Another FDA Advisor Blasts Aduhelm Approval
Johns Hopkins Center for Drug Safety and Effectiveness professor G. Caleb Alexander, who was on the advisory committee that voted 10-0-1 in 11/2020 not to recommend approval for Biogen’s Alzheimer’s treatment Aduhelm (aducanumab), has gone public with his concerns about the agency’s accelerated approval of the controversial drug. In addition to writing a New England Journal of Medicine editorial, Alexander was interviewed by HealthDay News, a section of U.S. News and World Report.
In the interview, Alexander said he was not surprised that the FDA accelerated approval led to considerable controversy, with some major academic medical centers saying they will not use the drug and FDA acting commissioner Janet Woodcock requesting an HHS inspector general’s review of the approval process. “I’m not surprised at the controversy because I think it’s a horrible decision,” he said. “I think FDA got it wrong. There are many gray areas to pharmaceutical regulation and there are many cases where FDA has to make tough calls. This wasn’t one of them. There wasn’t a lot of gray here. That’s the thing that’s so striking.”
Alexander said there remains a lot of concern and skepticism in the scientific community on whether Aduhelm works.
The professor says he does a lot of work with FDA and admires the work the agency and its staff do. And he says it’s still too soon to know if its reputation will suffer permanently from this decision. “I do a lot of work for FDA and I am proud of FDA,” he declared. “I think they get an extraordinary amount right. I’ve seen the high respect and high regard that regulators around the world hold FDA in. I know FDA is filled with thousands of outstanding scientists and staff that work tirelessly. I think that’s one of the things that make this case so striking. It’s at such odds with the typically good work and good science that FDA does.”
The article outlines Alexander's concerns with the way FDA changed the method in which clinical trial results were evaluated. He says the trials had been designed to assess whether Aduhelm helped slow or stop a decline in brain function among people with mild cognitive impairment or early Alzheimer’s disease. But for the accelerated approval, the agency focused on whether the drug was effective at lowering levels of beta amyloid. The problem, Alexander said, is that it isn’t clear that lowering amyloid helps ease symptoms or slow disease in people with Alzheimer’s.
“There are many, many experimental therapies that have been discontinued or abandoned that have targeted amyloid,” he said. “Several of these have demonstrated significant reductions in amyloid levels. In nearly all cases, there has been little to any evidence of cognitive gains associated with these reductions. You don’t have to look to other failed experimental therapies to have some doubts as to the suitability of amyloid as a surrogate. The case for aducanumab itself raises various concerns.”
Alexander also seconded the often-heard concern about an unnaturally close relationship between Biogen and FDA as seen at the advisory committee meeting. “The most striking thing was a jointly prepared review document at the committee,” he said. “I’ve never seen one of those before. I was quite surprised to come to the meeting and find a briefing that was prepared by Biogen with comments added by FDA for additional context. FDA didn’t prepare its own separate briefing document, which was highly irregular.”
He said some FDA staff at the advisory committee meeting referred to a “special work-stream collaboration” with Biogen. “It was never well defined exactly what that constituted and how that deviated from FDA’s protocol,” Alexander said. “It was implied there was an unusual collaboration between FDA and Biogen in moving forward” after the clinical trials initially failed.
He said advisory committee members also were troubled by significantly different versions of data presented by various FDA organizations. “It was hard to reconcile the almost unbridled enthusiasm of the medical review team with the serious scientific concerns expressed by the statistical review team,” he said. During the day of the meeting, I said it was almost [like] you’re watching TV and the audio and the video are out of sync. I think I used the words ‘strikingly discordant.’”
According to Alexander, a labeling change ordered by FDA after the 6/7 accelerated approval is not sufficient to ensure the drug is used appropriately. He said that as currently labeled, Aduhelm could be used on patients who would not be expected to receive any benefits. He also criticized the post-market effectiveness trial Biogen has to conduct because results won’t be available for nine years. “I think nine years is a heck of a long time to have to wait in order to understand whether this drug even works,” he said. He said he hopes the Centers for Medicare and Medicaid Services will require that more scientific evidence be gathered before the federal government will pay for Aduhelm, meaning that clinical trial data might come more quickly.
“I don’t think we should put too much stock in waiting nine years to figure out the results of a trial that may or may not address the key scientific and clinical and regulatory matters that, frankly, I believe should have been addressed prior to the product’s approval,” Alexander concluded.