The advisory committee, whose members repeatedly criticized the FDA for what they said was an overly positive view of the drug, met in an all-day session that included emotional testimony from desperate patients and families who pleaded for approval of the medication.
One family member, Jim Taylor, said his wife, Geri, showed “extremely slow” progression of the disease while she was in a clinical trial for the drug, called aducanumab, for four years. But when the trial was halted, he said, her cognitive decline rapidly accelerated.
Scott Emerson, a biostatistician from the University of Washington, blasted the FDA as being “terrifically one-sided" in making its arguments for the drug and seeming to de-emphasize information that cast doubt on its efficacy. He and others chastised the FDA for not explaining why the agency’s position on the drug was so upbeat when an FDA statistician wrote a blistering critique of it. They were unhappy that the reviewer, Tristan Massie, did not make a presentation at the meeting.
In his written review, Massie concluded that there was conflicting evidence of the drug’s efficacy, because one major study indicated that it was effective and another showed scant benefit. Only a third study could clear up the conflicting findings, he wrote.
By contrast, the FDA’s official position found that the single positive study, which was halted and reanalyzed with additional data, was sufficient to serve as the primary evidence of efficacy, with other studies providing additional support. That position was outlined by Billy Dunn, the acting director of the agency’s Office of Neuroscience, which is reviewing the drug. At the meeting Friday, Dunn emphasized the huge need for new Alzheimer’s treatments and the importance of agency flexibility in considering medications.
The agency has said it will decide by early March whether to approve the drug, which is administered intravenously once a month. The FDA is not required to follow the recommendations of outside advisers but often does.
The drug has strong support from many Alzheimer’s advocates. Joanne Pike, the chief strategy officer for the Alzheimer’s Association, said at the meeting that requiring another late-stage trial would be a mistake, because four more years would go by before the drug was potentially available.
“A four-year delay is too long to wait for millions of Americans facing a progressive, fatal disease,” she said.
The skepticism expressed by many of the FDA advisers echoed the views of David S. Knopman, a behavioral neurologist at the Mayo Clinic, who said in a comment filed to the committee that evidence of aducanumab’s benefiting patients is “terribly weak.” He added that “one trial positive and one negative does not constitute preponderance of evidence.”
“Perfection may be the enemy of the good, but for aducanumab, the evidence doesn’t even rise to ‘good,’ ” he said. “The evidence shows it will offer improvement to none, it will harm some of those exposed and it will consume enormous resources.”
About 5.8 million people in the United States have Alzheimer’s. Biogen, the maker of aducanumab, has said perhaps 1 million would be eligible to take the drug.
The medication is designed to treat patients in the earlier stages of the disease. If it is ultimately cleared, it would be the first drug approved to slow deterioration in brain function, not just to ease symptoms. But the treatment does not cure Alzheimer’s or reverse it, or prevent it from eventually progressing.
Aducanumab is a monoclonal antibody that targets amyloid beta, a protein that can build up in the brain and has been considered a possible cause of Alzheimer’s. The drug is developed from immune cells taken from older people who do not have cognitive problems.
The advisory committee concluded that there was evidence that the drug targets amyloid beta but said it was not clear whether that, in turn, successfully treats Alzheimer’s.
Aducanumab’s path has been bumpy. After an early trial produced promising data, Biogen began two large trials to test the drug’s efficacy. The company stopped the trials in March 2019 after a “futility analysis” indicated that the drug did not work. But Biogen later took another look at the results, adding more data. The new look suggested that people in one trial who received the highest dose experienced slower cognitive decline.
The FDA, when considering whether to approve a drug, typically requires “substantial evidence” that it is effective — as shown in data from two large, well-controlled clinical trials. But the agency sometimes clears products on the basis of just one large trial and some smaller ones.
Thomas Wisniewski, a neurologist at NYU Langone Health, one of the clinical trial sites for the drug, said FDA approval would be a milestone for Alzheimer’s patients and their families.
“It showed clear and significant cognitive benefits, which is unheard of” in a late-stage trial for Alzheimer’s, he said.
The drug, if cleared, would be a $1 billion-a-year blockbuster, analysts say. That high cost, said Walid Gellad, the director of the University of Pittsburgh’s Center for Pharmaceutical Policy and Prescribing, lends urgency to the arguments about its efficacy.
“If this were a cheap drug, people would be a lot less worried about it, as long as it did not have big side effects,” he said. “But there is no mechanism in the United States for drugs to be priced conditionally based on uncertainty about their value.”