Aducanumab Saga Continues as FDA Committee Members Resign Over Approval

FDA_Al Drago/CQ Roll Call

Al Drago/CQ Roll Call

On Monday, June 7, the U.S. Food and Drug Administration (FDA) approved Biogen’s controversial Alzheimer’s drug Aduhelm (aducanumab). In November 2020, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee voted against recommending the drug. And now, two members of the advisory panel resigned over the approval.

David S. Knopman, a neurologist at the Mayo Clinic, told The Washington Post he did not “wish to be part of a sham process.” In his email to the FDA, Knopman wrote, “The whole saga of the approval of aducanumab … made a mockery of the [advisory] committee’s consultative process. While I realize that the committee is advisory, the approval of aducanumab appears [to] have been foreordained.”

Earlier in the week, Joel S. Perlmutter, a neurologist at Washington University in St. Louis, resigned from the committee. Perlmutter told STAT that he resigned “due to this ruling by the FDA without further discussion with our advisory committee.”

The FDA is not obligated to follow the recommendations of their advisory committees, which are made up of outside experts. At least one study indicated the FDA approved drugs 21% of the time that the adcoms did not recommend, although those decisions typically involved close adcom votes. With aducanumab, 10 of the 11 committee members voted that there was insufficient evidence to demonstrate the drug slowed cognitive decline. The 11th panelist voted “uncertain.”

Aducanumab is a monoclonal antibody taken by infusion that clears beta-amyloid, a sticky protein that accumulates in the brains of Alzheimer’s patients and is believed to be at least partially involved in causing memory and cognitive problems in the disease. There appear to be other factors, such as neuroinflammation and potentially immune problems with the brain’s immune cells, microglia. Another abnormal protein, tau, also accumulates, although it is generally found later in the disease.

Although the controversies over the aducanumab have several components, this issue of beta-amyloid clearance is a central one. The FDA’s accelerated approval—which requires a post-market study to prove efficacy—was based on a “surrogate endpoint” that the drug cleared beta-amyloid, not on slowing cognitive decline. 

Several other monoclonal antibodies against beta-amyloid developed by other companies demonstrated they could clear amyloid, but did not show improvements in cognition and memory. Yet they were not even allowed to be submitted to the FDA. Yet, in the case of Biogen, FDA stated that the surrogate endpoint was “reasonably likely to predict a clinical benefit to patients.”

For background, Biogen and Eisai abandoned the drug program in March 2019 after a futility analysis said it would not hit its clinical endpoints. A few months later, after a fuller analysis, they found that the Phase III EMERGE study did hit the primary endpoint at the highest dose in one of the trials, demonstrating a significant decrease in clinical decline. 

The data was quite complex and controversial, and there were concerns and allegations over data manipulation and over-involvement on the part of the FDA. Many critics felt Biogen had not proven aducanumab was effective and that its risk-benefit profile was problematic. The drug has some neurotoxicities associated with it that can lead to brain bleeds.

Biogen has indicated it will be priced at about $56,000 per patient per year. The Institute for Clinical and Economic Review (ICER), a drug pricing watchdog that has no official standing with Medicare, insurers or drug companies, recommended a price point of $2500 and $8300 per patient per year, although they also were opposed to approval.

This kind of controversy, although not common, isn’t unheard of. In 2016, after a long and controversial approval process, the FDA approved Sarepta Therapeutics’ Duchenne Muscular Dystrophy (DMD) drug, Exondys 51. Rather than opposition from an advisory committee, there was opposition from within the agency itself, with the agency’s then acting chief scientist, Luciana Borio, and Ellis Unger, director of the office of drug evaluation, adamantly opposed to approval, arguing that Sarepta did not prove the drug’s efficacy. Janet Woodcock, who was then director of the FDA’s Center for Drug Evaluation and Research (CDER), pushed it through, overruling the staff. 

Woodcock is currently the interim commissioner of the FDA. He decided to then-commissioner Robert Califf, who had reservations similar to Borio and Unger, but ultimately sided with Woodcock.

Exondys 51 runs about $750,000 per year for one patient, depending on the weight of the patient. This is dramatically more expensive than the proposed price of aducanumab, at $56,000 per patient per year.

Another similarity between the Biogen approval and the Sarepta approval was that both were granted under the FDA’s Accelerated Approval pathway. Essentially this means that the drugs were approved on surrogate endpoints rather than clinical efficacy and the companies are required to conduct post-marketing studies to prove efficacy. And if they don’t, the approval could be rescinded. Five years after the Sarepta approval, the study has yet to be announced. The FDA gave Biogen a very long timeframe, nine years, to conduct their study.

Another puzzle over the Biogen approval surrounds the surrogate endpoints. Billy Dunn, the director of the FDA’s Office of Neuroscience, said at the November 2020 advisory committee meeting, “We’re not using the amyloid as a surrogate for efficacy.” As such, the advisory committee did not take that into account when they made their decision.

Then on Monday, the agency said they did take it into consideration. Dunn sent a letter to the panel chair on Monday saying that after the panel hearing, the FDA had held “further discussions” that “raised further consideration of the accelerated approval pathway…. Our discussions leading up to the decision to grant an accelerated approval for aducanumab considered a wide range of views, both external and internal to FDA. 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.”

Another advisory committee member, Aaron Kesselheim, director of Brigham and Women’s Hospital’s Program on Regulation, Therapeutics, and Law, said that the approval set “a dangerous precedent” related to the type of evidence needed for Alzheimer’s drug approvals, “but even more broadly for the idea that a company can turn around and at the last minute seek [accelerated approval] when their primary clinical endpoints in their trials don’t reach the level needed for FDA approval.”

FDA advisory committee has some permanent members, but for specific panel meetings, invite “temporary members.”

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