3 FDA Committee Members Resign Over Alzheimer’s Drug Approval

June 14, 2021 - Three experts have resigned from FDA’s advisory committee following the agency’s approval of Biogen’s Alzheimer’s drug, aducanumab, according to multiple reports.

FDA approved aducanumab at the beginning of last week. This marked the first Alzheimer’s drug approval in nearly 20 years and the first one to address cognitive decline in patients with the illness.

In November 2020, FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted against recommending the drug.

Specifically, 10 of the 11 committee members voted that there was not enough evidence to show aducanumab could slow cognitive decline, recommending against its approval, according to STAT. The 11th member voted “uncertain.” 

Joel Perlmutter, MD, a Washington University neurologist, was the first committee member to resign.

He stated that FDA approved the drug without further discussion with its advisors. Just days later, David Knopman, MD, a Mayo Clinic neurologist, panel member, and an investigator in clinical trials of Biogen’s drug, also resigned. 

"I was very disappointed at how the advisory committee input was treated by the FDA," Knopman told Reuters following his resignation. "I don't wish to be put in a position like this again.”

Aaron Kesselheim, MD, professor at Harvard Medical School and director of the program on regulation, therapeutics, and law at Brigham and Women’s Hospital, was the last committee member to resign. 

Kesselheim explained that FDA did not gather enough proof that the drug will help Alzheimer’s patients. He said that the agency needs to re-evaluate how it uses the advisory committees because their concerns were not integrated into the overall decision-making process. 

“This week, the aducanumab decision by FDA administrators was probably the worst drug approval in recent US history,” Kesselheim said in his resignation letter to FDA.

“At the last minute, the agency switched its review to the Accelerated Approval pathway based on the debatable premise that the drug’s effect on brain amyloid was likely to help patients with Alzheimer’s disease. But this pivotal question was not discussed at the Advisory Committee meeting and its premise was specifically excluded from discussion,” he continued.

For nearly five years before FDA approved aducanumab, there was notable controversy surrounding the drug’s efficacy. 

In March 2019, Biogen discontinued its Phase 3 trials for the drug, EMERGE and ENGAGE, based on a futility analysis conducted by an independent data monitoring committee.

Although EMERGE met its primary endpoint and elicited a significant reduction of clinical decline from baseline at 78 weeks, ENGAGE did not meet its primary endpoint. 

Overall trial results showed that aducanumab administered as a monthly infusion was not better at slowing memory loss and cognitive impairment than placebo. Therefore, trials were unlikely to meet their primary endpoint upon full completion.  

Although recent brain scans revealed that aducanumab effectively reduced A-beta in the brain, it is unclear whether this reduction comes with consistent improvements in quality of life. 

Therefore, some doctors and scientists see FDA’s approval as premature because they aren’t convinced that the drug actually works, given the mixed trial results over the years. Approving a drug that’s not effective will set Alzheimer’s research back, critics argue. 

FDA’s approval may also make it difficult for Biogen to find enough patients to participate in its next clinical trials, as patients might not want to risk getting the placebo now that they can get the drug without being in a study.

Patrizia Cavazzoni, director of FDA’s Center for Drug Evaluation and Research, said that FDA is “well-aware” of the attention surrounding the approval of aducanumab. But, in determining that the application met the requirements for Accelerated Approval, the agency ultimately concluded that the benefits of the drug for patients with Alzheimer’s disease outweighed the risks.