The U.S. Food and Drug Administration approved the first new Alzheimer’s drug in decades over the objection of agency statisticians who said there was insufficient evidence to support approval, according to newly released internal memos.
In the internal memos released Tuesday, FDA officials discussed whether to approve the drug from Biogen Inc. over objections from the agency’s drug statistics office, which said that clinical trial data fell short of the proof typically required to put a new product on the market.
Ultimately, top officials decided that the evidence indicating that the drug worked, while inconclusive, was strong enough to allow doctors and patients to decide for themselves whether to take it, according to the memos.
"FDA, then, is faced with a situation where the available evidence on the clinical endpoints is short of what we would require for standard approval of aducanumab," wrote Peter Stein, director of the FDA’s office of new drugs, in a memo detailing his support for approval. "At the same time, patients with [Alzheimer’s] have a serious, progressive, ultimately fatal disease and are desperate for treatments."
The FDA made public its internal deliberations as it faces criticism from some doctors and scientists over the June 7 approval of the drug, called Aduhelm.
The critics say the FDA ignored the scientific standards it typically holds drugmakers to and could prompt the federal government to spend billions of dollars on a drug that may not work.
"While I fully support the Center’s recent decision to approve the therapy, I acknowledge that there are different opinions about this decision, including within FDA, and there likely will continue to be questions around our process for review and the data we considered to support the approval," said FDA Acting Commissioner Janet Woodcock. "In the end, an experienced group of medical reviewers at FDA concluded that there was sufficient evidence to approve the Alzheimer’s therapy via the accelerated approval pathway."
Supporters say the FDA decision provides a lifeline to patients who have lacked any medicine promising to slow the progression of Alzheimer’s, and that the decision could spur the development of more, better medicines.
The agency usually releases approval documents after a decision, though not typically as quickly as it did this time. The 83 pages of memos appear to be a portion of the FDA’s deliberations, largely reflecting the exchanges of top officials.
Tristan Massie, a biostatistics reviewer for the FDA, "does not agree that the totality of the data provides sufficient evidence to support the efficacy of aducanumab in Alzheimer’s disease and does not recommend approval," one of the internal documents shows.
Patrizia Cavazzoni, the FDA’s top-ranking drug-evaluation official, wrote in another memo that the agency’s drug biostatistics office "provided documentation for its recommendation that substantial evidence of effectiveness had not been provided in the application."
That office’s full dissenting analysis wasn’t included in the materials made available Tuesday, but portions of it were.
Despite the objections, Cavazzoni wrote that Biogen had met the requirements for an "accelerated approval," a type of regulatory clearance that allows a drug to be marketed even when there remains uncertainty about its clinical benefit if it fills an unmet need for a serious disease and has effects against a biological sign of the disease.
Cavazzoni wrote that Aduhelm met that standard because of its effect of reducing a sticky substance called amyloid which "is reasonably likely to predict clinical benefit."
Some doctors and scientists say targeting the amyloid plaques hasn’t been proven to slow Alzheimer’s. Some members of a panel of advisers that recommended the FDA reject the drug have resigned from the committee, citing the agency’s approval.
Biogen listed the price of Aduhelm at $56,000 a year, and patients and Medicare could also face testing charges.
About six million Americans suffer from Alzheimer’s, a progressive condition that robs people of their memories and cognitive abilities. Biogen has said that as many as two million of them may benefit from the medicine.
The FDA approval sent Biogen’s stock soaring. The company has said it expects only minimal revenue from the drug this year, in part because of the logistical challenges in administering the medicine, but that sales would begin to increase next year.
Analysts estimate sales of $946.3 million in 2022, according to FactSet. Sales are seen growing to $5.2 billion in 2026.
The memos show FDA officials attempting to balance the subpar study data for Aduhelm with the desire of Alzheimer’s patients and their families to try any new treatment that might help.
"There remains residual uncertainty regarding clinical benefit," Stein wrote. But if the FDA were to wait for the company to finish another clinical study, "any approval would occur after a multiple year delay" and patients "could suffer irreversible loss of brain neurons and cognitive function and memory," he wrote.
The FDA said it plans to release more documents regarding its decision making as early as next week.
The FDA’s approval was based primarily on two large Phase 3 clinical trials launched by Biogen to prove its drug helped slow the cognitive decline of people with early-stage Alzheimer’s.
In March 2019, the company halted the studies early after an independent monitoring board concluded the drug was unlikely to help patients.
Seven months later, however, the company made a surprising reversal and said it was now planning to seek FDA approval after conducting additional analyses of trial data that came in after the studies were halted. The company said its analyses found the drug was successful in one study but failed in the second.
The FDA memos provide some new details on Biogen’s about-face. In June 2019, the company met with FDA officials and both sides agreed the studies shouldn’t have been stopped, according to a "summary memorandum" document.
At the meeting, FDA officials recommended that Biogen analyze the studies further to understand if it was still possible to draw conclusions from the data, despite the halt of the trials and conflicting results.
Several months later, in October 2019, the agency and company met again and agreed that the studies could still be used to evaluate the drug’s effectiveness, according to the memo.
The following day, on Oct. 22, Biogen announced it would seek approval for the medicine, sending up its share price and adding billions of dollars to its market value.
The company had been quietly re-examining the data for months, but didn’t have the confidence to move forward until the latest meeting with FDA officials, Biogen Chief Executive Michel Vounatsos said in an interview at the time.