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Medication to Prevent Preterm Birth Is Ineffective, Should Come Off the Market

Makena Should Not Have Been Approved by the FDA in 2011

WASHINGTON, D.C. – A medication approved for preventing preterm birth in certain pregnant women is not effective and should be removed from the market, Public Citizen and an expert in maternal-fetal medicine said in a petition filed today.

The U.S. Food and Drug Administration (FDA) should remove from the market Makena (generic name hydroxyprogesterone caproate) and all generic versions of the medication and prohibit pharmacy compounding of the medication because a recent clinical trial found it is not effective for preventing preterm birth or major complications related to preterm birth, the petition says.

Hydroxyprogesterone is a synthetic progesterone hormone initially approved by the FDA in 1956 under the brand name Delalutin to treat several gynecological and obstetrical conditions, including habitual and threatened miscarriages. However, by 1973, the FDA concluded that hydroxyprogesterone had not been shown to be effective for this latter use and was unsuitable to treat any pregnancy-related conditions because of evidence linking it to congenital heart defects in infants of mothers given the drug during pregnancy.

In 2000, at the request of the manufacturer Bristol-Myers Squibb, the FDA withdrew approval of Delalutin because the drug had not been marketed for several years. However, hydroxyprogesterone subsequently remained available exclusively through pharmacy compounding with limited regulatory oversight.

The FDA approved hydroxyprogesterone again in 2011 as the brand-name product Makena solely to reduce the risk of preterm birth in certain high-risk women, under the accelerated approval pathway. This process allows the FDA to fast-track the approval of a new drug that has been studied for safety and effectiveness in treating a serious or life-threatening disease or condition and that provides meaningful therapeutic benefits to patients over existing treatments.

However, Makena’s approval was based largely on evidence from a single clinical trial that an FDA advisory committee found did not adequately prove that the medication reduced the rate of fetal and neonatal health problems and death – the key meaningful clinical outcomes related to preterm birth. And an FDA statistical expert opposed approval of the medication because data from that trial failed to provide convincing evidence that Makena was effective. In fact, the data even suggested that early fetal loss increased among women treated with hydroxyprogesterone.

“The FDA never should have approved Makena under the accelerated approval process because the data that were relied on to establish the medication’s effectiveness were seriously flawed,” said Dr. Michael Carome, director of Public Citizen’s Health Research Group.

Per the requirements of the accelerated approval pathway, the FDA in 2011 told Makena’s then- manufacturer, Hologic, Inc., to complete a larger trial to determine the medication’s effectiveness. On March 8, 2019, AMAG Pharmaceuticals, the current manufacturer of Makena, announced that the trial – called the PROLONG trial – showed that hydroxyprogesterone was not effective in reducing the rate of preterm birth prior to 35 weeks of pregnancy or the rate of fetal and neonatal health problems and death.

“It is inconceivable that the FDA would have approved Makena if the results of the PROLONG trial had been available prior to approval,” said Meena Aladdin, health researcher at Public Citizen’s Health Research Group.

“I counsel pregnant women every day on the issue of preterm birth and have lots of experience delivering very premature babies,” said Dr. Adam C. Urato, chief of maternal-fetal medicine at MetroWest Medical Center in Framingham, Mass., and a co-petitioner. “It makes no sense to inject women with a synthetic hormone that carries risks – including injection site reactions, possibly increased rates of gestational diabetes and the unknown long-term adverse effects to the baby – but offers no meaningful benefits. The FDA must pull this product off the market.”

Read the petition here.