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Amyloid analysis — stress testing FDA’s logic on a surrogate endpoint for Alzheimer’s: a BioCentury podcast

Jun 24, 2021 | 1:49 AM GMT

Documents released by FDA Tuesday to resolve arguments over the agency’s decision to grant accelerated approval to Biogen’s aducanumab have done the opposite, fueling rather than settling a contentious debate over the use of amyloid clearance as a surrogate endpoint for Alzheimer’s disease. On a Special Edition of the BioCentury This Week podcast, BioCentury’s editors discuss the reasoning behind FDA’s decision and the implications for the standards for future surrogate endpoints.

The data package supporting the accelerated approval of Aduhelm aducanumab from Biogen Inc. (NASDAQ:BIIB) involved many post hoc analyses open to different conclusions. But members of FDA’s Peripheral and Central Nervous System Advisory Committee came to a single conclusion in November: The drug should not receive full approval. After that meeting, FDA decided to grant accelerated approval — a topic it had led the panel to believe was not under consideration.

The decision has created a firestorm. Acting FDA Commissioner Janet Woodcock strongly defended the move in an exclusive interview with BioCentury last week, adding that Tuesday’s documents would explain why the agency went all-in on the amyloid hypothesis.

Those documents come up short, argues Executive Editor Selina Koch, who expressed surprised that the agency based its decision in part on amyloid being the fundamental pathology that leads to Alzheimer’s.

“This is highly controversial in the field,” says Koch, who added that Peter Stein, director of CDER’s Office of New Drugs, “notes in his memorandum that it’s clear that the relationship between levels of amyloid in the brain and symptoms is very unclear. The literature shows that, yet he and everybody else kept restating over and over again that this is central to the disease.”

While using Biogen’s own efficacy data, which was insufficiently convincing to support full approval, as support for the conclusion that amyloid clearance is likely to predict clinical benefit creates a circular logic, stronger support for the surrogate endpoint comes from recent Phase II data from two amyloid-lowering agents, Koch says.

BioCentury Editor in Chief Simone Fishburn found the “absolute circularity” of FDA’s logic “disappointing — because we don’t want that from FDA.”

Washington Editor Steve Usdin said that FDA could have presented evidence for accelerated approval to an advisory committee or to some other scientific forum that could have provided public advice on whether amyloid clearance is reasonably likely to predict clinical benefit.

“I think it didn’t do it for a simple reason,” Usdin said. “It knows that if it had done that, it wouldn’t have achieved scientific consensus. Dr. Woodcock told me that FDA officials are acutely aware of the controversy, and of course, they are. So, they just decided to make the decision themselves.”

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