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

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In a marked disagreement over the Food and Drug Administration’s approval of Biogen’s controversial Alzheimer’s drug earlier this week, three scientists stepped down from the independent committee that advised the agency on the treatment.

“This could be the worst regulatory decision the FDA has made 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 and expressed dismay at the drug’s approval, although the committee overwhelmingly opposed it after reviewing clinical trial data in November.

The committee found that the evidence was inconclusive that Aduhelm could slow cognitive decline in people with the early stages of the 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.

“In addition, 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, an FDA spokeswoman, said the agency does not comment on matters that affect 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 FDA’s decision to give the go-ahead was the first approval of an Alzheimer’s treatment in 18 years. Patient advocacy groups had pushed for approval because there are only five other drugs for the debilitating disease and they only treat dementia symptoms for a few months.

But since last fall, several respected experts, including some Alzheimer’s doctors who worked on the clinical trials of aducanumab, have said that the evidence available casts significant doubts on the drug’s effectiveness. 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 that.

“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 the 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 FDA’s approval decision.

One problem is that the FDA has 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 key part of the FDA’s rationale for granting the 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, FDA 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 FDA announced that it did 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 director of the Center for Drug Evaluation and Research of the FDA, Dr. Patrizia Cavazzoni wrote on the agency’s website about the decision to make the drug available under a program called accelerated approval.

The advisory committee members said, however, that the committee was never advised that the agency would be considering 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 Mayo Clinic, wrote in an email to FDA officials informing them of his resignation from the advisory committee on Wednesday: “Biomarker justification for approval in the absence of consistent clinical benefit 18 months of treatment is “unreasonable.”

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 heads the Office of New Drugs at the FDA Center for Drug Evaluation and Research, said in a briefing with reporters following the decision that the agency’s reviewers were convinced of what he saw as a strong relationship between plaque reduction and potential clinical benefit described by Aduhelm, which he said had not been seen in previous studies of amyloid-eradicating drugs.

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 of approval, the FDA said Biogen would conduct another clinical trial and give the company approximately nine years to complete. These terms apply to some experts as well. They say the drug will be available without restriction during these years, and if the new study doesn’t 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 will be used a lot.”

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