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Confirmatory Trial for Drug to Prevent Preterm Birth Finds No Benefit, So Why Is It Still Prescribed?

In 2011, the US Food and Drug Administration (FDA) approved Makena (hydroxyprogesterone caproate) for the prevention of preterm birth (PTB) in pregnant women with a history of spontaneous preterm delivery. The drug received accelerated approval based on one study demonstrating a benefit in reducing the risk of delivery before 37 weeks, on the condition that additional studies would be conducted to confirm the clinical benefit. However, the confirmatory study for Makena was published in late 2019 and found that the drug was no more effective than placebo. Yet, Makena remains on the market and continues to be prescribed. The FDA's accelerated approval was based on the so-called Meis trial, which was published in 2003. This study enrolled 463 pregnant women at 19 sites in the United States, who had had a previous spontaneous PTB (sPTB). The study reported that the drug reduced the risk of delivery at less than 37 weeks, less than 35 weeks, and less than 32 weeks. The findings were so dramatic that the study was stopped before reaching its planned enrollment target of 500 pregnant women. However, critics have noted that the study had a number of limitations, including uneven randomization and a lack of adequate information about treatment timing. The recent confirmatory study, called PROLONG (Progestin's Role in Optimizing Neonatal Gestation), began in 2009. It randomized 1130 pregnant women to Makena and 578 to placebo at 91 sites across the globe. The study showed no clinical benefit: PTBs before 35 weeks occurred in 11% of women in the treatment group and 11.5% in the placebo group. Of note, these rates were much lower than those found in the Meis trial (20.6% of women in the treatment group vs 30.7% in the placebo group). After the PROLONG findings were published, an FDA advisory committee met to discuss whether Makena should remain on the market. The advisory panel concluded unanimously that the PROLONG trial did not confirm a clinical benefit of Makena on improving neonatal outcomes. When asked if Makena should be withdrawn from the market, the vote was split: 9 panelists said it should be withdrawn, whereas 7 panelists (including 5 of the 6 practicing obstetricians on the panel) said it should remain on the market on the condition that another confirmatory trial is conducted. Today, both the Society for Maternal-Fetal Medicine (SMFM) and the American College of Obstetricians and Gynecologists (ACOG) continue to support the drug's use for its approved indication. It could be argued that making a practice shift away from the use of Makena is difficult without evidence of harm. Moreover, there is not a clear alternative treatment to prevent recurrent PTB. As the debate continues, some physicians continue to prescribe Makena, although most discuss the Meis and PROLONG findings and the uncertainty of benefit when counseling patients about the drug's use.