Alzheimer's adcomm members question FDA: How can you use amyloid as the basis for an accelerated approval?
The FDA has not yet provided a persuasive scientific basis for declaring beta-amyloid as a reasonable surrogate for an accelerated approval, seven members of the adcomm that reviewed aducanumab and unanimously voted against its approval, wrote Wednesday in the New England Journal of Medicine.
Although the FDA has released key reviews on the internal dissent around the agency’s decision to OK Biogen’s new controversial Alzheimer’s drug, the experts (three of whom have since resigned from the adcomm in protest over the approval) explained how more than two dozen therapies based on this amyloid hypothesis have undergone late-stage clinical trials, and none have shown meaningful clinical benefit.
Top FDA officials who signed off on the approval, including neuroscience head Billy Dunn and CDER director Patrizia Cavazzoni, simultaneously published a letter to the editor of NEJM on Wednesday, noting they disagreed with the adcomm members’ assertion that the benefit of aducanumab is “highly uncertain.”
They pointed to their own JAMA editorial on the issue (Biogen’s data has not been published in a peer-reviewed journal yet) to explain how “a controlled dose–response clinical trial of aducanumab was positive for both clinical end points assessing mental functioning, and one of the two phase 3 trials was strongly positive, showing statistically significant effects on all four endpoints assessing mental and daily life function— standard end points in Alzheimer’s trials.”
The first author of the NEJM perspective Caleb Alexander, professor at Johns Hopkins Bloomberg School of Public Health, disagreed, telling Endpoints News that the evidence speaks for itself, and that he’s already heard people misstating that the evidence is clear when it is not. He said the sustained public outcry pushing back on the approval is a testament to how irregular the agency’s decision-making was.
“It is hard to reconcile the lack of convincing clinical benefit across two prospective randomized trials with this expectation of some clinical benefit of unknown magnitude over an unknown period,” Alexander and co-authors wrote. They also noted that the “scientifically unjustified label” for Aduhelm may lead to billions of dollars in unnecessary Medicare expenditures, even if CMS restricts coverage in some way.
Biogen yesterday called for a wide NCD on a public comment hearing with CMS, as well as earlier payer coverage before that decision is in the books. When that might happen is unclear, but some major medical centers like the Cleveland Clinic are declining to use Aduhelm and some insurers are declining coverage too.
The adcomm members also commended Janet Woodcock, interim FDA commissioner, for her decision to call for an Office of the Inspector General investigation, which they said “should be expeditiously performed, so as to learn how this regulatory failure occurred and to ensure that it doesn’t occur again.”