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FDA releases fresh details on internal debate over controversial Alzheimer’s drug

Top agency officials concluded the treatment, assailed by outside critics as costly and possibly ineffective, was ‘reasonably likely’ to help patients

Marc Archambault was one of the first people to receive Aduhelm, a new Alzheimer's drug, outside of a clinical trial. The infusion was administered last week at Butler Hospital in Providence. (Jessica Rinaldi/Pool/Reuters)

The Food and Drug Administration on Tuesday released fresh details on why it approved a controversial Alzheimer’s drug in hopes of quelling a fierce debate over whether the agency should have cleared the costly treatment.

But the new information, included in interviews with agency officials and 83 pages of internal documents, might not quiet a furor over the drug Aduhelm that has drawn in Alzheimer’s doctors and patients, members of Congress, Medicare officials, and the agency itself.

The FDA approved the drug, also called aducanumab, on June 7, eight months after a harsh rejection of the treatment by an FDA advisory committee. Inside the agency, there were disagreements about how to handle the drug, which was designed to slow cognitive decline but had confusing data on effectiveness.

Eventually, the agency decided against full approval. One of the main clinical trials did not show a benefit to patients, but another late-stage trial and an early-stage trial showed the drug helped, agency officials concluded. They opted for an “accelerated approval” for the drug, saying its success at reducing amyloid beta plaque in the brain made it “reasonably likely” the treatment would slow cognitive decline in patients.

Peter Stein, director of the FDA’s Office of New Drugs, explained in one of the memos why the FDA decided to approve a drug whose benefits are far from certain.

“FDA has heard the voices of many patients afflicted with [Alzheimer’s disease] who express a desperate desire for an effective treatment,” Stein said. “… In summary, the medical need for new therapies to treat [Alzheimer’s disease], especially ones that target the underlying disease pathology, is substantial and urgent.”

That decision has drawn fire from some scientists who say even a conditional approval based on amyloid reduction was not warranted because numerous studies have shown that amyloid-targeting drugs don’t help patients. Amyloid beta plaque is a sticky substance that many scientists believe can damage and kill brain cells.

But in an interview Tuesday, acting FDA commissioner Janet Woodcock, who said she was not involved in the approval, defended the approach, saying she was “fairly confident” that reducing amyloid would help patients’ cognition. She noted that under accelerated approval, officials can approve a drug based on a surrogate endpoint — in this case, a reduction in amyloid — if it is “reasonably likely” to produce a clinical benefit.

“I feel it is a very solid accelerated approval,” she said.

Woodcock said there had been “a lot of despair” over amyloid-reducing drugs after multiple failures in clinical trials, but that recent data is providing a “clearer picture,” which is a correlation between the clearing out of amyloid plaque and a slowing of cognitive decline. While the drug class isn’t a cure, she said it is not correct to deem it a failure, either.

Stein added in an interview that the agency’s pharmacologists concluded that patients experienced clinical improvement from the drug when amyloid was reduced by a significant amount, but scant benefit when not much amyloid was reduced.

Matthew Schrag, an Alzheimer’s researcher at Vanderbilt University Medical Center, expressed skepticism about the argument, saying the FDA had not produced convincing new data that reducing amyloid benefited patients.

“The arguments are well-trodden and don’t account for the fact that the trials have not demonstrated a reproducible clinical benefit,” he said.

Three members of the advisory board quit after the FDA approved the drug, saying the FDA did not listen to their advice. One of them, Aaron Kesselheim, a Harvard Medical School professor, said the approval was the “worst drug approval decision” in recent history.

But Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, rejected the idea that the agency had ignored the outside committee. She said officials had listened to the panel and agreed the drug did not warrant a standard approval.

The monthly intravenous treatment is the first new Alzheimer’s treatment approved in almost 20 years, but its approval has been shadowed by a debate over its effectiveness and how it will be paid for. The drug has a list price of $56,000 a year per patient.

Some have praised the FDA for approving Aduhelm. They say the drug’s data contains signals that it will, indeed, help slow brain deterioration in early-stage patients. They argue that the field needs a jump-start because of the huge unmet need of Alzheimer’s patients.

James E. Galvin, an Alzheimer’s researcher at the University of Miami, said he believes accelerated approval was the right decision.

“It would have been nice if the second study had been positive,” Galvin said. “But I think there is a camp in neurology that thinks this makes sense and wants to see [effectiveness] demonstrated” in a confirmatory study.

A handful of drugs have been approved for Alzheimer’s, but they are designed to relieve symptoms, not to change the course of the disease, as Aduhelm is. About 6.2 million people in the United States have Alzheimer’s, a progressive, terminal disease.

The contentiousness over Aduhelm reflects its confusing history.

The drug’s maker, Biogen, in 2019 halted two late-stage trials after analysts concluded the studies would not reach their goals of slowing cognitive and functional impairment in Alzheimer’s patients. But several months later, in a sharp reversal, the company issued an analysis that used additional data and came to a different conclusion. In one of the clinical trials, that analysis found, people given the drug declined more slowly than those who received a placebo. The other trial failed to reach its goal.

The controversy has cast a spotlight on the leadership of the FDA and the continued lack of a permanent commissioner.

Sen. Joe Manchin III (D-W.Va.) last week wrote President Biden, asking him to dismiss Woodcock, the acting commissioner and to nominate an “acceptable” agency chief. Manchin has previously stated his opposition to Woodcock, who was the longtime head of the agency’s drug division, based on the way the agency approved opioids.

But Woodcock has strong support among the agency’s senior leadership, who report a restoration of calm at the agency after a tumultuous period during the Trump administration, when the FDA was under White House pressure to approve coronavirus vaccines before the November presidential election. And some patient groups have endorsed Woodcock, saying they believe she has been sensitive to people afflicted with diseases for which there are few treatments.

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