Statement of Dr. Diana Zuckerman
At the FDA Gastrointestinal Drugs Advisory Committee Meeting on Ocaliva
September 13, 2024
I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Our center is a nonprofit public health research center that scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products — so we have no conflicts of interest.
Thank you for the chance to share our views today and we thank this Committee for your important work. My expertise is in clinical trial design and data analysis, not in liver disease. Prior to my current position, I was a post-doc in epidemiology and public health at Yale Med School, and was as a faculty member and PI at Yale and Harvard. I also investigated FDA approval standards while working in the US Congress, HHS, and the White House. I’m a founding Board member of the nonprofit Alliance for a Stronger FDA, which educates Congress about the need to financially support the essential work of the FDA.
After accelerated approval, confirmatory trials are essential to keep those drugs on the market. When drugs are not confirmed to be safe and effective, we owe it to patients to rescind approval and urge the companies to either design better studies or conduct studies to determine if a subgroup of patients will benefit, and which ones will be harmed.
We agree with FDA’s criticisms, and note that the European Medicines Agency recommended revoking approval.
- Study 747-302 was a randomized controlled clinical trial, that DID NOT meet its primary endpoint. In fact, the probability value was greater than .30, which is at least 6x higher than is needed to reach statistical significance. In the relatively small USPI labeled population, 11 OCA patients died or needed a liver transplant compared to only 2 in the placebo group. If placebo patients took commercial OCA, this difference would be greater.
- Study 747-405 was an observational study with major flaws:
- Most important: The composite endpoint included 2 objective measures (death, transplantation) but also hepatic decompensation, which could be miscoded.
- The company’s “as treated” strategy was flawed because many OCA patients left the study because of complications and had serious problems after leaving the study. So the FDA conducted its own Intention to Treat type of analysis based on death or liver transplant. The difference was not statistically significant.
In conclusion: We concluded that the data do not meet the FDA required standards of adequate and well-controlled trials AND results do not prove that OCA is effective. In fact, the OCA patients’ health may be more likely to deteriorate even after they stop taking OCA.
The Advisory committee agreed with us and voted 13-1 that there is no clear evidence of benefit and therefore OCA should not get full approval. We expect this means its accelerated approval will be rescinded. Read more here.