Uproar Greets FDA’s Aduhelm OK for Alzheimer’s
[Report by Jim Dickinson and David McFarland] FDA’s 6/7 accelerated approval for Biogen’s Alzheimer’s drug Aduhelm (aducanumab-avwa) has provoked an immediate uproar among stakeholders over whether it undermines the agency’s coveted gold standard of scientific objectivity. Striking a positive lead from the legal constituency, Hyman, Phelps and McNamara attorneys Frank J. Sasinowski, and James E. Valentine, both former FDAers themselves, suggest that the approval could be a sign that the agency’s flexibility standard has broadened during the Covid-19 pandemic with its reliance on the emergency use authorization (EUA) provision. Writing in a 6/8 FDA Law Blog post, they say they believe that FDA’s endorsement of the accelerated approval pathway for the Alzheimer’s drug could be a “harbinger for future agency actions, especially in neuropsychiatric conditions.”
They write that what really stands out with the Biogen approval is the “reliance on an unvalidated surrogate that is merely ‘reasonably likely to predict’ clinical benefit (i.e., it is a surrogate that is not so well established that it would support a full, or traditional, approval). This is, in fact, accounting for ‘potential benefits’. So, maybe yesterday’s action is in some way a hidden outgrowth of the agency’s new experience with and comfort from exercise of its EUA authority in these Covid times. It may well be that FDA’s Covid experiences have revealed to FDA that it could employ that ‘potential benefit’ part of the EUA standard in the context of accelerated approval…. such an epiphany could come from being hidden in plain sight all this time. Perhaps someday we will look back and count today’s action as the harbinger of those unexpected findings and this epiphany that led to a new way to position accelerated approval as a finding the potential benefits of a therapy outweighed its known and potential risks.”
Meanwhile, other FDA watchers are reacting vigorously, with many pointing to the unusual turn to accelerated approval following FDA’s 11/2020 Peripheral and Central Nervous System Drugs Advisory Committee meeting that voted down Biogen’s study data. Interestingly, panel members were not asked for their input on whether accelerated approval was a viable option. Panel members also were concerned about FDA’s statistical reviewer, Tristan Massie, who wrote in a briefing paper that the one positive trial of aducanumab could not overcome the negative one (see earlier story). “There is no compelling evidence of treatment effect or disease slowing and … another study is needed to confirm or deny the positive study and the negative study,” she wrote. FDA Office of Neuroscience director Billy Dunn told the panel that issues with the negative trial don’t “meaningfully detract from the persuasiveness” of the positive trial. He suggested the drug might still have a clear path to approval.
Harvard Medical School professor Aaron Kesselheim weighed in on the controversial decision, posting on Twitter: “Accelerated approval is not supposed to be the backup that you use when your clinical trial data are not good enough for regular approval.” The Institute for Clinical and Economic Review (ICER) also criticized the approval. “Our review of the evidence was concordant with that of many independent experts: current evidence is insufficient to demonstrate that aducanumab benefits patients,” ICER said. “The avenue forward has seemed clear: another study would be needed to reduce the substantial uncertainty about the drug’s effectiveness, a requirement of even greater priority because of the drug’s common and potentially serious side effects. However, instead of waiting for such a trial, the FDA chose to move the goalposts and approve aducanumab based on the surrogate outcome of removing amyloid from the brain rather than the patient-centered outcome of clinical benefit, which has been required of all previous emerging treatments for Alzheimer’s disease. Many other drugs have been shown to remove amyloid from the brain, yet have failed to help patients, making this decision all the more puzzling.
“Additionally,” ICER continued, “the FDA granted approval for treatment of all patients with Alzheimer’s disease despite the fact that the drug has been studied only in patients with mild cognitive impairment (MCI) and mild dementia. Trials of other amyloid therapies in later Alzheimer’s disease have all failed. Thus, there appears to be no evidentiary basis to justify the FDA’s decision to extend the label of aducanumab beyond the study populations.”
Naturally, patient groups welcomed FDA’s shift to approve the Alzheimer’s therapy under accelerated approval. The Alzheimer’s Association had this to say: “This approval is a victory for people living with Alzheimer's and their families. This is the first FDA-approved drug that delays decline due to Alzheimer’s disease. This means individuals may have more time to actively participate in daily life, have sustained independence and hold on to memories longer... Aducanumab addresses Alzheimer's in a new way compared to currently approved drugs. This therapy slows progression of the disease, rather than only addressing symptoms.”
Additionally, the abovementioned Hyman Phelps FDA Law Blog post sees the Biogen approval as a reassuring endorsement of the accelerated approval program after recent concerns were raised about FDA conducting post-approval reviews of oncology accelerated approval products (see story). Statements by senior FDA officials supporting the Biogen approval “emphasized the utility of accelerated approval in devastating conditions where the needs for treatments are urgent,” the post contends. “This is certainly the case in Alzheimer’s disease — and as FDA articulates in its December 2019 draft guidance on substantial evidence of effectiveness, is exactly the context in many rare diseases. The attorney authors also believe the Biogen approval shows that FDA “intends to include the accelerated approval pathway in its armamentarium of ways in which to exercise flexibility.”