Biogen’s licensing application for aducanumab has generated controversy throughout the Alzheimer’s field, with different voices clamoring for its approval or rejection. Now, three researchers who sat on the Food and Drug Administration’s advisory committee for aducanumab are speaking out against the application. In the March 30 JAMA, Caleb Alexander at Johns Hopkins Bloomberg School of Public Health in Baltimore, Scott Emerson at the University of Washington in Seattle, and Aaron Kesselheim at Brigham and Women’s Hospital, Boston, argue that Biogen’s Phase 3 data fall short. “There is no persuasive evidence to support approval of aducanumab at this time,” they wrote.
Other members of the committee contacted by Alzforum concurred with the points made. “The editorial is an accurate summary of the discussion during the FDA’s AdCom meeting,” Madhav Thambisetty at the National Institute on Aging in Bethesda, Maryland, wrote to Alzforum, adding, “There was clear consensus on all the issues discussed.” Likewise, Joel Perlmutter at Washington University in St. Louis wrote, “I agree with this editorial.”
Biogen’s application rested on one positive and one negative Phase 3 trial, with the data complicated by early termination due to a flawed futility assessment (Mar 2019 news; Oct 2019 news; Dec 2019 conference news). The advisory committee voted against approval, noting there was no reason to favor the positive over the negative result (Nov 2020 news; Nov 2020 news).
In their editorial, Alexander and colleagues repeated the main points made during the meeting. They noted that while the EMERGE trial was statistically significant at p=0.01, in order to account for the post-hoc disregard of the negative ENGAGE trial, the p value would have to be adjusted to greater than 0.02. When the FDA has approved drugs based on a single pivotal trial, significance was typically below 0.01 (Morant et al., 2019).
The authors discounted Biogen’s post hoc analyses that sought to explain away ENGAGE’s negative findings, noting that such analyses are useful for generating hypotheses to test in subsequent trials. “Post hoc analyses should not be the basis for FDA approval,” they wrote.
The FDA has delayed a decision on Biogen’s application until June in order to consider new analyses submitted by the company in response to an FDA request (Feb 2021 news). The advisory committee members have not seen these analyses, nor been asked to evaluate them.
Biogen presented some additional data at the recent AD/PD meeting (Mar 2021 conference news). It is unclear if this was what was submitted to the FDA after the AdCom meeting.
Alexander was skeptical that new analyses would change anything. “No amount of post hoc analyses can take the place of well-designed, rigorously conducted, randomized controlled trials,” he wrote to Alzforum.
Thambisetty noted that none of Biogen’s Phase 3 data have been peer-reviewed yet. “Allowing the scientific community access to these data and subjecting the results/interpretation arising from them to rigorous peer review is the best way to assess the strength of the findings,” he told Alzforum.—Madolyn Bowman Rogers
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- Morant AV, Jagalski V, Vestergaard HT. Characteristics of Single Pivotal Trials Supporting Regulatory Approvals of Novel Non-orphan, Non-oncology Drugs in the European Union and United States from 2012-2016. Clin Transl Sci. 2019 Jul;12(4):361-370. Epub 2019 Mar 2 PubMed.
- Alexander GC, Emerson S, Kesselheim AS. Evaluation of Aducanumab for Alzheimer Disease: Scientific Evidence and Regulatory Review Involving Efficacy, Safety, and Futility. JAMA. 2021 May 4;325(17):1717-1718. PubMed.