Three F.D.A. Advisers Resign Over Agency’s Approval of Alzheimer’s Drug

Despite weak evidence that Aduhelm helps patients, the drug, a monthly infusion priced at $56,000 per year, was approved this week.

An independent committee of scientists that advised the Food and Drug Administration on Biogen’s controversial Alzheimer’s drug has resigned in strong protest against the agency’s approval.

“This might be the F.D.A.’s worst approval decision in my memory,” said Doctor, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, who resigned Thursday after six years.

As a result of so many different reasons, including the fact that there is no good evidence that the drug works, he said, the agency was wrong to approve aducanumab, marketed as Aduhelm, a monthly intravenous infusion that Biogen charges $56,000 per year..”

After reviewing clinical trial data in November, two other members of the committee resigned, expressing disappointment over the approval of the drug.

According to the committee, the evidence did not show that Aduhelm could slow cognitive decline in people in the early stages of the disease – and the drug could cause potential serious side effects such as brain swelling and bleeding. Ten members voted against the drug and one was uncertain. None of the 11 members considered the drug ready for approval.

“Approval of a drug that is not effective can seriously hamper future research into new treatments,” said Doctor, a neurologist at Washington University School of Medicine in St. Louis.

“Additionally, aducanumab therapy could cost billions of dollars, which would be better spent developing better evidence for aducanumab or other therapeutic interventions,” said Doctor.

F.D.A. spokeswoman Shannon P. Hatch said the agency does not comment on individual advisory committee members.

In about two weeks, Biogen plans to begin shipping out the drug. Over 900 sites across the country, typically memory clinics that treat dementia patients, will soon be able to administer the drug.

The Food and Drug Administration approved it on Monday, marking the first approval of an Alzheimer’s treatment in 18 years. The approval was pushed by patient advocacy groups since there are only five other medications available for the debilitating condition, and they only address symptoms for a short timeframe.

The available evidence, however, has raised significant doubts about the effectiveness of aducanumab, according to several respected experts, including some Alzheimer’s doctors who worked on the clinical trials. Even if it could slow cognitive decline in some patients, the suggested benefit – a slowing of symptoms for roughly four months over 18 months – might barely be noticeable to patients, and the risk of brain side effects would not outweigh the benefits.

Aside from the steep price tag of the drug, screening patients before treatment and regular MRIs to monitor their brains could add tens of thousands of dollars to the bill. The majority of the cost is expected to be covered by Medicare.

“Giving patients a drug that does not work and that is going to require multiple MRIs at a cost of $56,000 a year is putting patients and doctors in a very difficult position,” Doctor said.

In addition to believing that the evidence for Aduhelm’s benefits is weak, the advisory committee members who resigned and several prominent Alzheimer’s experts disagreed with two major aspects of the FDA’s approval.

The F.D.A. approved the drug for a much broader group of patients than many experts expected – anyone with Alzheimer’s. Only patients with early-stage Alzheimer’s or mild cognitive impairment were tested for the drug in clinical trials.

Secondly, a major part of the F.D.A.’s rationale for approving the drug was that its ability to attack the amyloid protein in patients’ brains would slow their cognitive symptoms.

“There is an urgent need to address this issue,” said Doctor.

There has been very little scientific evidence that reducing amyloid can help patients by improving their memory and thinking, even though it is considered a biomarker of Alzheimer’s disease due to its accumulation in the brain.

Other amyloid-reducing drugs have failed to slow cognitive decline in clinical trials over the past two decades. Aduhelm’s ability to treat symptoms was therefore especially important, according to many experts.

The FDA informed members of the advisory committee in November that it would not consider the drug’s ability to reduce amyloid as an indication that it might be effective. The FDA announced Monday that it had done just that in its decision.

“Aduhelm has been shown to reduce amyloid beta plaques in the brain and to be reasonably likely to predict significant benefits to patients, according to FDA’s Director of the Center for Drug Evaluation and Research, Doctor, wrote on the agency’s website about the decision to make the drug available under accelerated approval.

Although members of the advisory committee said the committee was never informed about the agency’s plans to consider approval based on amyloid reduction and that their opinion was never sought. The committee was not provided with any additional information or statistical analyses that would support approval, according to Doctor.

In an email on Wednesday, Doctor, a neurologist at the Mayo Clinic, informed F.D.A. officials of his resignation from the advisory committee: “In the absence of consistent clinical benefit after 18 months of treatment, the justification for approval of biomarkers is indefensible..”

Doctor, who had recused himself from the November meeting because he had served as a site principal investigator for one of the aducanumab trials, stated that “the entire saga of the approval of aducanumab, culminating on Monday in the accelerated approval, made a mockery” of the advisory committee.

According to Biogen, Aduhelm will cost an average of $56,000 per year for an intravenous infusion. Credit…Cody O’Loughlin for The New York Times

During a press conference after the decision, Doctor, director of the Office of New Drugs at the Food and Drug Administration, said agency reviewers were convinced by what he described as a strong relationship between plaque reduction and the potential clinical benefit of Aduhelm, which had not been observed in previous studies of amyloid-clearing drugs.

According to Stein, the drug could be useful beyond the early stages of Alzheimer’s, which is why the drug was approved for such a wide group of patients.

“Considering that amyloid is a hallmark of the disease throughout its entire course, it is expected that this drug will provide benefit throughout,” Doctor.

The F.D.A. said Biogen would have to conduct another clinical trial before receiving approval and would have about nine years to complete it. Some experts are also concerned about those terms. If the new trial does not find the drug beneficial, the agency can revoke its approval, but it is not required to and has not always done so.

Doctor, who directs Harvard Medical School’s program on regulation, therapeutics and law, said the timeline they provided for the so-called confirmatory trial, nine years, is problematic. There will be a lot of use of the product during that period.”

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