Makena indication may fall based on post-approval data

Regulatory NewsRegulatory News
| 06 November 2020 | By Mary Ellen Schneider 

The US Food and Drug Administration (FDA) is seeking to withdraw the approval of the only drug indicated to prevent recurrent preterm birth, based on a post-approval study showing a lack of efficacy.
Makena (hydroxyprogesterone caproate injection) was originally granted accelerated approval in 2001 and remains on the market. Makena’s manufacturer, AMAG Pharmaceuticals, has requested a public hearing to explore the issue. It is up to the FDA commissioner whether to grant the hearing request and ultimately whether to withdraw approval for the drug.
“We sympathize with women who are at risk for recurrent preterm birth that could result in death or significant lifelong health effects in neonates, but retaining on the market a drug not shown to be effective for this use does not protect or promote their health,” Christina Y. Chang, MD, and colleagues from the FDA Center for Drug Evaluation and Research (CDER) wrote in a perspective article published 3 November 2020 in the New England Journal of Medicine.
Makena’s accelerated approval was based on the success of Trial 002, a randomized, double-blind, placebo-control trial that demonstrated that hydroxyprogesterone caproate reduced the risk of birth before 37 weeks of gestation in women with a singleton pregnancy and previous preterm birth. However, the trial was not adequately designed to determine whether the drug would provide a neonatal benefit, something FDA asserts is essential to making the treatment clinically relevant.
Despite the lack of evidence on neonatal outcomes, the agency went forward with an accelerated approval, but required a post-approval confirmatory trial to look at the issue of neonatal outcomes.
The confirmatory study – called Trial 003 – enrolled 1,708 women from nine countries to receive either Makena or placebo. The study had two co-primary endpoints: the proportion of women delivering before 35 weeks of gestation and the proportion of neonates having at least one of six adverse health outcomes related to prematurity.
Trial 003 failed to show benefit for either preterm birth or neonatal outcomes. Specifically, the percent of women who experienced a birth before 35 weeks was 11% with Makena and 12% with placebo, a difference that was not statistically significant. The trial had similar results when looking at birth before 37 weeks. For neonatal outcomes, the results were virtually the same for Makena and placebo.
Meanwhile, a small group of clinicians and researchers are pushing back on CDER’s recommendation to withdraw the approval of Makena. In the same issue of the New England Journal of Medicine, Michael F. Greene, MD, a maternal-fetal medicine specialist at Massachusetts General Hospital in Boston, and his colleagues wrote that the different study population in the confirmatory trial, which had a much lower proportion of Black women, likely contributed to the change in efficacy.
They also urged FDA not to withdraw the Makena approval, noting it such an action would “leave a very vulnerable demographic group of US women at high risk for this complication of pregnancy with absolutely no available therapeutic option.” 
The CDER officials addressed this concern in their report. FDA performed multiple analyses to determine whether the different study populations in Trial 002 and Trial 003 explained the inconsistent findings and could not attribute the different results to differences in patient populations or risk level.
The CDER officials pointed out that if the inconsistent results of Trial 003 been available at the time of the initial marketing application, there would have been insufficient evidence of effectiveness. “Similarly, CDER is now left without sufficient evidence of effectiveness with which to support leaving Makena on the market,” they wrote.
CDER Perspective, Greene Perspective


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