The FDA is calling for withdrawal of the approval for the injectable agent 17α-hydroxyprogesterone caproate (17-OHPC; Makena) for pregnant women with a history of at least one spontaneous preterm birth, stating that the drug is ineffective in reducing preterm births, as well as other poor neonatal outcomes, according to released ahead of a 3-day advisory committee meeting.
On October 17, the Obstetrics, Reproductive and Urologic Drugs Advisory Committee will meet to discuss whether the drug and its generics should remain on the market.
"Makena has not been shown to improve neonatal outcomes from premature birth, is no longer shown to be effective for its approved use, and has known risks," wrote FDA staff. "For these and other reasons ... Makena should be withdrawn from the market."
The documents paint the picture of why an FDA advisory committee voted to pull accelerated approval for the drug back in 2019.
Covis Pharma, which manufactures the drug, has taken the opposite position, stating in their own that "there is no reason to deprive women of the only available FDA-approved treatment to reduce the risk of preterm birth in high-risk women while an additional study is conducted."
The agency countered that the continued marketing of the drug in the "absence of demonstration of benefit incurs false hopes," and represents an unnecessary burden on patients and healthcare resources. As an example, they noted that women receive up to 20 injections of 17-OHPC during pregnancy.
The FDA initially approved 17-OHPC in 2011 to reduce the risk of preterm birth before 37 weeks of pregnancy among women who had a history of spontaneous preterm birth. The drug was approved under the accelerated approval pathway, which allows the agency to expedite the approval process for certain medications based on a surrogate endpoint thought to predict clinical benefit.
The initial approval was based on clinical trial results that found that women who received a 250-mcg injection of 17-OHPC had a significantly lower risk of delivering before 37 weeks of pregnancy compared with those in a placebo arm. However, because the risk reduction in preterm births did not signify a direct clinical benefit to neonates born prematurely, the FDA required a postmarketing confirmatory trial.
The FDA's position to pull 17-OHPC and its generics from the market is based on results from this confirmatory trial, which contradicted the initial findings. In the PROLONG study, which included 1,700 patients, 17-OHPC did not have a statistically significant effect on preterm births before 35 weeks' gestation (relative risk [RR] 0.95, 95% CI 0.71-1.26) or a neonatal composite index that included outcomes such as death, respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis, among others (RR 1.05, 95% CI 0.68-1.61).
In addition, the drug did not improve the rate of preterm births before 32 weeks' gestation or 37 weeks' gestation (RR 1.06, 95% CI 0.88-1.28) -- the latter of which was the primary endpoint of the trial that supported accelerated approval. The drug also did not have a positive effect on subpopulations, including Black women, who have an increased risk of delivering prematurely. Covis, however, has stated that the PROLONG trial enrolled fewer Black women, which may have subjected its results to selection bias.
In their briefing materials, FDA staff noted that the benefit-risk calculation for 17-OHPC was not favorable, since the medication is not only ineffective, but also carries risks for adverse events such as blood clots or depression. Additionally, a recent observational study found that babies exposed to 17-OHPC in utero had a greater risk of cancer later in life.
"Failing to withdraw Makena would maintain FDA approval of a drug that, based on all available evidence, has not been shown to be more effective than, but is riskier than, no treatment," FDA staff wrote.
Covis has called on the FDA to maintain approval while additional studies are conducted, pointing out that pulling the drug's approval could have negative repercussions on health outcomes in populations at risk for preterm birth. However, the FDA has continued to uphold its position to withdraw approval while future research is pursued, arguing that it will be difficult to enroll patients in a study for a drug that is already available.