Adcomm gives big thumbs down to aducanumab

Regulatory NewsRegulatory News | 06 November 2020 |  By 

An advisory committee to the US Food and Drug Administration (FDA) handed the agency a resounding thumbs down not only on the Alzheimer’s disease candidate therapy aducanumab, but on the agency’s framing of the questions put before the committee and the contents of its briefing documents.
The advisory committee heard from FDA and from the sponsor, Biogen, in separate presentations, but an integrated briefing document was presented that, in the minds of some committee members, made it difficult to parse out FDA’s perspective and that of the sponsor.
The committee’s criticisms came with the caveat that Biogen and the FDA alike are in a difficult position: both pivotal aducanumab studies, 301 and 302, were stopped early for apparent futility by the data safety monitoring board, though later analysis of study 302 met some criteria for efficacy. The context for how to handle the conflicting data involves a seemingly endless stream of failed candidates that target beta amyloid, the protein whose plaques are seen via novel medical imaging techniques and in autopsies of patients with Alzheimer’s disease (AD).
The goal of early treatment with aducanumab is to slow the progression of AD, and no one attending the virtual meeting disputed the enormity of unmet need for an effective therapy for Alzheimer’s dementia.
However, FDA’s own statistical analyst, Tristan Massie, expressed reservations that even the most positive view of the pivotal studies would take aducanumab across the finish line for approval: “[T]here is no compelling, substantial evidence of treatment effect or disease slowing,” said Massie, calling for another study.
In a series of responses to four voting questions, the Peripheral and Central Nervous System (PCNS) Drugs advisory committee first rejected the notion that they could view just one clinical trial submitted by Biogen, apart from a second clinical trial. Trial 302 was assessed by FDA and Biogen as a positive trial; 301, a negative trial, was the one the committee was asked to disregard for the purposes of the voting question, which read: “Does Study 302, viewed independently and without regard for Study 301, provide strong evidence that supports the effectiveness of aducanumab for the treatment of Alzheimer’s disease?”
The implications were not lost on committee members. “I've real serious issues with how you can divorce the two studies from each other,” said committee member Michael Gold, MD, vice president for neurosciences development at AbbVie. Gold, a non-voting industry representative noted that he took “particular issue” with the question to the committee, “since both studies are identical in design. identical inclusion and exclusion criteria, and identical, presumably, in biomarker analysis.”
On this question, just one committee member registered a positive vote. Eight members voted “No,” and two members chose to press the novel “Uncertain” button that was offered for all voting questions at the meeting.
Another voting question asked whether a phase I study, dubbed 103, provided supportive evidence of the antibody’s effectiveness to treat Alzheimer’s disease. Here, the committee registered no positive votes; four members were uncertain, and the remaining seven registered a negative vote. Again, committee members went back to the question of whether study 302 alone sufficed to prove effectiveness. Said Aaron Kesselheim, MD, JD, of Harvard Medical School, “Since I don’t think that 302 provides convincing evidence of the effectiveness of the drug, it's challenging for me to think that study 103 provides supportive evidence.”
A third voting question asked whether Biogen had provided “strong evidence” of a pharmacodynamic effect on Alzheimer’s disease pathophysiology. Here, five members voted in the affirmative and six were uncertain; discussion affirmed that some clear reduction in amyloid proteins were seen.
The final question’s lengthy wording asked committee members to consider all three studies but to look to 302 for “primary evidence of effectiveness” of aducanumab to treat Alzheimer’s disease. The committee’s skepticism was manifest by ten negative votes and one “Uncertain” vote, with a round robin of comments looping back to a sense that the favorable study was being nudged forward for consideration not just by the sponsor, but by FDA.
“If you thought I was being critical you are absolutely correct,” said Scott Emerson, professor emeritus of biostatistics at the University of Washington, Seattle. “There was just no question that all of this was just terrifically one-sided, and again, I'm highly critical of the fact that the FDA presentation today was so heavily weighted to just giving the same conclusions that the sponsor did, and that there was not a presentation by the statistician who'd done a careful analysis” but who did not have an opportunity to give his own presentation, noted Emerson.
At least three committee members specifically thanked Massie, the statistician in their closing remarks. FDA is not obligated to follow the recommendations of its advisory committees, though it usually does.


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