The FDA’s Obstetrics, Reproductive and Urologic Drugs Advisory Committee of outside experts voted 14-1 to pull Covis Pharma’s controversial preterm birth drug from the market after its confirmatory trial from 2018 failed to confirm the drug’s benefit for babies or mothers.
The nearly 3-day saga amounted to a swift and almost unanimous vote as top CDER officials made the case that there isn’t strong enough evidence to keep Makena on the market. Only two members of the committee made the case to keep Makena on the market, in the lead-up to the vote, as they noted another trial will be difficult to conduct if it’s pulled, and that the failed confirmatory trial, which wasn’t run by Covis, was flawed.
Panelist Cassandra Henderson, a New York-based maternal-fetal medicine consultant, who cast the sole ‘Yes’ vote to keep Makena on the market, said she thought the drug does work in some populations, and she reiterated the sponsor’s concern that Black women may lose access to it, even as others questioned her presumption that losing access was a negative.
Peter Stein
Prior to the committee vote and discussion on Wednesday, Raghav Chari, chief innovation officer at Covis, and the FDA’s Office of New Drugs Director Peter Stein offered their closing arguments.
While Stein noted some nominally significant findings in subsets of subsets from the confirmatory trial, “these are not robust, reliable observations, not reliable evidence – and not evidence on which to base regulatory decisions or guide clinical practice decisions.”
Chari, meanwhile, called on the FDA to narrow the label to higher-risk patients identified by Covis in post-hoc analyses, and to keep the drug on the market while it conducts an RCT in this higher-risk population that will take 4-6 years, in addition to an observational study to establish relationship between gestational age and neonatal outcomes.
Esther Eisenberg
Taking the side of Covis in much of the discussion, Esther Eisenberg of NIH’s National Institute of Child Health and Human Development raised some questions on the design of the confirmatory trial, and while she abstained from voting on the second question on whether Makena is effective for its approved indication, she ended up voting to pull Makena but questioned at what point the FDA would remove an accelerated approval if the study done was flawed and unable to answer the question at hand.
While supportive of future studies, the vast majority of the committee members expressed doubts that the current evidence is adequate to keep Makena on the market, and they questioned Covis’ claims on the timeline for a future study (the confirmatory study took a decade), and that participants might not enroll in a future Makena trial if it’s not approved and unavailable.
Margery Gass
Panelist Margery Gass of the University of Cincinnati College of Medicine explained that the company has already had the benefit of the accelerated approval process, and there’s no strong evidence that the drug is effective. Disregarding a large study like the confirmatory one that says there’s no effectiveness would undermine the credibility of the FDA and this adcomm, she said.
On the two other voting questions, the panelists voted 15-0 against the idea that the confirmatory trial verifies the clinical benefit of Makena on neonatal morbidity and mortality from complications of preterm birth (a decision that Covis agreed with earlier Wednesday, and 13-1, with Eisenberg’s abstention, against whether the available evidence demonstrates that Makena is effective for its approved indication of reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.
Mara McAdams-DeMarco
Mara McAdams-DeMarco, associate vice chair for research in the department of surgery at New York University said that even in subgroups, there’s no evidence that pre-term birth would be prevented with the use of this medication. She said it’s a disingenuous argument to say the study design explains the null results.
Sarah Običan
Other panelists agreed that pulling Makena from the market may speed the enrollment of another trial, although Covis warned yesterday that if Makena is pulled from the market, the company likely will not pay for another trial.
Adcomm member Sarah Običan, associate professor of maternal-fetal medicine at the University of South Florida, said it may be difficult to recruit for a trial if it’s kept on the market and that another trial will likely take longer than 4-6 years as Covis suggested.
Back in 2019, a prior FDA adcomm also voted to pull Makena, but the final decision now comes before FDA commissioner Rob Califf and chief scientist Namandjé Bumpus.
