Based on Failed Confirmatory Trial, FDA Adcom Recommends Pulling AMAG's Makena From the Market


The U.S. Food and Drug Administration (FDA)’s Bone, Reproductive and Urologic Advisory Committee met yesterday to discuss and vote on a recommendation of AMAG Pharmaceuticals’ Makena (hydroxyprogesterone caproate injection). Makena has been approved to decrease preterm birth in pregnant women with a previous spontaneous preterm birth. The Adcom met to discuss and interpret the PROLONG (Progestin’s Role in Optimizing Neonatal Gestation) confirmatory clinical trial.

Ultimately, nine committee members voted to recommend the FDA pursue withdrawing approval for the drug, with seven members voting to leave it on the market under accelerated approval but require a new confirmatory trial.

There were six clinicians on the Adcom, five who practice obstetrics. The five obstetricians voted to keep the drug on the market and develop more data. AMAG indicates that it agrees with several committee members who expressed concern that taking the drug off the market would leave physicians with no safe treatment options for pregnant women.

Adcom recommendations are not binding. The FDA takes them into consideration and often follows the votes, but not always.

“We are disappointed with the nearly split vote on this key question and we are committed to working with the FDA to identify feasible ways to generate additional efficacy data on Makena while retaining current access to the therapy for at-risk pregnant women,” said Julie Krop, chief medical officer of AMAG.

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Krop went on to say, “Preterm birth is an urgent public health crisis and the implications of leaving pregnant women and providers without access to therapy that is manufactured in a safe and regulated way is profoundly troubling. For more than a decade, healthcare providers have relied on hydroxyprogesterone caproate to reduce preterm delivery in high-risk patients, which aligns with recently updated treatment recommendations of the American College of Obstetricians and Gynecologists, as well as the Society for Maternal-Fetal Medicine.”

The FDA approved Makena in 2011, but it was contingent on completing a follow-up study. It was given Orphan Drug exclusivity through February 3, 2018. It was approved based on the Meis clinical trial conducted by the National Institute of Child Health and Human Development and the Maternal-Fetal Medicine Units Network.

The PROLONG trial was run as part of the approval and was made up of more than 1,700 pregnant women. The data from the trial was published this week in the American Journal of Perinatology. The PROLONG trial did not meet the two pre-specified co-primary endpoints, which were reduction of preterm birth, which was defined as less than 35 weeks of gestation, and a reduction in the neonatal morbidity and mortality index. This was in contrast to the original Meis trial results, which were published in the New England Journal of Medicine in June 2003.

In the PROLONG trial, the drug did not show a statistically significant difference between the treatment and placebo arms for the co-primary endpoints. For incidence of preterm delivery at less than 35 weeks, the Makena group was 11% compared to 11.5% for placebo; for the other co-primary endpoint, percentage of patients who met the pre-specified neonatal morbidity and mortality composite index, the Makena group was 5.4% compared to 5.2% for the placebo group.

“After the initiation of the PROLONG trial and the approval of Makena in the U.S., Makena became the standard of care for pregnant women who have had a prior spontaneous preterm birth,” said Krop in a March 2019 announcement. “This led to a reluctance by U.S. physicians to enroll their patients in a placebo-controlled clinical trial and therefore, the majority of patients in the PROLONG trial were enrolled outside of the U.S., predominantly from Eastern European countries, with very different demographics compared to the Meis trial. In light of these recent findings and the inconsistencies with prior clinical evidence, we plan to conduct additional sub-group analyses of the PROLONG data, particularly focusing on patients at the highest risk of preterm delivery and the subset of patients enrolled in the U.S.”

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