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Regulatory Focus™ > News Articles > 2021 > 3 > FDA, unmoved by new meta-analysis, still recommends Makena withdrawal

FDA, unmoved by new meta-analysis, still recommends Makena withdrawal

Posted 29 March 2021 | By Kari Oakes 

FDA, unmoved by new meta-analysis, still recommends Makena withdrawal

The US Food and Drug Administration is standing by its October 2020 recommendation that Makena (intramuscular17-hydroxyprogesterone caproate, or 17-OHPC) be withdrawn from the market, notwithstanding a new meta-analysis of the efficacy of progestogens for prevention of preterm birth.
In a long-awaited Lancet publication, members of the Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) research team found that both vaginal progesterone and 17-OHPC, marketed as Makena by AMAG Pharmaceuticals and available under other trade names, reduced preterm birth before 34 weeks’ gestation in singleton pregnancies deemed high-risk. The absolute risk reduction was found to be greater for women with a short cervix.
However, Makena’s preterm birth benefit and its benefit in preventing some other prespecified adverse neonatal outcomes just missed statistical significance. The effect was clearest for reducing preterm birth before 34 weeks, where a 0.83 relative risk was seen for women receiving Makena (95% confidence interval, 0.68-1.01).  “Results for other birth and neonatal outcomes were consistently favorable, but less certain,” wrote the EPPPIC investigators.
When AMAG, now acquired by Covis Pharma, received its 2011 accelerated approval for Makena to reduce the risk of preterm birth for women with a prior history of spontaneous preterm birth, FDA directed that AMAG conduct a clinical trial to demonstrate clinical benefit to newborns. “A drug that prevents preterm birth is helpful if it ultimately improves the babies’ health,” wrote FDA in explaining its decision to propose Makena’s withdrawal.
“The required confirmatory trial failed to show that Makena is effective for improving the health of babies born to women with a history of unexplained preterm birth,” continued the agency. “We also determined that the available evidence does not show that Makena reduces the risk of preterm birth.” (RELATED: FDA seeks withdrawal of Makena, generics from market, Regulatory Focus 05 October 2020; Makena indication may fall based on post-approval data, Regulatory Focus 06 November 2020)
In the systematic review and meta-analysis, the EPPPIC team conducted an individual patient data (IPD) analysis of 31 trials involving 11,644 women and 16,185 offspring. However, not all trials were used for all data analyses, and few trials compared Makena head-to-head with vaginal progesterone. The trials also include those using oral progesterone, for which evidence was deemed “insufficient to support its use” by the trialists.
The newly published IPD meta-analysis follows two previous studies, OPPTIMUM and PROLONG, that “failed to confirm earlier study findings;” these trials found no statistically significant improvement in preterm birth or neonatal morbidity and mortality with either vaginal progesterone or Makena, noted Sherrine Ibrahim, MD, and David Haas, MD, of Indiana University School of Medicine, Indianapolis, in commentary accompanying the EPPPIC publication. However, other trials had earlier shown substantial benefit from progestogens in preventing preterm birth.
The EPPPIC meta-analysis was meant to settle the score – and for Ibrahim and Haas, data from this large IPD analysis “are more consistent in supporting the use of either 17-OHPC or vaginal progesterone to prolonged pregnancy, even with the inclusion of the negative findings from PROLONG.”
In considering the new EPPPIC meta-analysis together with the available body of evidence, however, FDA’s Center for Drug Evaluation and Research (CDER) declined to budge from their stance that MAKENA be withdrawn. In a 26 March announcement, CDER made the point that its earlier recommendation for withdrawal was itself based on many studies included in the EPPPIC IPD meta-analysis. “Therefore, the publication of the EPPPIC meta-analysis does not change CDER’s proposal to withdraw the approval of Makena,” wrote the agency.
CDER evaluated PROLONG along with four other placebo-controlled trials evaluating 17-OHPC (abbreviated as HPC by FDA staff) for the prevention of preterm birth in singleton pregnancies. The FDA analysis, in the end, found that one of the trials was stopped early and another two required that enrollees have a short cervix – a requirement not included for Makena’s indicated population.
CDER noted that the IPD analysis conducted by the EPPPIC team “grouped together HPC trials of patients with differences in their risk profiles, including combining women with a prior PTB [preterm birth] and those without a prior PTB, and women with and without a short cervix.” This strategy means that the meta-analysis “does not provide relevant information regarding Makena’s effectiveness for its approved use,” wrote CDER.
AMAG’s take on the Lancet publication was rosier. Its 26 March press release announced, “EPPPIC study reaffirms 17-OHPC for reducing early preterm birth in high-risk, singleton pregnancies.” That press release also acknowledged that the study was limited in its inability to “reliably differentiate in trial data between women with varying risk profiles,” along with other limitations.
AMAG has requested a hearing before CDER regarding the proposed withdrawal of Makena’s approval. The decision now lies with the FDA Commissioner’s Office whether to hold a public hearing and whether to withdraw Makena and approved 17-OHPC generics after the meeting. No date has been announced.

The EPPPIC meta-analysis was supported by the US Patient-Centered Outcomes Research Institute. Two authors reported receiving research support from AMAG and another, UT Health's Sean Blackwell, MD, reported uncompensated testimony at the FDA's Makena approval hearing on behalf of the sponsor. Ibrahim and Haas reported no relevant conflicts of interest.


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Tags: FDA, US

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