FDA Decision on Premature Birth Drug Withdrawal Looms: Patients and Regulators in Focus
The U.S. FDA is expected to decide soon on whether to withdraw Makena, a drug for preventing premature birth. The drug did not show a reduction in preterm birth risk in 2019 confirmatory trials, but its withdrawal would leave some high-risk pregnant women without the only approved preventive option. The FDA advisory committee recommended withdrawal by a vote of 14 to 1, with the final decision to be made by Commissioner Califf and Chief Scientist Bumpus. The controversy also involves deeper issues such as racial disparities, regulation of compounded formulations, and insufficient investment in preterm birth research.
Nicole's first child was born two months premature. When she became pregnant with her second child, worried about another early birth, she learned about a hormone injection that could reduce the risk.
"After having my first child, even the people in the NICU kept telling me, 'If you get pregnant again, you must get this shot,'" Nicole recalled.
Her doctor told her that a drug called Makena was her only option to prevent preterm birth—a condition linked to an increased risk of infant death and disability. But no one mentioned that the drug's approval was conditional and its effectiveness was questionable.
"They told me the benefits outweighed the risks," Nicole said. BioPharma Dive withheld her full name to protect her privacy.
Nicole followed the doctor's orders and ultimately delivered what she calls her "Makena baby" at 38 weeks, just shy of full term. She believes the drug is responsible for the persistent bladder and hormonal issues that began during her second pregnancy and worries about its effects on the fetus in utero.
The causes of preterm birth are not fully understood, but certain factors are associated with it, including lifestyle, a short cervix, and a history of prior preterm birth. According to data from the U.S. Centers for Disease Control and Prevention, about 1 in 10 births in the U.S. in 2021 was preterm, the highest rate since 2007.
When Nicole used Makena, the drug had been on the market for nine years under the U.S. Food and Drug Administration's (FDA) accelerated approval for preventing preterm birth. The approval was contingent on the manufacturer confirming in subsequent trials that Makena indeed reduces the risk of preterm birth.
However, years after the supporting evidence was overdue, a confirmatory clinical trial published in 2019 showed that Makena did not reduce the rate of preterm birth compared with a placebo.
In the years since, Makena has become a controversial case testing the FDA's power to withdraw drugs whose mandatory follow-up trials were not passed. FDA advisers, some doctors, and women who were prescribed the drug urged the FDA to act, citing Makena's uncertain benefits and known risks.
"If a drug remains on the market after it has been shown to be ineffective, then the very purpose of the FDA is questionable," said Amy Romano, a midwife and CEO of the consulting firm Primary Maternity Care, at an FDA hearing in October.
Covis Pharma, the drug's current owner backed by private equity, resisted the FDA's efforts to withdraw Makena's approval. Some doctors also felt conflicted—if Makena were removed from the market, high-risk women would have no drug to use.
The FDA's top leadership—Commissioner Robert Califf and Chief Scientist Namandjé Bumpus—are expected to make a decision soon, possibly this month. The ruling will determine Makena's future and is being closely watched by the pharmaceutical industry.
Known risks, unclear benefits
Makena consists of a synthetic hormone called hydroxyprogesterone caproate. The hormone was originally sold by Bristol Myers Squibb under a different name and had been used since the 1950s for various obstetric and gynecological conditions, but not for preterm birth prevention. After Bristol Myers Squibb stopped selling it in the late 1990s, the drug left the market.
In 2011, KV Pharmaceutical obtained FDA accelerated approval for the hormone under the name Makena for use in pregnant women with at least one prior preterm birth, based on a 2003 clinical trial conducted by the U.S. National Institutes of Health. That trial showed that women receiving the injections had a rate of delivery before 37 weeks that was reduced by about one-third.
KV was required to complete a larger study to confirm the benefit, a responsibility inherited by Amag Pharmaceuticals when it acquired KV in 2014. However, progress was slow, and results were not published until 2019. The data showed that Makena neither reduced preterm birth rates nor improved the health outcomes of preterm infants, casting doubt on its market position.
"In our view, the drug should never have been approved based on that 2003 trial," said Michael Carome, director of the health research group at the advocacy organization Public Citizen.
"Combined with the well-designed, larger post-marketing trial showing no benefit, it is clear the drug should be removed from the market because it is ineffective for its approved use," Carome added. Public Citizen, a frequent critic of the FDA and the pharmaceutical industry, has opposed Makena's continued sale.
