FDA advisory panel votes against Ocaliva for PBC citing ‘concern for real possible harm’
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Key takeaways:
- FDA panel voted 13 to 1 that confirmatory trials did not verify clinical benefits of Ocaliva in primary biliary cholangitis.
- Advisors reported data points to Ocaliva causing harm vs. being beneficial.
An FDA advisory committee voted against approval for obeticholic acid in primary biliary cholangitis without cirrhosis or compensated cirrhosis with portal hypertension, citing “concern for real possible harm”.
The Gastrointestinal Drug Advisory Committee voted 13 to 1 with no abstentions that the benefits of obeticholic acid (Ocaliva, Intercept Pharmaceuticals) on clinical outcomes in patients with PBC could not be verified with available data from the postmarketing requirement confirmatory trial, 747-302 and the observational study, 747-405.
The committee also voted 10 to 1 with 3 abstentions that obeticholic acid (OCA) did not have a favorable benefit-risk assessment for use as a second-line treatment in the United Stated Prescribing Information population.
“There was not unanimity, but there was a majority that voted that the benefit remains unconfirmed, and there is a concern for real possible harm,” Benjamin Lebwohl, MD, MS, chairperson for the Gastrointestinal Drug Advisory Committee, told attendees. “Abstainers noted that the benefit remains unclear, making it difficult to truly weigh the risk-benefit ratio.”
The panel based their decision on evidence presented by Intercept Pharmaceuticals representatives who reported on data from the 747-302 study, a double-blind, placebo- controlled trial conducted from December 26, 2014, to December 23, 2021.
Researchers randomly assigned 334 patients with PBC 1:1 to either OCA or placebo. Patients receiving OCA were initially given 5 mg then titrated to 10 mg depending on the presence of cirrhosis and Child Pugh Score. The primary endpoint was time to first occurrence of all-cause mortality, liver transplantation, hospitalization and presence of uncontrolled ascites.
In May 2021, the United States Prescribing Information label was updated to include contraindication of OCA use among patients with compensated cirrhosis or portal hypertension, cirrhosis or decompensated cirrhosis. Additionally, in September 2021, the primary endpoint was expanded to include new incidence of portal hypertension without decompensation and progression to hepatic decompensation. Researchers performed an additional retrospective analysis among both USPI indicated and contraindicated patients.
Most panelists noted that the 747-302 study did not verify clinical benefit for OCA since it did not meet the primary endpoint; instead, evidence pointed to OCA potentially causing harm to users.
“I deeply empathize with the high unmet need; however, the benefit is unconfirmed, and the signal of harm with increased risk of death and liver transplant is concerning,” Brian P. Lee, MD, MAS, associate professor of medicine in the division of gastrointestinal and liver diseases at Keck School of Medicine of USC, told attendees.
In the 747-405 study, a 67-month observational study using real-world data from the Komodo Health United States claims database identified patients with PBC who were nonresponsive for intolerant to UDCA, researchers compared patients with PBC treated with OCA against control patients who were not treated with OCA. The composite endpoints included risk of hepatic decompensation, liver transplant or death.
Most panelists agreed that data from this observational trial was uninterpretable “due to a number of potential methodological disagreements,” Lebwohl said.
Theo Heller, MD, hepatology chief of the National Institute of Diabetes and Digestive Kidney Diseases in Bethesda, Maryland, who voted no to both questions, noted that better trials need to be performed as “there was a lack of rigor” in the data presented.
“I don’t know if [OCA] is good or not – I don’t know if it’s safe,” he said. “Design and do a real study and then we can talk about data. But until that happens, with what I’ve seen today...it is not comfortable enough to say that it should be available for all patients.”
According to Lebwohl, while there is an unmet need for second-line treatment for patients with PBC, performing clinical trials for these patients is challenging.
“We need to do a better job in communicating the difference between surrogate endpoints and hard clinical endpoints, particularly when we communicate this to patients who are looking for effective therapies,” he said.
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FDA. Gastrointestinal Drug Advisory Committee meeting – Sept. 13, 2024. FDA briefing document. Available at: https://www.fda.gov/media/181747/download. Accessed: Sept. 13, 2024.
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