voted down Biogen’s study data. Interestingly, panel members were not asked for their input on whether accelerated approval was a viable option. Panel members also were concerned about FDA’s statistical reviewer, Tristan Massie, who wrote in a briefing paper that the one positive trial of aducanumab could not overcome the negative one (see earlier story). “There is no compelling evidence of treatment effect or disease slowing and … another study is needed to confirm or deny the positive study and the negative study,” Massie wrote.
Knopman, who was recused from the 11/2020 panel meeting because he was a site investigator in an aducanumab trial, cited “biased questions” posed by FDA’s review staff during the meeting. He also took issue with the agency’s reliance on a “biomarker” — the elimination of amyloid beta. “Biomarker justification for approval in the absence of consistent clinical benefit after 18 months of treatment is indefensible,” he told the Post.
Knopman has long doubted aducanumab’s effectiveness. He said in a comment filed to the advisory committee docket that evidence of a benefit from the drug is “terribly weak,” adding, “Perfection may be the enemy of the good, but for aducanumab, the evidence doesn’t even rise to ‘good.’”
Meanwhile, an Endpoints News survey found that 80% of respondents, mostly biopharma staffers and executives, did not agree with FDA’s decision to approve aducanumab. The respondents’ top criticisms: the lack of any clear efficacy data, worrying signs of a safety hazard, an outrageous timeline for completing a confirmatory study, and a price that would allow Biogen to reap billions of dollars from desperate patients with an unproven drug. “Meanwhile, a number noted that the FDA was essentially endorsing a likely dead end with amyloid, adopting a surrogate endpoint that’s never been validated, damaging any attempt to find a real answer to Alzheimer’s and establishing a precedent that would lead to more mistakes,” according to the survey.
Its findings are fully consistent with general top-tier industry and FDA practice attorneys’ attitudes toward the agency historically, notwithstanding frequent criticism of and lawsuits against individual FDA actions from time to time. Industry management traditionally recognizes that a strong, objective and even aggressive regulatory presence is needed to curb lawbreakers and maintain a level playing field for product approvals and subsequent marketing. The Aduhelm approval shakes that premise to its core.