Manufacturer Pulls Only Approved Preterm Birth Treatment From Market Following Lack of Confirmatory Data

Hydroxyprogesterone caproate injection was the only drug approved to help prevent preterm birth, but a confirmatory trial showed no benefit.

Hydroxyprogesterone caproate injection (Makena; Covis Pharma Group) is being voluntarily pulled from the market after the FDA Obstetrics, Reproductive, and Urologic Drugs Advisory Committee decided that a confirmatory trial showed that it did not help pregnant women.

The injection was granted accelerated approval by the FDA in 2011 to reduce the risk of preterm birth in women who had previously experienced a spontaneous preterm birth, defined as delivery of a baby before 37 weeks’ gestation. This accelerated approval was based on data from the Meis trial and indications that the drug would be effective and had a favorable risk-benefit profile. As part of this process, the company was required to conduct a clinical trial to confirm that the drug provided these benefits.1

According to an FDA statement, preterm birth can be serious and life-threatening for the infant and there were previously no approved treatments for preterm birth. Additionally, a single trial in the original application showed that hydroxyprogesterone caproate injection lowered the rate of preterm birth.1

However, the required, confirmatory PROLONG trial failed to show that the injection is effective for improving the health of infants born to women with a history of unexplained preterm birth. The FDA committee also determined that the available evidence does not show that the drug reduces the risk of preterm birth. As a result, the FDA’s Center for Drug Evaluation and Research (CDER) proposed in October 2020 that it be withdrawn from the market.1

A hearing was held in October 2023, during which the Obstetrics, Reproductive, and Urologic Drugs Advisory Committee voted on whether the confirmatory trial verified the clinical benefit of the drug and whether the FDA should allow it to remain on the market while another confirmatory study is designed and conducted. The FDA Commissioner and Chief Scientist would decide whether to withdraw the approval, but Covis Pharma Group has decided to independently pull it from the market.

“Covis respects the regulatory decision-making process and appreciated the opportunity to present our patient-focused study designs and data to the (CDER) at FDA and members of the Advisory Committee,” said Covis CEO Michael Porter, in a press release following the hearing in October. “We are also thankful for the viewpoints expressed by patients and organizations that see the importance of Makena and its generics.”2

Experts from Covis also said during the hearing that they believe hydroxyprogesterone caproate injection is effective in a higher-risk patient population.2 According to reporting by The New York Times, patients and physicians who wanted further research in these high-risk populations also spoke at recent meetings and hearings, arguing in favor of more confirmatory trials.3

The lack of treatment for preterm birth has long been a challenge, particularly for Black women who are more likely to experience preterm birth. According to data from the Population Reference Bureau, Black women in the United States are more than 50% more likely than White women to deliver a premature infant, with these trends documented for over a century.4

Racism-related stress may be a contributing factor, as characteristics such as the mother’s health, education, and income account for less than half of the disparity. Infants born to women with more socioeconomic resources tend to fare better, but researchers found that the gap between Black and White women exists at all socioeconomic levels and may be even wider among women with college degrees.4

Analyses of the original Meis trial and the confirmatory PROLONG trial for hydroxyprogesterone caproate injection did focus on factors that may increase the risk of preterm birth, including Black race and prior spontaneous preterm births. The number of women enrolled in both trials was similar, but the analyses showed that factors that differed between the 2 trials, such as race or being outside the United States, did not explain the different findings.1

CDER experts also examined a combination of factors in the PROLONG trial, such as race, level of education, partner status, number of prior preterm births, and substance use in pregnancy, that may represent low, medium, and high risk for recurrent preterm birth. They found no evidence that hydroxyprogesterone caproate injection was effective in any of these low-, medium-, and high-risk groups. After multiple analyses, CDER experts were unable to identify a group of women for whom the drug had an effect in the PROLONG trial.1


  1. Food and Drug Administration. Makena (hydroxyprogesterone caproate injection) Information. Updated January 18, 2023. Accessed March 8, 2023.
  2. Covis Pharma Reports on FDA Advisory Committee Hearing for Makena. News release. Covis Pharma; October 19, 2022. Accessed March 8, 2023.
  3. Jewett C. Preterm Birth Drug Withdrawn After 12 Years. New York Times. March 7, 2023. Accessed March 8, 2023.
  4. Scommegna P. High Premature Birth Rates Among US Black Women May Reflect the Stress of Racism and Health and Economic Factors. Population Reference Bureau. January 21, 2021. Accessed March 8, 2023.,with%209%25%20of%20white%20women.
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