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A committee for the US Food and Drug Administration now recommends that the approval of Makena, a drug used to reduce the risk of preterm births, should be withdrawn – and some women who have used the medication are sounding the alarm.

The 9-7 vote, which took place at a meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee on Tuesday, came in response to evidence suggesting that the drug was not effective.

The committee serves as an advisory group to the FDA and the voting results are not binding, said Dr. Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, who was not involved in the committee meeting.

“Most of the time the FDA will make a decision that aligns with the committee, but not always,” Gellad said.

“One study showed FDA will go against the committee about 20% of the time. But the committee did vote that removal of the drug from the market was warranted, which is relevant for supporting any FDA decision about withdrawal,” he said.

An FDA spokesperson confirmed in an email on Thursday that the committee voted 13-3 that there is not “substantial evidence of effectiveness of Makena in reducing the risk of recurrent preterm birth,” based on findings from two trials that were part of a study called PROLONG, published last week in the American Journal of Perinatology.

Nine members of the committee voted to “pursue withdrawal of approval for Makena,” and seven members voted to “leave Makena on the market under accelerated approval and require a new confirmatory trial.”

None voted to leave the drug on the market without requiring a new confirmatory trial.

Makena, sold by AMAG Pharmaceuticals, is a progestin hormone that gets delivered to a patient as an injection. In 2011, the FDA approved the medicine to reduce the risk of preterm birth in women who have a history of spontaneous preterm birth under the provisions of “accelerated approval” regulations.

“Accelerated approval is a mechanism for drugs to be approved by FDA before they have proven benefit. They need to address a high need clinical condition for which there are no or few other therapies, like premature birth, and they have to show some effect on a surrogate outcome – an outcome that is reasonably expected to be related to clinical benefit,” Gellad said.

“As a requirement for a drug that is approved through accelerated approval, the company must perform a confirmatory trial to show clinical benefit. In this case, it took eight years, and the confirmatory trial showed no benefit,” he said, adding that many of the patients in the trial were not from the United States.

“So one argument from the company is that the trial does not represent effectiveness in the US, and because there are no other drugs available, and a prior study showed effectiveness, and it’s recommended by various OB/GYN groups, that it should stay on the market and be evaluated in another trial,” he said. “The caveat is that this treatment existed even before accelerated approval because pharmacies could compound or make the therapy themselves – so if the drug leaves the market, there is still an option to use the drug.”

What this means for moms-to-be

Current guidelines in the United States recommend the use of progesterone supplementation, such as Makena, in women with prior spontaneous preterm births.

Last week, when the results of the PROLONG study were published, the Society for Maternal-Fetal Medicine released updated clinical guidance for providers to discuss important factors with patients, including “uncertainty regarding the benefit” of the drug.

Meanwhile, the American College of Obstetricians and Gynecologists released a statement from its Vice President for Practice Activities, Dr. Christopher Zahn, indicating that ACOG’s clinical guidance on the use of the medication will remain in effect.

“ACOG’s guidance is based on a review of the best available literature. As such, we will continue to monitor this topic, evaluate additional literature and any further analyses as published, and address findings as needed in relevant clinical guidance,” Zahn said in the statement.

Danielle Boyce, a mother of four and research consultant based in Philadelphia, had “significant preterm labor issues” with her first two children, including her eldest son, Charlie. He was born preterm at 34 weeks, developed a seizure disorder as a baby and now has Lennox-Gastaut syndrome, severe intellectual disability and autism, Boyce said.

When Boyce became pregnant for a third time at age 42, she was “very concerned” about having another preterm birth and made the shared decision with her physician to start using Makena. Her third and fourth children came home from the hospital and did not require a NICU stay. They are both healthy and developing normally, Boyce said.

“I am glad that I had the opportunity to use Makena while it was still available because it worked for me,” Boyce said in an email on Thursday.

Boyce added that she respects the decision the members of the FDA panel made – since it was based on evidence presented to them – but noted that “studies can be flawed.”

“As someone trained in epidemiology and statistics, as well as someone who has served on FDA panels myself, I can appreciate the difficult decision that the panel had to make given the evidence presented,” Boyce said.

“I agree that the study design could have been better and the statistical endpoints were not achieved,” she said about the evidence. “However, this is a rare case where the stakes are so high and the side effect profile is so low that an additional layer of scrutiny is warranted beyond the statistical evidence presented before a decision is made to pull this effective medication from the market.”

Boyce said that she would ask the FDA panel to consider ACOG’s judgment.

A drug left in limbo

Meanwhile, there also have been calls for the FDA to ban Makena.

Earlier this month, the consumer advocacy nonprofit Public Citizen submitted a petition to request that the FDA “immediately withdraw the approval of all medications containing hydroxyprogesterone caproate” (Makena).

Meena Aladdin, a health researcher at Public Citizen’s Health Research Group, testified during the FDA committee on Tuesday, arguing that “maintaining approval of Makena in the absence of any clinical benefits being demonstrated by Trial 002 or Trial 003 would make a mockery of the more than 50-year FDA legal standard requiring substantial evidence of a drug’s effectiveness.”

In response to the FDA vote, AMAG Pharmaceuticals’ Chief Medical Officer Dr. Julie Krop said in a statement that the company was “disappointed.”

“We are committed to working with the FDA to identify feasible ways to generate additional efficacy data on Makena while retaining current access to the therapy for at-risk pregnant women,” Krop said in the statement.

“For more than a decade, health care providers have relied on hydroxyprogesterone caproate (Makena) to reduce preterm delivery in high-risk patients, which aligns with recently updated treatment recommendations of the American College of Obstetricians and Gynecologists, as well as the Society for Maternal-Fetal Medicine,” she said.

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The medication now remains in limbo until the FDA makes a final decision based on its committee’s new recommendations.

“I predict FDA will remove the drug from the market, since the confirmatory trial showed no benefit, and removing the drug does not necessarily completely eliminate the opportunity for some women to receive the therapy,” Gellad said. “There is an 80% chance I will be right.”