Memos reveal internal FDA struggle over thorny Alzheimer's drug approval

The FDA on Tuesday made public new documents laying bare a struggle within the agency ahead of its controversial decision on June 7 to grant accelerated approval to Biogen and Eisai's Alzheimer's drug Aduhelm (aducanumab) amid heated debate about the treatment's effectiveness. The 83 pages of memos appear to be a portion of the FDA's deliberations, largely reflecting the exchanges of senior officials, while the agency said it plans to release more documents about its decision-making as early as next week.

In one memo detailing his support for approval, Peter Stein, director of the FDA's office of new drugs, said the agency was "faced with a situation where the available evidence on the clinical endpoints is short of what we would require for standard approval," but "at the same time, patients with [Alzheimer's] have a serious, progressive, ultimately fatal disease and are desperate for treatments."

The FDA approved Aduhelm based on the surrogate endpoint of amyloid clearing in the brain, which it said "is reasonably likely to result in clinical benefit." The decision was made over objections from the agency's biostatistics office, which said that clinical trial data fell short of the proof normally required to put a new product on the market. Meanwhile, an advisory committee convened in November last year to discuss the filing overwhelmingly voted down the drug, with three members having resigned from the panel in protest since Aduhelm's approval earlier this month.

Advisory panel was 'reset point'

Still, FDA officials said they viewed the advisory panel's input as a "reset point" that prompted them to consider the accelerated pathway after concluding that Aduhelm had not met the standard for regular approval. "What we heard really shaped our thinking in our discussions over these almost seven months between the advisory committee and the approval," stated Patrizia Cavazzoni, director of the FDA's Center for Drug Evaluation and Research.

The FDA approval was based primarily on the Phase III EMERGE and ENGAGE trials designed to demonstrate whether Aduhelm helped slow cognitive decline in patients with early Alzheimer's disease based on change from baseline on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) scale at week 78. The studies were stopped early for futility in March 2019, but the drug was resurrected seven months later, with Biogen and Eisai saying they planned to file for FDA approval after conducting additional analyses of trial data that came in after the studies were halted.

Stein said the data suggested a relationship between removing beta amyloid from the brains of Alzheimer's patients and improvements seen in the trials. "There remains residual uncertainty regarding clinical benefit," Stein wrote, but if the FDA were to wait for the company to finish another clinical study, "any approval would occur after a multiple year delay" and patients "could suffer irreversible loss of brain neurons and cognitive function and memory."

FDA advises Biogen to take closer look at studies

The FDA memos also shed some light on the period between the shelving of the EMERGE and ENGAGE studies in early 2019 and the companies' subsequent decision later that year to seek approval. According to a "summary memorandum" document, Biogen met with FDA officials in June 2019 and both sides agreed that the two trials should not have been stopped. At the meeting, FDA officials also recommended that Biogen examine the studies further to understand if it was still possible to draw conclusions from the data, despite the fact that the trials were stopped early and conflicting results. In October of that year, the FDA and Biogen met again and agreed that the studies could still be used to evaluate Aduhelm's effectiveness, according to the memo.

Biogen CEO Michel Vounatsos had said at the time that his company had been quietly re-analysing the data for months, but did not have the confidence to push ahead with an approval filing until the latest meeting with FDA officials.