Three FDA advisory panel members resign over approval of Alzheimer’s drugBMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1503 (Published 11 June 2021) Cite this as: BMJ 2021;373:n1503
Three members of a US Food and Drug Administration (FDA) advisory committee, which advised against authorising the Alzheimer’s disease drug aducanumab because of a lack of efficacy, have resigned after the agency went ahead and approved it.1
One of those who resigned, Harvard professor of medicine Aaron Kesselheim, wrote in a letter to acting FDA commissioner Janet Woodcock that the approval of Biogen’s drug was “probably the worst drug approval decision in recent US history.”
Kesselheim was joined in resignation by Mayo Clinic neurologist David Knopman and Washington University neurologist Joel Perlmutter. They were all members of the independent Peripheral and Central Nervous System Drugs Advisory Committee.
Aducanumab—which costs $56 000 (£40 000; €46 000) per year per patient— was approved through the FDA’s accelerated approval pathway, which is used when there are uncertainties over efficacy but there is an expected clinical benefit.
In a post on social media,2 Kesselheim said that “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 Peripheral and Central Nervous System Drugs Advisory Committee met in November 2020 to evaluate the evidence for the drug and submit recommendations to the FDA. They concluded that while the drug cleared amyloid plaques and reduced tau deposits in the brain, there was not enough evidence to show that this resulted in cognitive improvement. In contrast, the FDA approval notice said it expected the reduction in amyloid plaque to result in a reduction in clinical decline.
Knopman, who did not take part in the November meeting as he was an investigator in clinical trials of Biogen’s drug, told Reuters he was “disappointed at how the advisory committee input was treated by the FDA.” Perlmutter told the news agency Stat3 that he had quit because of the “ruling by the FDA without further discussion with our advisory committee.”
As part of the approval, the manufacturer must conduct post-approval studies—known as phase IV confirmatory trials—to “verify the anticipated clinical benefit.” However, just hours after the approval, Biogen’s chief executive Michel Vounatsos told CNBC the company has up to nine years to deliver the final results and that it only committed to not increasing the price of the drug for the next four years.4
Aducanumab has been tested in two phase III clinical trials. Both initially showed poor results, but an analysis of additional data from one of the trials—which had been stopped by the independent data monitoring committee because of efficacy concerns—then provided some positive results. The FDA normally requires two positive studies to approve a treatment.
In February research published in The BMJ pooled evidence from available trials and suggested that amyloid reduction strategies do not substantially improve cognition.5
In response6 to the paper, David Smith, professor emeritus of pharmacology at the University of Oxford, said, “Scientists should seriously question the validity of the basic amyloid hypothesis, as was pointed out more than 10 years ago in relation to earlier trials. The study also raises an ethical question: is it justifiable to ask patients to undergo yet more trials of anti-amyloid treatments?”