An FDA advisory committee recommended against full approval for Alfasigma and Intercept Pharmaceuticals’ rare liver disease drug Ocaliva by a 13-1 vote, concluding that confirmatory evidence didn’t verify that the treatment provided a clinical benefit.
Though the FDA is not required to follow the result of the vote, it often does so, likely jeopardizing Ocaliva’s ability to remain on the market in the US. Regulators appeared ready to pull the accelerated approval based on briefing documents released earlier this week, noting the confirmatory study missed statistical significance and saw patients fare worse than those on placebo.
Christopher Coffey, a professor at the University of Iowa’s biostatistics department, said part of the reason he voted no was because of how much the positions between the FDA and Intercept differed.
“It’s kind of an unfortunate case where a bunch of studies were done, and I feel like the answer that was set out to look for at the very beginning is just as unclear, perhaps at this point maybe more unclear, than it was because of the uncertainty,” Coffey said.
In a separate vote, panelists also voted 10-1 that the benefits of Ocaliva did not outweigh the risks, with three abstentions.
The debate during the adcomm centered around two studies that Intercept conducted: a traditional confirmatory study designed to be randomized and placebo-controlled (Study 302), and a real-world evidence trial (Study 405).
Intercept said that the first study wasn’t interpretable and couldn’t serve as the basis for full approval because of the challenges of running a placebo-controlled trial in a rare disease, like patient recruitment and retention. The company also said the landscape of the disease Ocaliva is indicated to treat — primary biliary cholangitis — had changed since it received accelerated approval in 2016.
Instead, Intercept put forth Study 405 as a substitute measurement of clinical benefit and to try to assuage concerns over liver-related side effects that the FDA has been studying since at least 2020.
At the session, the FDA held the opposite position, saying Study 302 contained enough evidence to determine that Ocaliva’s treatment benefit wasn’t confirmed, and that Study 405 couldn’t serve as the basis of a full approval.
Panel members largely agreed with the FDA’s view, and a handful expressed their doubts over the drug’s efficacy bluntly. One panelist said it hadn’t met the standards to be used, and another said that the data were poor and made it impossible to know if the drug was safe or effective.
The panelists also expressed concerns about liver toxicity at higher doses of the drug. Some said adequate studies can be properly designed in rare disease settings, but that the issues with Intercept’s studies left open too many questions. They expressed hope that patients could eventually see a well-designed study in the disease that incorporated some of their concerns.
The FDA is expected to make a final decision on whether to pull the accelerated approval or grant full approval by Oct. 15.
Ocaliva is already nearing removal from the EU market as well. The European Commission revoked its conditional approval of Ocaliva this month following a CHMP recommendation in June, which said the benefits of the drug did not outweigh the risks. But Advanz Pharma, the company that sells Ocaliva in the EU, sued the Commission to keep it on the market for now, and it will remain available “until further notice.”