‘The award for most memorable drug approval goes to…’

It's TV awards season, and an Emmy-worthy drama is unfolding around an unlikely subject: the U.S. Food and Drug Administration's approval of Biogen, Inc.'s Aduhelm (aducanumab), a novel biologic for the treatment of Alzheimer's disease.

Let's set the scene:

On June 7, FDA approved Aduhelm through the accelerated approval pathway, a narrow regulatory paradigm reserved for drugs directed to serious conditions that fill an unmet medical need. Under accelerated approval, a drug manufacturer may earn marketing approval for its product based on the drug's effect on "surrogate" or "intermediate" clinical endpoints - markers thought reasonably likely to predict clinical benefit -- rather than through the traditional demonstration of safety and efficacy in randomized control trials.

Accelerated approval is often used for cancer drugs, as tumor shrinkage is a surrogate endpoint considered reasonably likely to predict clinical benefit in patients lacking other options, even when it is unclear whether the new drug actually extends patient survival. However, prior to Aduhelm, accelerated approval had never been granted for an Alzheimer's treatment.

This may be because relatively little is known about the pathophysiology of Alzheimer's disease. We know the disease is characterized by extracellular beta-amyloid deposits, the protein components targeted by Aduhelm, but the mechanisms by which these deposits contribute to Alzheimer's disease progression are not well understood, and it is unsettled whether beta-amyloid reduction is a reliable surrogate endpoint. Therefore, approving Aduhelm on such a basis may raise false hopes and unwarranted investment by Alzheimer's patients and researchers alike.

Adding to the controversy is the fact that, prior to being considered for accelerated approval, Aduhelm seemed dead in the water. Biogen halted both of its late-stage Phase 3 trials of the drug in March 2019 after an independent data monitoring committee found they were unlikely to meet their primary efficacy objectives. Later, Biogen re-analyzed the data and determined that one study showed positive results at the highest dose, while the other similarly designed study remained negative. Biogen applied for approval based on the positive study and a small Phase 1 trial showing time- and dose-dependent reductions in amyloid plaque levels in prodromal and mild Alzheimer's patients.

Despite the contradictory findings, FDA praised the drug and study data, calling it "strongly positive," "robust," and "exceptionally persuasive." The scientific community raised a collective eyebrow, and experts began to react. Strongly.

Got your popcorn?

After evaluating the data, 10 of 11 members of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee voted against approval of the drug. The remaining member voted "uncertain." The American Geriatrics Society also urged the agency against an approval that would be "premature given the lack of sufficient evidence."

Upon FDA's approval of the drug (and rare rebuke of a near-unanimous panel vote), three prominent committee members resigned in protest. One former member, Dr. Aaron Kesselheim, in his resignation letter to Acting FDA Commissioner Janet Woodcock, called FDA's move "probably the worst drug approval decision in recent U.S. history," and noted that "some of the questions FDA asked the Committee to answer were worded in a way that seemed slanted to yield responses that would favor the drug's approval."

Following Dr. Kesselheim's resignation, an exposé by the medical news network STAT revealed a shadowy Biogen campaign to revive Aduhelm. The initiative, titled "Project Onyx" involved an off-the-books meeting between a top Biogen executive and Dr. Billy Dunn, director of FDA's Office of Neuroscience, regarding Biogen's positive re-evaluation of Aduhelm's Phase 3 study data. In the months following the meeting, Biogen and FDA enjoyed an unusually collaborative relationship, culminating in FDA's surprising proposal that Aduhelm be advanced through accelerated approval.

The scientifically fraught and ethically murky approval of Aduhelm, coupled with the drug's astounding $56,000 price tag, has prompted bipartisan congressional scrutiny of the drug's approval process and re-ignited public discourse about government-industry relations on a backdrop of corporate profit-seeking and, at the heart of it all, a devastating disease course too long without hope. Aduhelm is the first FDA-approved Alzheimer's therapy in nearly 20 years, the last being Forest Labs' Namenda (memantine) in 2003.

Facing a highly public controversy and mounting political pressure, FDA has begun backpedaling on its support for Aduhelm. On July 8, the agency narrowed its original broad label approval for Aduhelm to patients with mild cognitive problems, mirroring the study population in Biogen's late-stage trials. The next day, acting FDA head Woodcock called on the Office of the inspector general to conduct an independent investigation into the approval process of Aduhelm, including review of interactions between Biogen and FDA representatives "that may have occurred outside of the formal correspondence process."

It is exceedingly rare for the agency to call for an independent federal investigation into its own approval process. In her letter to OIG Acting Inspector General Christi Grimm, Woodcock professed her confidence in the integrity of the staff and leadership of the CDER involved in the Aduhelm review, but invited the investigation "to the extent these concerns could undermine the public's confidence in FDA's decision[.]"

Woodcock's gesture, while appreciated, may be too little too late. Already, two major medical centers -- the Cleveland Clinic and Mount Sinai in New York -- are refusing to administer Aduhelm at their facilities. In addition, several affiliates of Blue Cross Blue Shield posted policies stating they will not cover the drug because they consider it "investigational" or "experimental" despite FDA's approval. These stances come ahead of Medicare's National Coverage Determination, showing that private insurers don't feel the need to wait for CMS's signal to write off Aduhelm.

An apparent loss of confidence in FDA comes at the worst possible time, as concerns over the agency's regulatory rigor for accelerated therapies and private sector relationships continue to inform vaccine hesitancy in the face of the ongoing COVID-19 pandemic.

Weighing on all of this is the Biden administration's inertia towards naming a permanent FDA commissioner. President Joe Biden needs to act decisively to install a credible FDA head and stabilize the agency's leadership. Confidence in a robust U.S. regulatory system is more important now than ever, and with the public eye trained on FDA's handling of new drug approvals and regard for public safety, Aduhelm is an ongoing drama that won't be soon forgotten.