Harvard's Kesselheim quits AdComm over FDA's Aduhelm approval

Harvard University professor Aaron Kesselheim, M.D., has become the third advisory committee member to quit over the FDA’s approval of Biogen’s Alzheimer's disease drug Aduhelm. Kesselheim’s departure means the FDA has lost one-third of the permanent voting members of the committee in the days since the approval.

Joel Perlmutter, M.D., and David Knopman, M.D., respectively neurologists at Washington University and the Mayo Clinic, were the first two members of the FDA’s Peripheral and Central Nervous System (PCNS) Drugs advisory committee to quit. Kesselheim, in a letter seen by publications including Stat, went out swinging, calling the Aduhelm authorization “probably the worst drug approval decision in recent U.S. history” and a “debacle” that highlights problems with the FDA-AdComm relationship.

Kesselheim’s comments echo points he made in an opinion piece (PDF) in JAMA in the months after the FDA approval of Sarepta’s eteplirsen. At that time, professor and co-author Jerry Avorn, M.D., said the approval raised “questions about how to integrate subjective and anecdotal patient experience in the FDA review process” and warned that “speeding drugs to market based on such biomarker outcomes can actually lead to a worse outcome for patients.” Kesselheim voted against the eteplirsen approval.

Having seen the advisory committee overruled twice by the FDA, in both cases by approving a drug on a surrogate endpoint with an unproven link to clinical outcomes, Kesselheim has decided to walk away from PCNS. The Harvard professor’s four-year term was due to run until early 2023.

The departure leaves Caleb Alexander, M.D.; Nathan Fountain, M.D.; Richard Kryscio, Ph.D.; Michelle Mielke, Ph.D.; Bruce Ovbiagele, M.D.; and consumer representative Dawndra Jones as the only remaining permanent voting PCNS members. Fountain’s term is set to end early next year, suggesting the FDA may soon need to find four new members at a time when its standing in the neurology community is taking a beating over the Aduhelm approval.

At the November PCNS advisory committee meeting on Aduhelm, then only known as aducanamab, Kesselheim made many of the same points as the other experts on the panel. Kesselheim used the meeting to call out the limitations of relying on a trial that stopped early and, as such, was “half, or even at best two-thirds of a study” as evidence of the effectiveness of a drug.

“There is a suggestion of an effect, but there are enough red flags in terms of the changes to the protocol, the concerns about unblinding and the observation of the effect in the 78-week analysis. Without a full cohort of patients being able to contribute to that analysis, to me doesn't add up to a strong evidence,” Kesselheim said.