Double resignation over Aduhelm approval depletes FDA's CNS adcomm

FDA press room

Two members of an FDA advisory committee have now resigned in protest over Monday's approval of Biogen's Alzheimer's disease drug Aduhelm despite an overwhelming vote against doing so.

Washington University neurologist Joel Perlmutter was the first to announce he was stepping down from the Peripheral and Central Nervous System Drugs Advisory Committee on the day after the approval, and he was joined yesterday by  Mayo Clinic neurologist David Knopman.

[caption id="attachment_81165" align="alignleft" width="150"] Joel Perlmutter[/caption]

Perlmutter was one of the 10 members of the 11-member panel who voted against approval of Aduhelm (aducanumab), while Knopman – who would have been the 12th panellist – was recused from the meeting over conflict of interest as he was an investigator on Biogen's trials of the drug.

The panel voted overwhelmingly against the principal study supporting the drug's marketing application, with just one saying they were uncertain about the data, and none were convinced that the clinical trial results proved Aduhelm was effective.

Perlmutter said that he had decided to step down from the committee because the FDA's approval of Aduhelm had been taken without further discussion with its advisors, while Knopman said that he did not "wish to be part of a sham process" that resulted in the decision.

[caption id="attachment_81166" align="alignright" width="150"] David Knopman[/caption]

Knopman told Reuters that he was "very disappointed at how the advisory committee input was treated by the FDA," adding: "I don't want to be put in a position like this again."

The approval of Aduhelm based on clearance of amyloid plaques in the brain as a surrogate marker – with an "expectation of clinical benefit" according to Patrizia Cavazzoni, director of the FDA's Centre for Drug Evaluation and Research (CDER) – has been a bone of contention among the panellists.

Specifically, the FDA indicated at the adcomm meeting that it was not considering granting approval based on a surrogate endpoint, and the advisors were not asked to gauge Aduhelm on that basis. Other trials of amyloid-busting drugs have cleared plaques effectively but had no significant impact on cognition in Alzheimer's disease.

The FDA granted Aduhelm an accelerated approval, meaning that Biogen has to carry out a post-marketing trial to confirm that it is effective, but critics say results from that will be years away.

Meanwhile, the decision to approved the drug for all Alzheimer's patients, rather than just the patients with mild cognitive impairment (MCI) and mild dementia included in Biogen's studies of the drug, has also raised eyebrows.

In a letter to the adcomm chairman Nathan Fountain of the University of Virginia School of Medicine, the FDA's head of neuroscience – Billy Dunn – said that internal discussions at the FDA after the meeting "raised further consideration of the accelerated approval pathway" and the possibility of a green light based on a surrogate endpoint.

"We appreciate the comments from the advisory committee members and can assure you that we listened carefully and viewed the meeting proceedings as an important source of input as we discussed the appropriate action," Dunn wrote.

"Ultimately, the decision on whether aducanumab will be used for treatment will be made by patients, their families and caregivers, and health care professionals," he added.