In a marked disagreement over the Food and Drug Administration’s approval of Biogen’s controversial Alzheimer’s drug, three scientists have stepped down from the independent committee that advised the agency on the treatment.
“This could be the worst approval decision the F.D.A. that I can remember, ”said Dr. Aaron Kesselheim, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, who resigned Thursday after six years on the committee.
He said the agency’s approval of the drug aducanumab, marketed as Aduhelm, a monthly intravenous infusion that Biogen has set at $ 56,000 a year, was incorrect “because of so many different factors, including the fact that there is no good evidence ”. that the drug works. “
Two other members of the committee resigned earlier this week, expressing dismay at the approval of the drug despite the committee’s approval overwhelming rejection thereof after review of clinical trial data in November.
The committee found that the evidence was inconclusive that Aduhelm could slow cognitive decline in people with early disease – and that the drug could potentially cause serious side effects of brain swelling and hemorrhage. None of the eleven committee members thought the drug was ready for approval: ten voted against, one was unsure.
“The approval of an ineffective drug has serious potential to interfere with future research into new treatments that may be effective,” said Dr. Joel Perlmutter, a neurologist at Washington University School of Medicine in St. Louis, who first stepped down from the committee.
“Furthermore, aducanumab therapy will potentially cost billions of dollars to introduce, and those dollars could be better spent developing better evidence for aducanumab or other therapeutic interventions,” added Dr. Mother-of-pearl added.
Shannon P. Hatch, a spokeswoman for the F.D.A., said the agency does not comment on matters relating to individual advisory committee members.
Biogen plans to ship the drug in about two weeks. It expects more than 900 locations across the country, usually memory clinics that treat patients with dementia, to be ready to administer the drug soon.
The F.D.A.s decision Giving the go-ahead, announced Monday, marked the first approval of an Alzheimer’s treatment in 18 years. Patient representatives had pushed for approval because there are only five more Medication available for the debilitating condition and they only treat dementia symptoms for a few months.
But since last fall at the latest have several respected experts, including some Alzheimer’s doctors who worked on aducanumab clinical trialssaid the available ones Evidence cast considerable doubt whether the drug is effective. They also said that even if it could slow cognitive decline in some patients, the proposed benefit – slowing symptoms down for about four months over 18 months – might be barely noticeable to patients and outweigh the risks of side effects on the brain would.
In addition to the high price of the drug, the additional cost of screening patients before treatment and having regular MRIs needed to monitor their brain for problems could add tens of thousands of dollars to the bill. Medicare is expected to cover much of the bill.
“Giving patients a drug that is not working, and of course has great risks that require multiple MRIs costing $ 56,000 a year, puts patients in a really challenging position and puts doctors in a difficult position.” said Kesselheim.
Aside from believing that existing evidence of Aduhelm’s benefits is weak, the resigning advisory committee members – as well as several prominent Alzheimer’s experts – rejected two important aspects of the F.D.A.’s approval decision. from.
One problem is that the F.D.A. approved the drug for a much broader group of patients – anyone with Alzheimer’s – than many experts expected. In the clinical trials, the drug was only tested in patients with early-stage Alzheimer’s disease or mild cognitive impairment from the disease.
The other problem is that a significant part of the F.D.A. for approval was that the drug’s ability to attack the amyloid protein in patients’ brains would help slow their cognitive symptoms.
“This is a big problem,” said Dr. Mother-of-pearl.
While amyloid is considered a biomarker of Alzheimer’s disease because its buildup in the brain is an important aspect of the disease, there is very little scientific evidence that reducing amyloid can actually help patients by relieving their memory and thinking problems.
Clinical studies of other amyloid-lowering drugs for more than two decades have shown no evidence that the drugs slow cognitive decline. As a result, many experts had said it was especially important to have solid evidence of Aduhelm’s ability to treat symptoms.
In November F.D.A. Officials told advisory committee members that the agency would not count the drug’s ability to reduce amyloid as an indication of its effectiveness. But in Monday’s decision, the F.D.A. announced that they had done just that.
“The FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain, and that reducing these plaques is likely to predict important benefits for patients,” said the Center for Drug Evaluation’s director Research of the FDA, Dr. Patrizia Cavazzoni, wrote on the agency website on the decision to use the drug under a program called. to provide accelerated admission.
However, members of the advisory committee said the committee was never told that the agency would consider approval based on amyloid reduction and that their opinion on this significant change was never sought. Dr. Perlmutter said the committee was “unaware of any additional information or statistical analysis to support approval”.
Dr. David Knopman, a clinical neurologist at the Mayo Clinic, wrote in an email to F.D.A. Officials who informed them on Wednesday of his resignation from the advisory committee: “The rationale for approving biomarkers in the absence of consistent clinical benefit after 18 months of treatment is unjustifiable.”
Dr. Knopman, who stepped out of the November meeting for serving as the lead investigator for one of the aducanumab trials, added that “the whole aducanumab approval saga, which culminated in accelerated approval on Monday, is a mockery “The role of the advisory board.
Dr. Peter Stein, who runs the F.D.A. The Center for Drug Evaluation and Research’s Office of New Drugs said in a briefing with reporters following the decision that the agency’s reviewers were convinced of what he described as a strong relationship between plaque reduction and potential clinical benefit with Aduhelm in his opinion it had not been seen in previous studies on drugs to eradicate amyloid.
Dr. Stein also defended the agency’s decision to approve the drug in such a broad patient population, saying it could be relevant beyond the early stages of Alzheimer’s.
“Since amyloid is a hallmark of the disease throughout its course, this drug is expected to provide benefits across this spectrum,” said Dr. Stone.
As a condition for admission, the F.D.A. said Biogen needed to conduct another clinical study and would give the company about nine years to complete. These terms apply to some experts as well. They say the drug will be fully available in these years, and if the new study does not prove the drug beneficial, the agency may, but is not required to, withdraw its approval and has not always done so for other drugs.
“The timeframe they gave for the so-called confirmatory study of nine years is problematic,” said Dr. Kesselheim, who also directs Harvard Medical School’s regulation, therapy, and law program. “During this time, the product is used a lot.”