A Harvard Medical School professor who resigned from a US Food and Drug Administration advisory panel over approval of a controversial Alzheimer’s treatment called the agency’s decision “perhaps the worst” drug authorization in its recent history.
Dr. Aaron Kesselheim is the third member of an FDA committee that advised against authorizing the new drug from Biogen to resign in the wake of the agency’s decision Monday to green light Aduhelm, despite widespread doubts in the medical community about whether it works.
Kesselheim said in an interview that the decision “sets an extremely low bar for what the FDA will consider to be evidence,” and could undermine the trust the medical community and patients have in the agency.
“It is important that the FDA maintains that trust by ensuring the drugs it gives validation to have reasonable science behind them,” he said. “Maybe the resignations will bring attention to the fact that there is concern in the scientific community that in these cases, that is not happening.”
His comments are part of a rising tide of dissent from scientists and policy experts who are calling for the FDA to explain its decision more clearly.
Kesselheim’s resignation from the committee followed similar moves by Dr. David Knopman, a neurologist at the Mayo Clinic, who resigned Wednesday, and Dr. Joel Perlmutter, a neurologist at Washington University in St. Louis, who quit on Monday.
The panel, known as the Peripheral and Central Nervous System Drugs Advisory Committee, voted 10-0 in November, with one panelist voting “uncertain,” that the results from Biogen’s late-stage clinical trial should not be relied on as “primary evidence of effectiveness” for the medicine.
A spokesperson for the FDA said the agency “doesn’t comment on matters related to individual members of advisory committees.” A spokesperson for Biogen said the company had no comment.
The approval was cheered by Alzheimer’s patients, their families, and advocates who have yearned for a drug more effective than the five previously approved to treat symptoms of cognitive decline. Biogen’s therapy is the first that promises to slow the progression of the fatal illness. Alzheimer’s afflicts an estimated 5.8 million Americans and is the sixth leading cause of death in the United States.
The resignations add to the cloud hanging over Aduhelm at a time when the authorization is a massive victory for Biogen, which at times in recent years saw its Alzheimer’s efforts on the verge of failure. The drug is the first new treatment for Alzheimer’s in almost two decades and could bring the Cambridge biotech billions in revenues.
In one of its trials, people given the Biogen drug declined 22 percent more slowly than those who received a placebo. The other trial failed to reach its goal. Nonetheless, Biogen concluded that the medicine slowed cognitive decline and that the key to effectiveness was giving patients a high enough dose.
The FDA approved Aduhelm under an “accelerated approval program,” which allows the agency to clear drugs even if there is uncertainty about whether they work. Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, said in the agency’s decision letter that it determined the drug was “reasonably likely” to benefit patients based on its ability to reduce the presence of beta amyloid.
Beta amyloid is a sticky plaque that builds up inside the brain, and some scientists believe it contributes to memory loss and cognitive decline associated with Alzheimer’s disease. In Biogen’s clinical trials, reducing beta amyloid was considered to be a “surrogate endpoint,” a measure reasonably likely to predict a clinical benefit.
That’s where Kesselheim takes issue.
“At the advisory committee, we actually talked about the surrogate, and the FDA said they are not considering beta amyloid to be a reasonable surrogate for efficacy,” he said.
According to a transcript of the meeting on Nov. 6, Billy Dunn, the director of the FDA office of neuroscience said, “We’re not using the amyloid as a surrogate for efficacy.”
“Something changed in their perspective in the last six months, and I think it would be important to have a full understanding of how and why that changed,” Kesselheim said.
Chris Morten, a lawyer and scientist who teaches at New York University School of Law, said the resignations are “a big deal.”
“Scientists can disagree, that does happen,” he said. “But it feels like the committee wasted its time. ... If [the FDA] was going to focus on the beta amyloid data, they should have asked [the panel] about it.”
Michael Carome, a director at public health watchdog Public Citizen, said in an interview that if the agency was going to alter its position on using amyloid as a surrogate for efficacy, it should have reconvened the expert panel. He said the resignations reflect “tremendous disappointment that the agency disregarded the advice, recommendations, and input.”
The FDA “did not want the input of the committee or anyone else in a public setting,” Carome said. “Undoubtedly, the agency would have gotten another negative vote.”
The panel Kesselheim served on reviews data about the safety and efficacy of drugs that aim to treat neurological diseases, such as Alzheimer’s. It is one of 47 advisory committees that provide independent advice and recommendations to the agency. While their conclusions are influential, the FDA is not bound to follow the recommendations of its advisory panels.
An expert in health policy and law as well as a physician at Brigham and Women’s Hospital, Kesselheim submitted his resignation to acting FDA Commissioner Janet Woodcock Thursday, saying the FDA did not properly take the panel’s advice into consideration.
“We do a lot of work to prepare for these [meetings], and put a lot of time into trying to make useful recommendations,” he said in the interview. “It was clear that all of this effort was not being absorbed at the FDA. ... Why are you bringing us together to do this if it is not going to make any difference at all in how things proceed?”
Meanwhile, criticism has been mounting against Woodcock, who was named the FDA’s acting commissioner in January by President Biden. She has worked at the agency for more than 30 years and was part of a similarly controversial FDA decision in 2016 involving another Cambridge drugmaker, Sarepta Therapeutics.
Woodcock pushed the FDA to approve Sarepta’s therapy for Duchenne muscular dystrophy, despite concern from the agency’s advisory committee, which had declined to recommend its approval. (As now, Kesselheim was among the advisory committee members skeptical of the drug’s potential.)
In a tweet on Thursday, Gregg Gonsalves, an assistant professor of epidemiology at Yale University and global health activist, called on Woodcock to resign, citing previous decisions that he said put “industry’s interests above the public health.”
“It is not trivial that three people resigned,” Gonsalves said in an interview. “It should send shock waves to the White House.”