The advisory panel that reviewed the controversial and expensive Alzheimer's disease drug Aduhelm criticized the Food and Drug Administration for approving it, saying that the agency used a standard not supported by evidence.
The advisory committee, known as the Peripheral and Central Nervous System Advisory Committee, examined the evidence for Aduhelm in November 2020 and recommended against it. In June, the FDA overruled the committee and approved Aduhelm, produced by drugmaker Biogen, using the “accelerated approval” pathway, which is intended to provide early access to patients with serious disease.
The committee said in a just-released article in the New England Journal of Medicine that the “FDA’s decision is at odds with the evidence and with the agency’s biostatistical review."
The committee criticized the FDA’s use of beta-amyloid as a measure of improvement in Alzheimer’s patients. Beta-amyloid is a sticky plaque common in the brains of Alzheimer’s patients that is believed by some scientists to interfere with the ability of brain cells to process information.
The FDA used beta-amyloid as a “surrogate marker” in tests of Aduhelm. A surrogate marker is one that is used as a substitute for a clinically meaningful result. In the case of Alzheimer’s disease, reduction of beta-amyloid would be a surrogate if it reliably predicted cognitive improvement in patients.
“The FDA has never carefully and comprehensively explained the scientific rationale for the use of beta-amyloid as a surrogate,” said Dr. Caleb Alexander, an epidemiologist at Johns Hopkins Bloomberg School of Public Health and a member of the advisory committee. “There are many lines of evidence calling beta-amyloid into question as a surrogate.”
One such line of evidence that the committee examined in its article is previous treatments that targeted beta-amyloid in Alzheimer’s patients. More than two dozen drugs have been developed based on the hypothesis that the accumulation of beta-amyloid in the brain causes Alzheimer’s disease. None of the trials of those drugs have produced any evidence that lower levels of beta-amyloid provide cognitive benefits for Alzheimer’s patients.
The advisory committee contends that it was never consulted about the suitability of beta-amyloid as a surrogate marker and was told by an FDA scientist that it was “not using the amyloid as a surrogate for efficacy.”
Aduhelm did reduce the amount of beta-amyloid in two trials, but in only one trial was there any sign of cognitive improvement in the patients. The improvement was so small that the advisory committee declined to approve the drug.
“No one goes to bed at night wondering about their amyloid levels,” Alexander said. “What matters at the end of the day to patients and their loved ones is whether their signs and symptoms of Alzheimer’s disease are improving.”
The FDA’s approval of Aduhelm has proven so controversial that the head of the FDA, Janet Woodcock, has called for the Office of Inspector General to conduct an investigation. The House and the Senate have also announced hearings on the matter.
The list price of the drug is $56,000 for a year's supply. Outside analysts have warned that its use could add tremendous costs for the federal government.
“What we need is full transparency and we need it quickly because we cannot afford to make this mistake again,” Alexander said. “It’s important to understand what happened and how the train went off the rails.”
The other committee members included Dr. David Knopman, Dr. Scott Emerson, Dr. Bruce Ovbiagele, Richard Kryscio, Dr. Joel Perlmutter, and Dr. Aaron Kesselheim. Knopman, Perlmutter, and Kesselheim all resigned from the committee in protest over the approval.
Alexander explained why he has remained on the committee.
“Resigning expresses dissatisfaction with the FDA process, and by now, the FDA has heard that loud and clear,” he said. “I can help more by staying and assisting the FDA in fixing this.”
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Original Author: David Hogberg