Sunday, January 16, 2022

Three FDA advisers resigned over approval of Alzheimer’s drug agency

In a powerful statement of disagreement with the Food and Drug Administration’s approval of Biogen’s controversial Alzheimer’s drug, three scientists resigned from the independent committee advising the agency on treatment.

“This is perhaps the worst approval decision the FDA has made that I can remember,” said Dr. Aaron Kesselheim, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, said he resigned after six years on the committee. .

He said the approval of the agency, aducanumab, marketed as Aduhelm, a monthly intravenous infusion costing Biogen $ 56,000 a year, was “wrong” due to so many different factors, due to the fact that no good evidence is not that the remedy works. ”

Two other members of the committee resigned earlier this week and expressed their dismay at the approval of the drug, despite the fact that the committee overwhelmingly rejected it after reviewing the clinical trial data in November.

The committee found that the evidence did not convincingly show that Aduhelm could slow down cognitive decline in people in the early stages of the disease – and that the drug could cause serious side effects from swelling of the brain and bleeding from the brain. None of the 11 members of the committee considered the drug approved: ten voted against it and one was unsure.

“Approval of a drug that is not effective has serious potential to harm future research on new treatments that may be effective,” said Dr. Joel Perlmutter, a neurologist at the Washington University School of Medicine in St. Louis. Louis, said. of the committee.

“In addition, the implementation of aducanumab therapy could cost billions of dollars, and these dollars could be better spent developing better evidence for aducanumab or other therapeutic interventions,” said Dr. Perlmutter added.

Shannon P. Hatch, an FDA spokeswoman, said the agency did not comment on cases involving individual members of advisory committees.

Biogen plans to ship the drug in about two weeks. It is expected that more than 900 sites across the country, typically memory clinics that see patients with dementia, will soon be ready to administer the drug.

The FDA’s decision to alleviate it, announced Monday, was the first approval of an Alzheimer’s treatment in 18 years. Advocacy groups for patients demanded approval because there are only five others medication available for the debilitating condition and they only treat symptoms of dementia for a few months.

But since at least last fall, several respected experts, including some Alzheimer’s doctors working on clinical trials for aducanumab, said the available evidence raised significant doubts as to whether the drug was effective. They also said that even though it may delay cognitive decline in some patients, the proposed benefit – a slowing of symptoms for about four months to 18 months – for patients is hardly noticeable and does not increase the risks of side effects. brain does not.

In addition to the drug’s steep price tag, additional costs for examining patients before they are treated and for regular MRIs needed to monitor their brains for problems can add tens of thousands of dollars to the sheet. Medicare is expected to shell out a large portion of the bill.

“Giving patients a medicine that does not work and of course carries significant risks that require multiple MRIs at $ 56,000 a year puts patients in a very challenging position and also puts doctors in a difficult position,” said Dr. Said Kesselheim.

In addition to their belief that the existing evidence in favor of Aduhelm was weak, the resigning advisory committee members, as well as several leading Alzheimer’s experts, objected to 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. The clinical trials tested the drug only on patients with an early stage of Alzheimer’s or mild cognitive impairment of the disease.

The other issue is that an important part of the FDA’s reason for approval was that the ability of the drug to attack the amyloid protein in patients’ brains would slow down their cognitive symptoms.

“This is a big problem,” said Dr. Perlmutter said.

Although amyloid is considered a biomarker of Alzheimer’s disease because its accumulation in the brain is an important aspect of the condition, there has been very little scientific evidence that reducing amyloid can help patients by reducing their memory and thinking problems. relieved.

Clinical trials with other amyloid-reducing agents for more than two decades could not provide evidence that the drug slowed cognitive decline. Consequently, many experts have said that it is especially important to have good evidence for Aduhelm’s ability to address symptoms.

In November, FDA officials told advisory committee members that the agency would not count the ability of the drug to reduce amyloid as an indication that it could be effective. But in Monday’s decision, the FDA announced that it had done just that.

“The FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plates in the brain and that reducing these plates is likely to predict important benefits for patients,” said the FDA’s director of the Center for Drug Evaluation and Research. , dr. Patrizia Cavazzoni, wrote on the agency’s website about the decision to make the drug available under a program called accelerated approval.

According to advisory committee members, the committee was never told that the agency intends to consider approval based on the reduction of amyloids and that they are never asked about this important change. Dr Perlmutter said the committee was “not made aware of any additional information or statistical analyzes that would support it”.

Dr. David Knopman, a clinical neurologist at the Mayo Clinic, wrote in an email to FDA officials Wednesday informing them of his resignation from the advisory committee: ‘Biomarker justification for approval in the absence of consistent clinical benefit after 18 months of treatment indefensible. ”

Dr Knopman, who withdrew from the November meeting because he served as a lead investigator for one of the aducanumab trials, added that “the whole saga about the approval of aducanumab, which culminates Monday in the accelerated approval,” a mockery ”of the role of the advisory committee.

Dr Peter Stein, who heads the FDA’s Center for Drug Evaluation and Research’s Office of New Drugs, said in a briefing with reporters after the decision that agency judges were convinced by what he described as a strong link between the reduction of plaque and potential clinical benefit with Aduhelm, which according to him has not been seen in previous studies of drugs designed to clear amyloid.

Dr. Stein also defended the agency’s decision to approve the drug for such a broad group of patients, saying it may be relevant as the early stage of Alzheimer’s.

“Because amyloid is a hallmark of the disease throughout its course, it is expected that this drug will benefit the entire spectrum,” said Dr. Stein said.

As a condition of approval, the FDA said that Biogen would need another clinical trial and that the company would allow about nine years to complete it. These terms also apply to some experts. They say the drug will be available without restriction during those years, and if the drug is not beneficial, the agency can revoke the approval, but it is not necessary and has not always done so with other drugs.

“The timeline for nine years for the so-called confirmation test is problematic,” said dr. Kesselheim said, who also leads the Harvard Medical School program on regulation, therapy and legislation. “The product will be used a lot during that time.”

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