FDA calls for investigation into industry influence during Alzheimer’s drug approval

The acting commissioner of the US Food and Drug Administration (FDA) has asked the health department’s inspector general to investigate allegations of improper contact between FDA regulators and a company whose Alzheimer’s disease treatment won a controversial approval last month.

“Given the ongoing interest and questions,” Janet Woodcock wrote on Twitter, “today I requested that the inspector general conduct an independent review and assessment of interactions between representatives of Biogen and FDA during the process that led to the approval of Aduhelm.”1

The request came hours after the agency restricted the potential market of aducanumab (Aduhelm), retreating from a June approval2 that would have made it available to all US patients with Alzheimer’s disease, estimated at over six million people. Instead, the drug’s labelling will indicate its use only in those who have not progressed beyond mild cognitive impairment or early dementia—about 1.5 million people.

The allegations of improper contact appeared on the medical news website Stat.2 Its report claimed that after aducanumab failed to show clinical benefit in two trials, Biogen launched “project onyx,” a plan to secure FDA approval.

A top Biogen official met with Billy Dunn, the head of the FDA’s neuroscience office, at a conference in Philadelphia, Stat reported. The meeting was not officially recorded, though it is said that under FDA procedures it should have been.

FDA officials suggested several possible avenues of approval to the company, including the “accelerated approval” that was eventually granted, Stat contended. But FDA officials told an expert advisory committee on aducanumab that this type of approval was not being considered.

The advisory committee, meeting in November 2020, voted heavily against approval.4 Aducanumab was effective at clearing amyloid plaque from the brain, most committee members said, but the theory that such plaque was the causative agent in Alzheimer’s disease had never been proven. The studies did not show meaningful clinical improvement in patients taking the drug, the committee found. Three committee members laid out their reservations in the Journal of the American Medical Association.5

Biogen later reanalysed some data from the trials and said it had detected a signal of clinical benefit. Then, on 7 June 2021, the FDA granted accelerated approval, overriding the recommendation of its expert committee. Under the terms of accelerated approval, the company will have to prove actual clinical benefit in a post-market study set to run until 2030.

The paucity of existing treatments for Alzheimer’s disease and the huge unmet need were factors in the approval, wrote three FDA regulators, including Billy Dunn, in the Washington Post.5 They had also “concluded that the reduction in amyloid plaque correlates with slowing of disease progression and is reasonably likely to predict clinical benefit.”

But while some Alzheimer’s groups and specialists welcomed the decision, it also ignited a firestorm of criticism. Three members of the expert committee resigned in protest.6 Committee member Scott Emerson compared the company’s analysis of the trial data to “firing a shotgun at a barn and then painting a target around the bullet holes.”

The FDA’s embrace of the unproven amyloid theory of Alzheimer’s pathogenesis risked shutting down other avenues of research, critics said, and trials would no longer be able to recruit patients, who would not risk getting a placebo when an approved treatment existed.

Clinicians worried that news of the approval would spark false hope in millions of patients. The FDA’s decision to approve the drug for all Alzheimer’s patients was a particular point of contention, as it had only been studied in mild disease.

Making the drug available to all Alzheimer’s patients could place an unsustainable burden on Medicare, given its price tag of $56 000 (£40 340; €47 240) a year for an average weight patient. Even with the new more limited label, it could cost Medicare over $50bn each year.

Janet Woodcock remains an acting commissioner only as Democratic senator Joe Manchin of West Virginia, the chamber’s swing vote, is urging the White House not to confirm her in the post. Accused by critics within the agency of being too receptive to patient demand for new drugs, she has been blamed by Manchin for the easy availability of opioids in his state.

Biogen said in a statement that “we will, of course, cooperate with any inquiry.”