At a time when the FDA can little afford another reputation challenge, an advisory panel review for Biogen's much-debated Alzheimer's candidate turned out to be a debacle—and the fallout was immediate.
Scientists, researchers and analysts piled on the agency after the panel of outside experts first roasted the agency's hype for aducanumab and then capped it off with a resounding “no” vote for approval.
The FDA's image is already under a cloud after this year's emergency authorizations of questionable COVID-19 treatments—under apparent political pressure. FDA Commissioner Stephen Hahn was forced to apologize for misrepresenting data on convalescent plasma at a presidential press conference. As if to redeem those mistakes, the agency took some quick steps to de-politicize vaccine development as the election loomed.
A hit to the FDA's reputation isn't just about the agency, either. It bleeds onto the pharma industry, too, as consumers take to social media to voice their worries about drugs FDA approves—and, crucially, question a COVID-19 vaccine even if stamped with the agency's approval.
Enter aducanumab, which has been controversial for years, and only came out of the Biogen dustbin after a follow-up analysis of one trial offered a glimmer of hope. Ahead of the meeting, the sliced-and-diced data itself came in for criticism from analysts and beyond.
The FDA put itself in the line of fire by publishing pre-meeting documents that seemed designed to push for a full-on approval, despite some less-than-flattering statistical analyses buried in the briefing packet.
“The applicant has provided substantial evidence of effectiveness to support approval,” the documents said up front, in a sentence that rang across social media when the documents were released.
During Friday's meeting, the panelists excoriated FDA officials for teeing up aducanumab for a rubberstamp approval. In the end, they voted unanimously against backing the drug for approval, with one abstention.
Former FDA reviewer Erick Turner, M.D., called the AdComm “kabuki theater,” on Twitter, adding later that the “FDA is on a slippery slope. Later step could be to fire statisticians.”
Analysts quickly said the discussion and vote didn't bode well for the Biogen drug—partly because the FDA simply can't afford to give it a green light now.
“Approving aducanumab, in the face of such an overwhelmingly negative vote and commentary, is virtually impossible and would destroy the agency's reputation at a very tenuous time for the regulator, ahead of potential actions on COVID vaccines,” Baird’s Brian Skorney wrote.
Bloomberg’s biotech and pharma columnist Max Nisen wrote the day before the AdComm about the public trust and image issue the FDA was courting.
“The agency’s reputation eroded this year after ill-advised emergency authorizations of hydroxychloroquine and convalescent plasma to treat Covid-19,” he said. “As it attempts to rebuild trust ahead of the evaluation and rollout of a Covid-19 vaccine, it should demonstrate that there's still a high bar instead of further tarnishing its image.”
Yet that’s exactly what may happen. It’s still possible the FDA could approve the drug; it generally follows panel recommendations but isn’t required to do so.
As SVB Leerink analysts wrote, “While we have never seen a drug get approved with such a negative panel, we also have never seen FDA briefing documents that were so blatantly obvious about the FDA’s positive view.”
While the aducanumab AdComm was unusual in its intensity, there have been other cases where negative panel recommendations still ended in an FDA drug approval. Sarepta’s Duchenne muscular dystrophy med Exondys 51 got a nod in 2016 despite having limited data and a negative AdComm. Its more recent Duchenne drug Vyondys 53 was initially rejected by the FDA in August 2019, but in a surprise approval, greenlighted in December.
The aducanumab approval went through the same FDA neuroscience advisory group, led by director Billy Dunn, as the Sarepta drugs.
Karyopharm Therapeutics’ Xpovio to treat multiple myeloma was approved in July after an advisory committee voted against the approval due to safety concerns.
Statistically, however, the opposite is generally true.
A study last year found that only 22% of the FDA’s final actions were “discordant” with AdComm recommendations.
Among the 82 panels when the two disagreed, 75% of the cases were favorable recommendations where the FDA acted more restrictively, while the other 25% were negative AdComms where the FDA acted less restrictively, according to the study by Millbank Quarterly which looked at 376 voting meetings from 2008-2015.
Its summary? “The FDA disagrees with the recommendation of its advisory committees a minority of the time, and in these cases it tends to be less likely to approve new products or supplemental indications and take safety actions.”