An independent panel of advisers to the Food and Drug Administration recommended last week that a medication to prevent preterm birth be taken off the market because, the advisers decided, the preponderance of evidence suggests it doesn’t work. But some other leading OB-GYNs say they hope the FDA won’t take the panel’s advice this time.
The medication is a synthetic form of the hormone progesterone, brand-named Makena.
“It was a really hard vote” says Dr. Vivian Lewis, professor emerita of obstetrics and gynecology at the University of Rochester Medical Center in New York, and chairperson of the FDA advisory panel. The panel was made up of 16 people, including physicians of several specialties and statisticians.
“It really came down to two camps,” Lewis tells NPR. All agreed the totality of the evidence gathered so far does not support the medication’s effectiveness for its intended use. But some advisers wanted to leave the medication on the market for now, and require additional study, while others thought it should be pulled.
By a slim majority of just two votes the advisory board recommended the drug be taken off the market.
Makena first gained FDA approval for sale in 2011, largely on the basis of findings from a 2003 study sponsored by the National Institutes of Health.
That study involved 463 pregnant women who had previously had a spontaneous preterm delivery and were therefore at increased risk for another preterm delivery. The women were divided into two groups — one that received progesterone, while the other received a placebo.
Women in the progesterone group got weekly injections of the drug starting at 16 to 20 weeks of pregnancy and continuing until 36 weeks of pregnancy. The study found that treatment with progesterone significantly reduced the risk of preterm delivery at less than 37 weeks gestation.
“There was a 66% drop in the rate of recurrent preterm birth among women taking progesterone,” says Dr. Eva Pressman, chair of obstetrics and gynecology at the University of Rochester. “We think that progesterone acts as a uterine muscle relaxant, which seems to decrease the ability of the uterus to contract,” Pressman explains.
With the highly beneficial findings from that study, the medication was fast-tracked through the FDA approval process, with one major caveat: Makena’s manufacturer was required to do a larger follow-up study to confirm the drug’s benefit.
But that’s not how the findings turned out. The follow-up study, published in late October, found Makena “did not decrease recurrent preterm births.”
The FDA’s advisory panel was charged with reviewing all the evidence and determining whether the benefits of the drug outweighed any risks. The agency doesn’t have to follow an advisory panel’s recommendation, but, typically, it does.
Dr. Christopher Zahn, vice president for practice for the American College of Obstetricians and Gynecologists says he thinks taking Makena off the market would be a mistake.
While the second study “was designed to be a confirmatory trial, there are some factors that make it difficult to interpret,” Zahn says. Although it was much larger than the first study, the second one included a far higher percentage of women who were at low risk of preterm delivery.
This makes direct comparisons of conflicting findings from the two studies difficult, Zahn says, and underscores a need for further confirmatory research.
Makena is the only medication currently available to prevent preterm birth, Zahn notes, and is now the standard of care for women at high risk who have a previous preterm birth.
“It’s one thing to have concern raised because of conflicting data,” he says, “but if that particular medication isn’t available, it no longer becomes an option.” Zahn worries that pulling the drug could produce an uptick in premature births, which creates a host of tragic problems for babies.
“It’s well known that infants born prematurely have increased risks of poor outcomes — including death — and that the risk decreases as gestational age increases” says Zahn. After birth, he adds, premature infants can have “breathing or respiratory problems, organ dysfunction, difficulty with vision and hearing and neural developmental delay.”
In response to the advisory panel’s recommendation, ACOG has issued a statement declaring that its current guidance will remain in effect for now. In part, ACOG’s guidance says, “A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16-24 weeks of gestation to reduce the risk of recurrent spontaneous preterm birth.”
The obstetricians’ group also says it will “monitor this topic, evaluate additional literature and any further analyses as published.”
Pressman says she agrees that more study of the drug’s relative usefulness is “probably needed.” And she notes that the University of Rochester Medical Center, where she works, will not advise discontinuing the medication for women who have already been receiving weekly injections — “because there is some data indicating that withdrawing progesterone and stopping the treatment can increase the risk of preterm birth more than if they hadn’t started in the first place.”
Lewis, too, calls for more research to better understand the conflicting data. Some patients, she says, do need to be treated for this very serious condition and physicians and other providers want to do the best thing for those patients.
But right now, she says, “it’s very difficult to make a choice, based on the evidence that we have.”