Executive Summary

The intensely negative advisory committee for Biogen’s proposed Alzheimer’s therapy was a shocker. Would it have happened if US FDA had been able to convene an in-person event instead of a ‘virtual’ one?

Center for Drug Evaluation & Research Deputy Director for Clinical Science Robert Temple has not yet participated in a “virtual” advisory committee meeting hosted by the US Food & Drug Administration, but he is concerned about the impact of the format.

“As a general matter, it matters when people are in the room,” Temple said during a Prevision Policy/Friends of Cancer Research event recorded on 20 October. “They look at each other. They talk to each other. They think of things they didn’t think of before.”

“I think mutual presence matters,” he said. “I don’t know for sure that advisory committees are weakened by this, but I am worried about it.”

Those worries may have been borne out two weeks later during a very high-profile event: the Peripheral & CNS Drugs Advisory Committee review of the potential first Alzheimer’s disease modifying agent aducanumab. The meeting looked set to be a landmark event, based on a robustly positive FDA clinical review of Biogen, Inc.’s once-failed trials – but played out as an extraordinarily negative event for both the sponsor and the agency. (Also see “What Did US FDA Do Wrong In Its Review Of Aducanumab? AdCom Members Have A List” – Pink Sheet, 7 Nov, 2020.)

Whatever the scientific merits and the “right” outcome, there is no question but that the virtual format, which did not include video, was not conducive for this particular kind of review: re-analyzed trials – one successful, one not – for a product designed to address a significant patient population with potentially vast medical and commercial implications. Several panelists referred to the magnitude of the decision the committee was being asked to make, and the day likely would have gone better for FDA in an in-person setting.

FDA’s approach to presentations in the virtual format also backfired. While the agency’s clinical team was clearly positive on the application, the statistical reviewer had a very different view. Both views were released ahead of the meeting – but during a “normal” in-person meeting, the dissenting view would have been presented during the morning session.

Instead, Office of Neuroscience Director Billy Dunn was the sole FDA presenter, and what could have been an important statement by the FDA decision maker of his view after weighing different internal perspectives instead sounded to committee members like a simple repeat of the sponsor’s position – and almost an effort to obscure the dissenting view.

The committee, of course, would always have been free to side with the dissenting view and against Dunn. (See sidebar.) But it is almost unimaginable that it would have done so with so much vitriol if the FDA team was literally sitting at the same table with them.

Another flaw highlighted by FDA’s Temple about virtual meetings is his sense that fewer people participate. “Everybody is around,” he said, “but the number of people talking is reduced. I think there is less interaction. I’m not entirely sure why that is, but I think it is true.”

That also seemed to be a factor in the aducanumab review, with two committee members (University of Washington biostatistician Scott Emerson and Johns Hopkins epidemiologist Caleb Alexander) dominating the discussion with their negative views of the data and FDA’s review.

The virtual format also likely blunted the emotional impact of the open public hearing. The session featured an overwhelming number of patients and caregivers who supported approval of aducanumab. Some said symptoms of Alzheimer’s returned after stopping treatment and when the trials concluded. The Alzheimer’s Association argued in favor of approval, noting that another clinical trial would delay access to aducanumab by another four years.

Those anecdotal voices are always difficult for an advisory committee to weigh – but it is also much harder to look patients in the face and tell them you don’t believe the therapeutic effect they see with a new treatment is really there.

https://pink.pharmaintelligence.informa.com/PS143281/Flaws-Of-Virtual-A…