Aduhelm one of FDA's 'most controversial' approvals in agency history, experts argue

The FDA’s decision to approve Aduhelm represented one of the agency’s “most controversial [approvals] ever,” according to a piece published in the Ideas and Opinions section of Annals of Internal Medicine.

“[Aduhelm] was approved despite the concerns of scientists and regulatory experts about its efficacy,” the researchers wrote.

One of the researchers who authored the piece, G. Caleb Alexander, MD, MS, is professor of epidemiology and medicine at Johns Hopkins Bloomberg School of Public Health, founding codirector of the Center for Drug Safety and Effectiveness and principal investigator of the Johns Hopkins-FDA Center of Excellence in Regulatory Science and Innovation. Alexander was also on an FDA advisory committee that reviewed Aduhelm (aducanumab, Biogen/Eisai). Jason Karlawish, MD, professor of medicine in the division of geriatrics at the Perelman School of Medicine, University of Pennsylvania, cowrote the piece with Alexander.

“Notably, an FDA statistician and an advisory committee on which one of us served (GCA) reviewed the product at a November 2020 hearing and concluded that it should not be approved on the basis of the evidence to date,” Alexander and Karlawish wrote. “Nevertheless, the FDA approved it, using an ‘accelerated approval’ pathway that the advisory committee had been informed was not being considered.”

The first issue Alexander and Karlawish outlined with Aduhelm involved the accelerated approval it was granted. Under this strategy, according to the authors, a drug receives FDA approval based on its effect on a surrogate marker of disease, which is, in this case, beta-amyloid levels in the brain. This is in comparison to drugs that receive FDA approval based on clinical outcomes, such as the signs or symptoms of AD. The approval granted to Aduhelm requires Biogen, the drug’s manufacturer, to conduct a new randomized controlled trial to ascertain the drug’s benefit. Should that new trial fail to verify a benefit, the FDA “may initiate proceedings to withdraw approval of the drug,” according to a press release issued by the FDA at the time of the approval.

According to Alexander and Karlawish, Biogen has stated that new trial will be completed by 2030. The researchers called that 9-year timeframe “unacceptably long” when the stakes for patients are so high. They also noted that these confirmatory studies could still fail to demonstrate the “true clinical benefit” for Aduhelm.

Another concern related to the accelerated approval process, according to the researchers, is that it is meant for products that are “expected to provide a meaningful advantage over available therapies for a serious disease” when there is uncertainty about the agent’s clinical benefit. They acknowledged that AD “is a serious disease,” with no proven therapies for managing it.

“Elevated measures of [beta]-amyloid, together with tau protein, are diagnostic of pathologic [AD]. [Aduhelm’s] phase 1 study indicates the drug reduces beta-amyloid levels,” Alexander and Karlawish wrote. “Whether [beta]-amyloid alone is a valid surrogate for treatment of [AD] is unclear and was, until the morning of 7 June 2021, a topic of ongoing and important study. Now, treatment of an amyloid level is suddenly clinical practice.”

The researchers also discussed the “notable” effect Aduhelm will have on drug development and regulation. Specifically, they cited the impact of the FDA’s willingness to take amyloid as a surrogate marker, which could prompt Biogen and other companies “to seek approval for other drugs that reduce levels of amyloid or other biomarkers but have unclear clinical benefits.” This scenario could cause patients with AD to withdraw from clinical trials, or not enroll in them at all, and take Aduhelm instead, according to Alexander and Karlawish.

“This decision is of course their ethical privilege, and if aducanumab were effective, their collective action could revolutionize [AD] trials,” they wrote. “Imagine, for example, head-to-head comparison studies [designed] to show which of two treatments is safer and more effective.”

Finally, Alexander and Karlawish discussed “reverberating problems with care,” specifically regarding the cost of the drug. They raised a question from the point of view of insurance companies about whether Aduhelm represents “a reasonable and necessary treatment” for their beneficiaries, in addition to questions about which patients should receive it and how to determine what benefits come from the agent.

“Payers retain significant leverage that can be used to negotiate price and to help optimize use,” they wrote. “It is all but certain that insurers will have to qualify the kinds of patients who are eligible for treatment as well as what tests and copayments will be required.”

Alexander and Karlawish also noted that Aduhelm “will be a problem for the American family,” tying the copayments for the drug to the current “billion-dollar economic burden” of AD.

“Clinicians will have to practice a most unusual clinical conversation to address uncertainty about whether Aduhelm is even beneficial,” they wrote. “The discussion of the drug’s well-documented risks for brain swelling and microhemorrhages should include how this may be associated with having a gene associated with late-onset [AD], the APOE4 gene, raising the prospect that families will face genetic as well as monetary risks.”

According to Alexander and Karlawish, questions about the impact of Aduhelm’s approval “will take time” to be answered.

“What is certain now is that its approval will reverberate for years. Patients, caregivers, providers, and scientists must adapt to a peculiar world,” they wrote. “The FDA has approved a first-in-class product for [AD] on the basis of reduction in [beta]-amyloid plaques. We all must wait for evidence of whether this in fact benefits patients.”