The drug was approved on June 7 under the agency’s accelerated approval pathway, despite the agency’s Peripheral and Central Nervous System Drugs Advisory Committee voting against the drug in November 2020 and having been assured at that time the agency was not considering an accelerated approval.
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More details are emerging over the U.S. Food and Drug Administration (FDA)’s controversial approval of Biogen’s Aduhelm (aducanumab) for Alzheimer’s disease. The drug was approved on June 7 under the agency’s accelerated approval pathway, despite the agency’s Peripheral and Central Nervous System Drugs Advisory Committee voting against the drug in November 2020 and having been assured at that time the agency was not considering an accelerated approval.
An accelerated approval allows for surrogate endpoints—in the case of Aduhelm, removal of amyloid plaques—instead of clinical evidence of improvement in cognition and memory. It also requires post-marketing studies to be conducted, although Biogen has nine years to run those studies. Three members of the advisory committee have resigned over the approval.
The new details about the agency’s procedures include interviews with agency insiders and 83 pages of internal documents. According to the documents, there were disagreements by officials on how to deal with the drug, partially because the data on its effectiveness was confusing. One of the primary clinical trials failed to show clinical benefit while another late-stage study and an early-stage trial suggested the drug helped.
In one of the internal memos, Peter Stein, director of the FDA’s Office of New Drugs, wrote, “FDA has heard the voices of many patients afflicted with [Alzheimer’s disease] who express a desperate desire for an effective treatment. … 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.”
Numerous researchers are pushing back on the decision to approve the drug based on decrease of amyloid, arguing that a number of studies show that drugs that target and successfully clear amyloid don’t result in clinical improvements.
Janet Woodcock, acting FDA commissioner, says she was not involved in the approval, but defended it, saying she was “fairly confident” that clearing amyloid helps patients’ cognition. “I feel it is a very solid accelerated approval,” she said.
Matthew Schrag, a researcher into Alzheimer’s at Vanderbilt University Medical System, does not believe the FDA has produced good new data showing that cutting amyloid benefits patients. “The arguments are well-trodden and don’t account for the fact that the trials have not demonstrated a reproducible clinical benefit,” he told The Washington Post.
This is far from the first time Woodcock has been involved in a controversial FDA decision. In 2016, while then director of the FDA’s Center for Drug Evaluation and Research (CDER), she pushed through an approval for Sarepta Therapeutics’ Exondys 51 (eteplirsen) for Duchenne muscular dystrophy (DMD) after a highly controversial process, and against the recommendations of the agency’s acting chief scientist, Luciana Borio, and Ellis Unger, director of the office of drug evaluation. Like Aduhelm, it was approved under an accelerated approval process.
West Virginia Senator Joe Manchin III (D-W.Va.) recently sent a letter to President Joe Biden, asking the president to fire Woodcock from the acting commissioner position over the Aduhelm decision. The nonprofit watchdog, Public Citizen, also sent a similar letter to Xavier Becerra, secretary of the Department of Health and Human Services (HHS), demanding her resignation and that of FDA officials, Patrizia Cavazzoni, director of CDER, and Billy Dunn, director of CDER’s Office of Neuroscience (ON).
“The FDA’s decision to approve aducanumab for anyone with Alzheimer’s disease, regardless of severity, showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency,” said Michael Carome, director of Public Citizen’s Health Research Group, in the letter. “The sheer recklessness of the FDA’s approval of aducanumab cannot be overstated. This decision is a disastrous blow to the agency’s credibility, public health, and the financial sustainability of the Medicare program.”
Despite this, Woodcock has broad support within the agency, particularly after the Trump administration’s difficult relationship with the agency, when President Trump was pressuring it to approve COVID-19 vaccines before the November presidential election and pushing for approval of unproven treatments, such as malaria drug hydroxychloroquine. Some patient groups have also endorsed Woodcock, appreciating her sensitivity to people afflicted with diseases for which there are few effective treatments.
Although there is broad criticism of the approval, it is far from unanimous. James E. Galvin, an Alzheimer’s researchers at the University of Miami, told The Washington Post that he believed the accelerated approval was the right decision.
“It would have been nice if the second study had been positive,” he 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.
