Fallout continues from the Food and Drug Administration’s contentious decision this week to approve Biogen’s Alzheimer’s drug Aduhelm (aducanumab) despite a lack of efficacy data.
Three experts who sat on an advisory committee for the FDA have now resigned over the decision.The advisory committee reviewed the data behind Aduhelm last November and voted overwhelmingly against approval. Of the 11 advisors on the committee, 10 voted “no” on the question of whether Biogen had collected enough evidence to indicate that the drug is effective. The remaining advisor voted “uncertain.”
Nevertheless, the FDA approved the drug on Monday. Though the regulator acknowledged that there are “residual uncertainties regarding [the] clinical benefit” of Aduhelm, the FDA said it decided to lower the requirements for approval after the advisory committee voted. Instead of basing the approval on the drug’s demonstrated efficacy, the agency relied on a “surrogate endpoint.” In this case, the surrogate is the ability of the drug to reduce amyloid beta plaques in the brains of some Alzheimer’s patients.
“This reduction in plaques is reasonably likely to result in clinical benefit,” Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, wrote in a statement this week.
The approval and explanation riled advisory committee member Aaron Kesselheim, a professor at Harvard Medical School who is also director of the Program On Regulation, Therapeutics, and Law at Brigham and Women's Hospital. In a searing resignation letter sent to acting FDA Commissioner Janet Woodcock on Thursday, Kesselheim called the FDA’s decision "probably the worst drug approval decision in recent US history."
He noted that the surrogate endpoint was not discussed by the advisory committee—in fact, he notes, the FDA told the committee specifically that it would not use amyloid beta plaque clearing as a surrogate for efficacy.
Kesselheim also criticized other aspects of how the FDA oversaw the committee meeting, writing:
At our public meeting, concerns about trial data from one of the FDA’s own reviewers were not given adequate time for discussion, and some of the questions FDA asked the Committee to answer were worded in a way that seemed slanted to yield responses that would favor the drug’s approval.
Overall, he described the decision as a debacle and wrote that “it is clear to me that FDA is not presently capable of adequately integrating the Committee's scientific recommendations into its approval decisions." As such, he resigned from the committee, on which he had served since 2015.
In resigning, he joins neurologists David Knopman of the Mayo Clinic in Minnesota and Joel Perlmutter of Washington University in St. Louis, both of whom also announced resignations this week.
As for the remaining questions about the efficacy of Biogen’s Aduhelm, the FDA required Biogen to conduct another clinical trial to assess the drug’s efficacy. If the company does not indicate that the drug is effective, the FDA could rescind the approval. However, Biogen has up to nine years to submit its data. Throughout that time, the drug can be prescribed to patients—at a list price of $56,000.
In an interview with Axios published Friday, Biogen’s chief medical officer Maha Radhakrishnan responded to the question of why the company hadn’t simply begun additional trials already, given the clear uncertainty in the data seen as long ago as 2019. Radhakrishnan said that the FDA didn’t ask the company to do so in order to earn approval.