An FDA advisory committee recommended that the agency withdraw 17α-hydroxyprogesterone caproate (17-OHPC; Makena), an injectable agent to prevent recurrent preterm birth, deciding that the drug was ineffective both to reduce the risk of preterm delivery and to improve neonatal outcomes.
The Obstetrics, Reproductive and Urologic Drugs Advisory Committee voted 14-1 that 17-OHPC and its generics should not be allowed to stay on the market while a confirmatory trial is designed and conducted, siding with the FDA's position that the drug's risk-benefit profile was not favorable. The drug was initially approved in 2011 for preventing recurrent preterm birth under the agency's accelerated approval pathway.
"While I think that there are not significant harms that have been shown with Makena, there are still costs to having it on the market while we try to figure out who it would work for," said Anjali Kaimal, MD, of the University of South Florida in Tampa, casting her vote in favor of withdrawing approval.
At the conclusion of the three-day meeting on Wednesday, the panel also voted unanimously that evidence from a prior confirmatory trial (PROLONG) failed to verify the clinical benefit of 17-OHPC on neonatal morbidity and mortality from complications of preterm birth, and voted 1-13 (one abstention) that the medication was effective for its approved indication.
Committee members expressed disappointment and frustration at the lack of available treatments for patients at risk of preterm birth, which is a poorly understood yet highly detrimental condition.
"We desperately want a good treatment modality to treat this overwhelming disease," said Sarah Obican, MD, also of the University of South Florida in Tampa, who voted to recommend pulling 17-OHPC from the market. "It's frustrating that at this time, the evidence in the subsequent analyses have not shown effectiveness."
The committee's discussion centered around the contradictory findings of two clinical trials.
The Meis trial, which provided the basis for 17-OHPC's accelerated approval, found that , specifically among patients who had a previous preterm delivery before 37 weeks of pregnancy. The preliminary trial of more than 450 patients enrolled a high number of Black women (59% of the study population), who face a disproportionate risk of preterm birth compared with other racial and ethnic groups.
But the PROLONG study, a larger postmarketing trial required as a condition of accelerated approval, failed to show that 17-OHPC reduced preterm births before either 35 or 37 weeks' gestation, and failed to show that the drug reduced neonatal morbidity and mortality.
Manufacturer Covis Pharma argued that PROLONG did not enroll enough high-risk patients -- including Black women -- to properly evaluate the effectiveness of the drug in that population. However, many panel members agreed that although there is a known increased risk of preterm birth in these vulnerable populations, there was still not enough compelling evidence that 17-OHPC benefitted high-risk groups in sub-analyses.
"Just because we think this condition disproportionately burdens certain populations does not mean that we have to rush to provide any treatment in those populations," said Joseph Alukal, MD, of the Columbia University Irving Medical Center in New York City, who voted in favor of revoking approval. "We may be doing harm as opposed to good, even though our intentions are good."
Nearly all of the agency's advisors said that future study is needed to investigate the effectiveness of 17-OHPC, and treatments for preterm birth in general. While there was some concern about investigators' ability to recruit participants if FDA withdrew approval of 17-OHPC, advisory members were hopeful that future randomized, placebo-controlled trials would be possible.
Cassandra Henderson, MD, of Garden OB/GYN in New York City, the only advisory committee member who voted to keep 17-OHPC on the market, said she believed the Meis trial indicated strong signals of the drug's benefit in high-risk populations, including among Black patients, that were not properly evaluated in the PROLONG trial (7% of the study population were Black).
Henderson added that revoking approval of 17-OHPC may increase the prevalence of compounded formulas, subjecting high-risk patients to unknown risks.
Covis representatives presented several post-hoc analyses of the PROLONG trial, showing some nominal, but not statistically significant, reductions in early preterm birth in high-risk populations. But Peter Stein, MD, of FDA's Center for Drug Evaluation and Research, who presented the agency's position on 17-OHPC, said these results were merely hypothesis-generating, and not enough to justify the drug's indication.
The manufacturer proposed to narrow 17-OHPC's indication to a high-risk population, including women with a recent spontaneous preterm birth before 35 weeks' gestation who had an additional risk factor, such as multiple previous preterm deliveries, a recent pregnancy, or a social determinant indicating risk. But members of the advisory committee voted to recommend to remove its approval entirely.
While advisory committee members largely agreed that the risk-benefit profile of 17-OHPC was not favorable enough to keep it on the market, they also recognized that more research is critical to serve patients at risk of delivering prematurely.
"We are back to square one," said Susan Ellenberg, PhD, a professor emerita at the University of Pennsylvania School of Medicine in Philadelphia, who voted against the drug. "We're back to the situation where you just don't know."
The FDA is not required to follow the advice of its advisory committees, but it usually does.