Two years ago, Biogen’s two trials of experimental Alzheimer’s drug aducanumab were canceled early after failing to show efficacy and demonstrating a high rate of fluid retention in the brain. But Biogen continued pushing the FDA to approve the drug.
Now, a new article in JAMA explains that Biogen and the FDA have been collaborating on analysis after analysis of these failed trials in the hope of salvaging Biogen’s drug.
The article was written by G. Caleb Alexander, Scott Emerson, and Aaron S. Kesselheim, all of whom served on the FDA’s advisory committee that considered Biogen’s application for aducanumab in November of 2020.
“This undertaking reflected an unusual degree of collaboration between the FDA and manufacturer of aducanumab, and the arrangement has been criticized as having potentially compromised the FDA’s objectivity in reviewing the New Drug Application,” the authors write.
The authors first explain the failure of the two clinical trials (dubbed ENGAGE and EMERGE). Halfway through, the trials already demonstrated that the drug was ineffective and caused amyloid-related imaging abnormalities (ARIA), including dangerous fluid accumulation in the brain (called vasogenic edema).
35.2% of the people in the high-dose aducanumab group experienced ARIA, compared with only 2.7% in the placebo group. Because of the drug’s lack of efficacy and the high rate of adverse effects, the trials were terminated early.
However, Biogen continued collecting data for some participants, despite the cancellation of the trials, and then re-analyzed the data. They found that ENGAGE still showed the drug to be ineffective, but EMERGE did reach statistical significance—although the difference between groups was so small that it was not clinically significant (less than half a point on the CDR-SB 18-point scale).
Biogen’s prespecified plan for the trials included safeguards. If the primary endpoints were not met, the company agreed not to conduct post-hoc analyses on the subgroups to try to find an effect. But Biogen, in collaboration with the FDA, did just that.
“A wide variety of post-hoc analyses were presented during the FDA advisory committee meeting,” the authors write. For instance, Biogen tried removing the people for whom the drug didn’t work from their analyses in order to find a larger effect—which is a highly unethical practice.
“Any treatment will appear to be more effective if individuals in whom it works least are removed from the analysis,” the authors write.
According to the authors, these analyses—conducted without controlling for the fact that Biogen was cherry-picking just the results that supported their desire to promote the drug—“introduce what may be regarded as unacceptable threats to statistical validity and scientific rigor.”
At the November 2020 meeting, the advisory committee voted on whether this evidence was sufficient to consider EMERGE a positive enough study to approve aducanumab despite the previous failures. The committee voted to recommend against approval. The vote was 1 yes, 8 no, and 2 uncertain.
According to the authors, the FDA must take this vote into consideration when they decide whether or not to approve the drug. However, they may still decide to approve, against this committee’s advice. Their final decision is expected in June of 2021.
Alexander, G. C., Emerson, S., & Kesselheim, A. S. (2021). Evaluation of aducanumab for Alzheimer’s disease: Scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA, 325(17), 1717-1718. doi:10.1001/jama.2021.3854 (Link)