[3/26/2021] The U.S. Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) is aware of the recently published EPPPIC meta-analysis reporting the efficacy of various progestogens, with various routes of administration (vaginal progesterone, oral progesterone, intramuscular hydroxyprogesterone caproate [HPC]) to reduce the risk of pre-term birth (PTB) in at-risk women with singleton or multifetal pregnancies. CDER’s recent proposal to withdraw the accelerated approval of Makena (HPC) was based upon a large randomized trial that failed to confirm the benefit of this drug to newborns or reduce the risk of PTB. In making the decision to propose Makena’s withdrawal, CDER also reviewed results from prior studies of progestins (HPC and other similar drugs) for PTB, including studies relevant to Makena that are included in the EPPPIC meta-analysis. Therefore, the publication of the EPPPIC meta-analysis does not change CDER’s proposal to withdraw the approval of Makena.
The EPPPIC meta-analysis is a patient level meta-analysis of 31 randomized, controlled trials evaluating the effect of various progestogens in reducing the risk of PTB. EPPPIC included 15 trials evaluating HPC; only five of these evaluated singleton pregnancies (the indicated population for Makena) and compared HPC with placebo.
CDER previously conducted a thorough review of the five placebo-controlled trials included in the EPPPIC meta-analysis that evaluated HPC in singleton pregnancies. These five studies were considered in the decision to propose Makena’s withdrawal. Two of these five trials were the Meis trial (Trial 002) and the PROLONG trial (Trial 003). CDER reviewed the Meis trial as the basis for Makena’s accelerated approval, and the PROLONG trial led to CDER’s proposal to withdraw the approval of Makena. Another one of the five HPC trials did not provide interpretable results because it was stopped early due to uncertainties about the drug’s potency. The two remaining HPC trials (PHENIX Singleton and SCAN) required that patients have a short cervix in the current pregnancy as the risk factor for PTB and did not focus on patients with prior spontaneous PTB; very few of the women in this population also had prior spontaneous PTB. Thus, the population in these two trials differs from Makena’s approved population, which is women at risk for recurrent PTB because of a prior spontaneous PTB, regardless of cervical length.
The EPPPIC meta-analysis grouped together HPC trials of patients with differences in their risk profiles, including combining women with a prior PTB and those without a prior PTB, and women with and without a short cervix. Because of this grouping, the meta-analysis does not provide relevant information regarding Makena’s effectiveness for its approved use. CDER continues to conclude the available data have not shown Makena is effective for reducing morbidity or mortality in newborns or for the prevention of recurrent PTB in women with a prior spontaneous PTB.
Currently, AMAG Pharmaceuticals has requested a hearing regarding CDER’s proposal to withdraw Makena’s approval. The Commissioner’s Office will determine whether to hold a public hearing and, following such hearing, decide whether to withdraw approval of Makena and its approved generic equivalents.
Visit CDER’s Makena webpage for more information and background about CDER’s proposal to withdraw Makena’s approval.