Fallout Continues as Third FDA Panel Member Resigns Over Aduhelm Approval



Aaron Kesselheim, a professor of Medicine at Harvard Medical School and has served on the advisory committee since 2015, has stepped down.


A third member of the U.S. Food and Drug Administration’s (FDA) Peripheral and Central Nervous System Drugs Advisory Committee has resigned in protest over the agency’s approval of Biogen’s Aduhelm (aducanumab) for Alzheimer’s disease.

As was reported yesterday, two members, David S. Knopman, a neurologist at the Mayo Clinic, and Joel S. Perlmutter, a neurologist at Washington University in St. Louis, resigned in protest earlier this week.

Now, Aaron Kesselheim, a professor of Medicine at Harvard Medical School, has stepped down. Kesselheim served on the advisory committee since 2015.

“My rationale was that the FDA needs to re-evaluate how it solicits and uses the advisory committees … because I didn’t think that the firm recommendations from the committee in this case … were appropriately integrated into the decision-making process,” Kesselheim told Reuters.

In November 2020, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee met to discuss and vote on a recommendation for the drug, which is an antibody against beta-amyloid, a key factor in Alzheimer’s disease. To the question, “Does Study 302 (EMERGE), viewed independently and without regard for Study 301 (ENGAGE), provide strong evidence that supports the effectiveness of aducanumab for the treatment of Alzheimer’s disease?”

The committee voted 1 yes, 8 no, and 2 uncertain. Another question was, “Does Study 103 (PRIME) provide supportive evidence of the effectiveness of aducanumab for the treatment of Alzheimer’s disease?” The committee voted 0 yes, 7 no and 4 uncertain.

Another question was, “Has the Applicant presented strong evidence of a pharmacodynamic effect of aducanumab on Alzheimer’s disease pathophysiology?” The committee voted 5 yes, 0 no and 6 uncertain. And finally, to the question, “in light of the understanding provided by the exploratory analyses of Study 301 and Study 302, along with the results of Study 103 and evidence of a pharmacodynamic effect on Alzheimer’s disease pathophysiology, is it reasonable to consider Study 302 as primary evidence of the effectiveness of aducanumab for the treatment of Alzheimer’s disease?” The committee voted 0 yes, 10 no and 1 uncertain.

A few months later, the FDA requested additional information from Biogen, which caused the target action date to be moved from March 2021 to June 7, 2021. On June 7, the agency approved the drug.

The agency also gave it Accelerated Approval, which has certain implications. One, it requires the company to conduct post-market evaluations of the efficacy of the drug. It typically also means that the approval was based on surrogate endpoints.

In the case of aducanumab, the surrogate endpoints were that the drug cleared beta-amyloid. Other experimental drugs have cleared beta-amyloid, but not shown improvements in cognition and memory. The decision was that it was not approved based on its effectiveness in slowing or halting the progress of the disease or the symptoms of cognition and memory problems.

The adcom members have a particular problem with this decision because at the November 2020 advisory committee meeting, Billy Dunn, director of the FDA’s Office of Neuroscience, specifically stated, “We’re not using the amyloid as a surrogate for efficacy.”

Yet in a letter to the chair of the panel sent on June 7, Dunn said the FDA held “further discussions” that “raised further consideration of the accelerated approval pathway.”

At the time, Kesselhim said it set a “dangerous precedent” associated with the type of evidence required for drug approvals for Alzheimer’s disease, “but even more broadly for the idea that a company can turn around and at the last minute seek [accelerated approval] when their primary clinical endpoints in the trials don’t reach the level needed for FDA approval.”

Although the reason was over the Biogen decision, Kesselheim also cited a 2016 decision by the FDA to approve Sarepta Therapeutic’s Exondys 51 (eteplirsen) for Duchenne muscular dystrophy. The opposition there wasn’t from advisory committee members, but within the FDA itself.

Its then acting chief scientist, Luciana Borio, and Ellis Unger, director of the office of drug evaluation, were significantly opposed to approval. Janet Woodcock, then director of the FDA’s Center for Drug Evaluation and Research (CDER), pushed it over their protests, overruling the staff. She is currently the acting commissioner of the FDA. She took that decision to Robert Califf, who was then commissioner. He had reservations about the approval but finally sided with Woodcock.

The issue was similar. DMD is caused by a shortage of dystrophin protein due to a gene mutation. The drug was able to generate slightly higher levels of the protein, which was a surrogate endpoint. The children involved in the trials also conducted a walk test, which can be subjective, and the data on the walk tests were not convincing to the scientists at the FDA. A critical difference between DMD and Alzheimer’s is that DMD is a rare disease, while Alzheimer’s affects millions of people worldwide.

Although some of the FDA advisory committee members are permanent, temporary members are invited for specific panel meetings.

In his resignation letter, Kesselheim said the agency’s decision on Biogen “was probably the worst drug approval decision in recent U.S. history.”