FDA Reviewers: Why We Are Against Approval of Aducanumab for Alzheimer's

Alicia Ault

May 05, 2021

Three members of a US Food and Drug Administration (FDA) advisory committee are explaining why they do not support approval of the drug aducanumab (Biogen, Eisai) for the treatment of Alzheimer's disease (AD).

G. Caleb Alexander, MD, Scott Emerson, MD, PhD, and Aaron Kesselheim, MD, JD, MPH, all serve on the FDA's Peripheral and Central Nervous System Advisory Committee and participated in the November 2020 meeting in which they were asked to consider whether current trial data support approval of the drug.

Only one panellist supported aducanumab's approval. Eight panellists, including Alexander, Emerson, and Kesselheim, voted no, while two others were uncertain of whether it warranted FDA approval.

At the time, committee members noted that results from the drug's one large positive trial did not provide strong enough evidence of efficacy for treating AD.

Although early trials of the drug were promising, two phase 3 trials were discontinued for futility after an interim analysis. However, investigators later reported that further analysis from the EMERGE trial showed that the drug did, in fact, meet its primary endpoint of significant reduction in clinical cognitive decline.

Still, the majority of panel members did not believe this trial data was enough to support the drug's approval and Alexander, Emerson, and Kesselheim note that nothing has changed in the interim.  

"There is no persuasive evidence to support approval of aducanumab at this time," they write in a Viewpoint published online March 30 in the Journal of the American Medical Association.

During the ongoing controversy, AD advocates such as the Alzheimer’s Association and US Against Alzheimers have thrown their support behind aducanumab, even though it mostly failed in clinical trials.

In addition, the FDA openly assisted Biogen and Eisai in tailoring the trials for the drug's approval, noting the collaboration in briefing documents submitted jointly by the agency and the manufacturers.

Some groups have criticized the partnership, including Public Citizen's Health Research Group. Its members wrote to US Secretary of Health and Human Services Xavier Becerra on April 1 to seek a number of immediate changes in how the agency is handling aducanumab's ongoing review, including the temporary ouster Billy Dunn, MD, the FDA’s neuroscience chief.

The FDA is slated to make an approval decision by June 7.

Post-hoc Analyses Unacceptable

Alexander, Emerson, and Kesselheim document the drug's history, noting that Biogen and Eisai stopped aducanumab trials in March 2019 because "the planned interim analysis met prespecified futility criteria."

When further analysis indicated aducanumab might have shown efficacy in one of the two trials, study 302 (EMERGE), the FDA worked with the companies to further analyze and shape the data, according to the agency and the manufacturers.

The companies used a variety of post hoc analyses in an attempt to show that at least some patients in study 302 had a true treatment effect, the current authors note. The companies asked to use that trial as the basis for approval.

However, Alexander, Emerson, and Kesselheim caution against post-hoc studies in general, noting that they "introduce what may be regarded as unacceptable threats to statistical validity and scientific rigor."

In addition, "any treatment will appear to be more effective if individuals in whom it works least are removed from the analysis," they write.

Post-hoc analyses for aducanumab "provided limited information useful in deciding the benefit of this new drug," they add. This information "should not be the basis for FDA approval."

Instead, "randomized trials should remain the primary means that regulators use to assess product efficacy" in order for the public, clinicians, and policymakers to be confident in the safety and effectiveness of new drugs, the authors write.

A "Black Eye" for the FDA

In the letter to Becerra, Michael Carome, MD, Public Citizen's Health Research Group director, writes that the FDA's collaboration with Biogen is a "black eye for the agency, further undermining public confidence in the agency, and demands your immediate attention."

The watchdog organization had already asked the HHS Office of Inspector General in December to investigate the collaboration. Now it wants HHS to press for an immediate inquiry.

The FDA should also remove Dunn, Carome writes, because of his role in supervising the collaboration with Biogen and Eisai — at least until an investigation is complete. In addition, Public Citizen is seeking to have the FDA's review of aducanumab completed by agency staffers who were not previously involved with the two companies.

Overall, aducanumab should not be approved, said Carome, noting that the evidence does not support its effectiveness.

"The premature approval of aducanumab could impede the development of other experimental treatments for Alzheimer's disease for many years, potentially delaying progress on drugs that actually may turn out to be beneficial," he writes.

Medscape Medical News reached out to Biogen and Eisai several times for comment but received no response.

Alexander is past chair and a current member of the FDA's Peripheral and Central Nervous System Advisory Committee, is a cofounding principal and equity holder in Monument Analytics, and is a past member of OptumRx's National P&T Committee.

Emerson reports having served as a paid member of independent data monitoring committees for AstraZeneca, Bayer, BioAtla, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Denovo, Esteve, Inovio, Mirati, Novartis, Pfizer, Principia, Roche, and Takeda. He also provided paid statistical consulting for Acadia, Alkermes, Arbor, Avenue, GlaxoSmithKline, Insmed, Merck, and Novo Nordisk, none of which are related to indications for Alzheimer's disease.

Kesselheim is a member of FDA's Peripheral and Central Nervous System Advisory Committee and reports grants from Arnold Ventures.

JAMA. Published online March 30, 2021. Viewpoint

Alicia Ault is a Lutherville, Maryland-based freelance journalist whose work has appeared in publications including Smithsonian.com, the New York Times, and the Washington Post. You can find her on Twitter @aliciaault.

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