In a powerful statement of disagreement with the Food and Drug Administration’s approval of Biogen’s controversial Alzheimer’s disease drug, three scientists resigned from the independent committee that advised the agency on treatment.
“This is possibly the worst FDA approval decision I can remember,” said Dr. Aaron Kesselheim, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, who presented his resigned Thursday after six years on the committee. .
He said the agency’s approval of the drug, aducanumab, which is marketed as Aduhelm, a monthly intravenous infusion that Biogen priced at $ 56,000 per year, was flawed “because of so much different factors, starting with the fact that there is no good evidence that the drug works.
Two other committee members resigned earlier this week, expressing dismay at the drug’s approval despite the committee’s overwhelming rejection after reviewing clinical trial data in November.
The committee found that the evidence did not convincingly show that Aduhelm could slow cognitive decline in people in the early stages of the disease – and that the drug could cause potentially serious side effects of brain swelling and brain bleeding. . None of the 11 committee members considered the drug ready for approval: ten voted against and one was uncertain.
“The approval of a drug that is not effective has serious potential to hinder future research into new treatments that may be effective,” said Dr. Joel Perlmutter, a neurologist at the Washington University School of Medicine in St Louis, who was the first to resign. of the committee.
“Additionally, implementing aducanumab therapy will potentially cost billions of dollars, and those dollars could be better spent developing better evidence for aducanumab or other therapeutic interventions,” added Dr. Perlmutter. .
Shannon P. Hatch, spokesperson for the FDA, said the agency does not comment on issues related to individual members of advisory committees.
Biogen plans to start shipping the drug in about two weeks. He expects more than 900 sites across the country, usually memory clinics that take in patients with dementia, to be ready to administer the drug soon.
The FDA’s decision to give it the green light, announced on Monday, marked the first approval of a treatment for Alzheimer’s disease in 18 years. Patient advocacy groups have been pushing for approval because there are only five other drugs available for the wasting disease and they only treat dementia symptoms for a few months.
But since at least last fall, several respected experts, including some doctors with Alzheimer’s disease who have worked on clinical trials for aducanumab, have said the available evidence raised significant doubts about the efficacy. of the drug. They also said that while it may slow cognitive decline in some patients, the suggested benefit – slowing symptoms for about four months out of 18 months – might be barely noticeable to patients and would not outweigh the risks. brain side effects.
Beyond the high price of the drug, the additional costs for screening patients before treatment and for the regular MRIs needed to monitor their brains for problems could add tens of thousands of dollars to the bill. Medicare should shoulder a large part of the bill.
“Giving patients a drug that does not work and of course carries significant risks that will require multiple MRIs at the cost of $ 56,000 per year puts patients in a very difficult position and also puts doctors in a difficult position,” he said. said Dr. dit Kesselheim.
Beyond their belief that the existing evidence in favor of Aduhelm is weak, the resigning advisory committee members – along with several prominent Alzheimer’s disease experts – objected to two major aspects of the decision to FDA approval.
One problem is that the FDA has approved the drug for a much larger patient group – anyone with Alzheimer’s disease – than many experts anticipated. Clinical trials have tested the drug only on patients with early-stage Alzheimer’s disease or mild cognitive impairment of the disease.
The other problem is that an important part of the FDA’s rationale for granting the approval was its claim that the drug’s ability to attack the amyloid protein in patients’ brains would help slow their cognitive symptoms.
“This is a major problem,” Dr. Perlmutter said.
While amyloid is considered a biomarker for Alzheimer’s disease because its accumulation in the brain is a key facet of the disease, there is very little scientific evidence that reducing amyloid can actually help patients. patients by relieving their memory and thinking problems.
Clinical trials of other amyloid-reducing drugs over more than two decades have failed to prove that the drugs slow cognitive decline. Therefore, many experts have said that it is especially important to have strong evidence of Aduhelm’s ability to treat symptoms.
In November, FDA officials told members of the advisory committee that the agency would not count the drug’s ability to lower amyloid as an indication of its effectiveness. But in Monday’s decision, the FDA announced it had done just that.
“The FDA has determined that there is substantial evidence that Aduhelm reduces beta-amyloid plaques in the brain and that reducing these plaques is reasonably likely to predict significant 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 Fast Track Approval.
But members of the advisory committee said the committee was never told the agency was planning to consider an approval based on amyloid reduction and that their opinion was never sought on this significant change. Dr Perlmutter said the committee was “not made aware of any additional information or statistical analysis that would support” the approval.
Dr David Knopman, clinical neurologist at the Mayo Clinic, wrote in an email to FDA officials advising them of his resignation from the advisory committee on Wednesday: “The biomarker’s rationale for approval in the absence of benefit constant clinic after 18 months of treatment is untenable. “
Dr Knopman, who recused himself from the November meeting because he had been the site’s principal investigator for one of the aducanumab trials, added that “the whole aducanumab approval saga , culminating Monday with fast-track approval, made a mockery of the role of the advisory committee.
Dr Peter Stein, who heads the Office of New Drugs at the FDA’s Center for Drug Review and Research, said in a briefing with reporters after the ruling that the agency’s reviewers were convinced by this which he described as a strong relationship between plaque reduction and potential clinical benefit with Aduhelm, which he said had not been seen in previous studies on drugs designed to remove amyloid.
Dr Stein also defended the agency’s decision to approve the drug for such a large group of patients, saying it could be relevant beyond the early stages of Alzheimer’s disease.
“Because amyloid is a hallmark of the disease throughout its course, this drug is expected to provide benefits across this spectrum,” said Dr Stein.
As a condition of approval, the FDA said it would require Biogen to conduct another clinical trial and give the company about nine years to complete it. These terms also apply to certain experts. They say that during those years the drug will be available without restriction, and if the new trial does not find the drug beneficial, the agency can revoke its approval, but it is not obligated to and has not. always done with other drugs.
“The timeline they’ve planned for the so-called nine-year confirmatory trial is problematic,” said Dr Kesselheim, who also heads Harvard Medical School’s program on regulation, therapeutics and law. “There is going to be a lot of use of the product during this time.”