The US Food & Drug Administration (FDA) has withdrawn from the market the drug Makena, the only medication ever approved – in 2011 – to prevent preterm births, after a 2019 study found no evidence that it works.
Thousands of women were prescribed the drug since it launched and amid mixed opinions on its efficacy.
Drugmaker Covis said last week that the decision comes after an expert FDA panel voted on its withdrawal in 2022, the latest development in a years-long controversy at the crossroads of racial health disparities, pharmaceutical profits and science.
The Washington Post reports that while some black health groups had advocated for keeping Makena, which went through an accelerated FDA approval process after a promising early, smaller-scale trial, on the market, the debate has split doctors’ opinions on whether to continue prescribing it, and sparked several days of hearings at the FDA last year.
Raghav Chari, a top health executive at Covis, said the company continues to “stand by” what he described as Makena’s “favourable benefit-risk profile”. But they decided to voluntarily withdraw the drug “particularly given the complexity around … mixed efficacy data and a positive safety profile”, he said.
Since Makena was approved 12 years ago, some 350 000 people have taken the progesterone injection, intended for those who have previously had spontaneous singleton preterm births. The progesterone hormone keeps the uterus “quiet and happy”, said Kristina Adams Waldorf, an OB/GYN and professor at the University of Washington, who supports the withdrawal.
It was originally thought that “by giving additional progesterone, it will prevent contractions from prematurely starting before the due date”, she said, but those mechanisms are not completely understood.
The treatment was introduced in 2011, but a confirmatory trial published in 2019, in which 1 130 women received Makena and 578 received a placebo, found that the drug did not prevent preterm births. In October 2020, the FDA’s Centre for Drug Evaluation and Research wanted to pull it off the market because it “failed to verify clinical benefit”.
Covis argued in a 2022 filing with the FDA that the 2019 study was flawed. They noted the study had a significantly lower percentage of black patients and that the subjects had lower health risks compared with a previous, smaller study. This “left the study not appropriately powered to demonstrate efficacy”, Covis wrote.
Adams Waldorf said she was not convinced by the argument that Makena might be effective for just a portion of the population. “As soon as you have something in science that’s very difficult to replicate, it should engender a lot of suspicion in all of us,” she said.
“I understand the hope that maybe it works for a subset of a subset of the population. But that is not good enough for the most important problem in obstetrics to date.”
But Larry Rand, an OB/GYN and director of perinatal services at the University of California San Francisco Foetal Treatment Centre, said “available evidence” suggests that Makena could make a difference in reducing preterm births among black women.
He said the conflicting trial data considered by the FDA might not be “comparable enough to draw definitive conclusions about Makena’s effectiveness” and that withdrawal of the drug would make treatment “much harder” and “potentially take us back to the days when we had to turn to compounding pharmacies to make the drug”.
Study details
17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial
Sean Blackwell, Cynthia Gyamfi-Bannerman, Joseph Biggio, Julie Krop et al.
Published in PubMed Trials on 25 October 2019
Abstract
Background
Women with a history of spontaneous preterm birth (SPTB) are at a significantly increased risk for recurrent preterm birth (PTB). To date, only one large U.S. clinical trial comparing 17-OHPC (17-α-hydroxyprogesterone caproate or "17P") to placebo has been published, and this trial was stopped early due to a large treatment benefit.
Objective
This study aimed to assess whether 17-OHPC decreases recurrent PTB and neonatal morbidity in women with a prior SPTB in a singleton gestation.
Study design
This was a double-blind, placebo-controlled international trial involving women with a previous singleton SPTB. Women were enrolled at 93 clinical centres (41 in the United States and 52 outside the United States) between 160/7 to 206/7 weeks in a 2:1 ratio, to receive either weekly intramuscular (IM) injections of 250 mg of 17-OHPC or an inert oil placebo; treatment was continued until delivery or 36 weeks. Co-primary outcomes were PTB < 35 weeks and a neonatal morbidity composite index. The composite included any of the following: neonatal death, grade 3 or 4 intraventricular haemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotising enterocolitis, or proven sepsis. A planned sample size of 1,707 patients was estimated to provide 98% power to detect a 30% reduction in PTB < 35 weeks (30% to 21%) and 90% power to detect a 35% reduction in neonatal composite index (17%-11%) using a two-sided type-I error of 5%. Finally, this sample size would also provide 82.8% power to rule out a doubling in the risk of fetal/early infant death assuming a 4% foetal/early infant death rate. Analysis was performed according to the intention-to-treat principle. Results Baseline characteristics between the 1,130 women who received 17-OHPC and 578 women who received placebo were similar. Overall, 87% of enrolled women were Caucasian, 12% had >1 prior SPTB, 7% smoked cigarettes, and 89% were married/lived with partner. Prior to receiving study drug, 73% women had a transvaginal cervical length measurement performed and <2% had cervical shortening <25 mm. There were no significant differences in the frequency of PTB < 35 weeks (17-OHPC 11.0% vs. placebo 11.5%; relative risk = 0.95 [95% confidence interval (CI): 0.71-1.26]) or neonatal morbidity index (17-OHPC 5.6% vs. placebo 5.0%; relative risk = 1.12 [95% CI: 0.68-1.61]). There were also no differences in frequency of foetal/early infant death (17-OHPC 1.7% vs. placebo 1.9%; relative risk = 0.87 [95% CI: 0.4-1.81]. Maternal outcomes were also similar. In the subgroup of women enrolled in the United States (n = 391; 23% of all patients), although the rate of PTB < 35 weeks was higher than the overall study population, there were no statistically significant differences between groups (15.6% vs. 17.6%; relative risk = 0.88 [95% CI: 0.55, 1.40].
Conclusion
In this study population, 17-OHPC did not decrease recurrent PTB and was not associated with increased foetal/early infant death.
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