FDA advisers who voted against the approval of Biogen’s Alzheimer’s disease drug aducanumab have reiterated their objections in a JAMA article. The article restates the case against aducanumab ahead of a June decision by the FDA on whether to approve the controversial, closely watched medicine.
Caleb Alexander, M.D., Scott Emerson, M.D., Ph.D., and Aaron Kesselheim, M.D, all spoke out strongly against the approval of aducanumab on the basis of current evidence at a FDA advisory committee meeting late last year. Perhaps most memorably, Emerson said the “analysis seems to be subject to the Texas sharpshooter fallacy, a name for the joke of someone first firing a shotgun at a barn and then painting a target around the bullet holes.”
The JAMA article makes the same point in more technical language, arguing that post hoc analyses of the aducanumab clinical trials risk “inadvertently selecting data precisely because those data were consistent with the outcomes that were hoped for.”
The arguments put across in the article aren't new. However, the article brings the case against aducanumab back to the fore in the run-up to the FDA’s decision. The three-month delay to the FDA’s decision on aducanumab has created an unusually long lag between the advisory committee and the final ruling. Through the JAMA article, the experts have re-exposed the FDA to the dissection of the case for aducanumab
As the three experts, who work at Johns Hopkins Bloomberg School of Public Health, the University of Washington and Harvard Medical School, see it, the post hoc analyses fail to explain why the two aducanumab clinical trials generated divergent results. Biogen stopped one study for futility, only for data from the second trial to persuade it that action was premature.
Biogen argues the divergent results reflect the proportion of people who received the high dose and the split of patients whose condition deteriorated rapidly. The three experts are unpersuaded by the arguments, stating in the JAMA article that the long history of failures of amyloid clinical trials means the divergence between the two aducanumab studies is “consistent” with a false positive finding.
Given the high unmet need in Alzheimer’s, there is an argument that the FDA should authorize aducanumab even if the evidence falls short of the normal standard for approval. The argument rests on the premise that the benefits of aducanumab, however uncertain they may be, outweigh the risks.
Aducanumab does carry some risks, though. The JAMA article highlights the rate of amyloid-related imaging abnormalities (ARIA) in aducanumab patients. Most cases of ARIA were asymptomatic, and advocates argue imaging and dosing management can mitigate the risk. However, the experts have doubts about “how consistently and comprehensively” the mitigating measures could be performed in clinical practice.
The experts also took aim at how the FDA and Biogen worked together to determine whether the available data supported a filing for approval. “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,” the experts wrote.