The uncertainty over Makena's benefits has drawn more attention to its risks. Although neither the 2003 study nor the confirmatory trial raised major safety concerns about the drug, Makena still carries side effects and was associated with higher numbers of miscarriages and stillbirths in the 2003 trial.
"If something has no benefit, then it only has risks. And the risks are real," Romano said at a recent FDA meeting, calling for the drug's withdrawal.
Adam Urato, a maternal-fetal medicine specialist in Framingham, Massachusetts, holds the same view. "We have essentially been injecting pregnant women for 20 years with a synthetic hormone that is ineffective and poses risks to both mother and baby," Urato said.
In the regulatory spotlight
Last fall, an expert advisory meeting convened by the FDA debated many of the concerns raised by Romano and Urato. The hearing was the latest step in a years-long regulatory tug-of-war between the FDA and the drug's owner over the failed study.
The FDA first attempted to withdraw Makena from the market in October 2020, a year after the same advisory committee voted 9 to 7 in favor of the FDA revoking the drug's approval.
By then, Makena had a new owner—Covis had just completed its acquisition of Amag. The two companies disputed the FDA's proposal, requesting a second hearing, which delayed the process and ultimately led to the three-day meeting last October.
At the meeting, doctors, experts, and patients testified both against and in support of Makena. Covis argued that the drug should remain on the market with restrictions while another trial is conducted.
"I think Makena might be in that state right now," said Aaron Caughey, a maternal-fetal medicine specialist and obstetrician at Oregon Health & Science University.
As a member of the FDA panel last October, Caughey voted against Makena remaining on the market as is, calling for further research in high-risk populations. But he added in an interview that while Makena's evidence does not seem to meet FDA approval standards, many drugs are used off-label by doctors for specific populations.
"I would offer the drug and discuss the currently imperfect evidence with the patient, viewing it as an opportunity for 'shared medical decision-making' between the patient and physician."
The FDA argued that keeping Makena on the market while Covis conducts another trial is "not feasible" because it would be difficult to give women a placebo in a trial of a drug still being sold. Results would also not come quickly—Covis estimated that a trial enrolling 400 participants would take four to six years to complete.
Covis and supporters of Makena also cited its status as the only approved drug to reduce the risk of preterm birth, while the rate of preterm birth in the U.S. continues to rise.
"This is the only safe and effective drug, and you want to remove it from the market, denying access to some of the most vulnerable patient populations," said Sally Greenberg, CEO of the advocacy group National Consumers League, testifying in support of Makena at the October meeting.
Ultimately, the FDA advisers were not convinced. They voted 14 to 1 to recommend that the FDA withdraw Makena from the market, providing support for the agency's action. Final documents from Covis and the FDA's review office must be submitted by March 6, after which Califf and Bumpus will make the agency's decision.
If something has no benefit, then it only has risks. And the risks are real.
Amy Romano
CEO of Primary Maternity Care
The fairness debate
In arguing for keeping Makena, Covis pointed to potentially greater benefits for Black women—who have higher rates of preterm birth than white or Hispanic women.
The company's position is based on data from the 2003 trial that led to Makena's approval. In that study, 273 of the 310 participants who received the drug were non-Hispanic Black women.
In contrast, the confirmatory study was conducted in Europe and enrolled mostly white women. Covis therefore argued that the trial failed to reflect Makena's benefits in high-risk individuals.
"These patient populations are underserved and have not received the attention and research needed to ensure safe pregnancies," Greenberg said. "This group already faces issues with healthcare access, which makes ensuring they receive safe and effective drug treatments even more difficult."
But at the October meeting, the advisers were skeptical of Covis's claims. According to the FDA, no subgroup of women in the confirmatory trial benefited from Makena, including the Black women enrolled.
Caughey of Oregon Health & Science University was also cautious about attributing differences in Makena's benefits by race.
"There is no evidence that Black women have biological differences from the majority population—white women or other racial and ethnic groups," Caughey said. "A more reasonable assumption is that the effects of systemic and structural racism in the U.S. and other countries harm overall health."
Another debate over compounded formulations
Before Makena was approved in 2011, its ingredient hydroxyprogesterone caproate was available at compounding pharmacies—a regulatory gray area not subject to the same pharmaceutical oversight as brand-name drugs.
The FDA's approval changed that landscape, as the agency urged doctors to prescribe its approved formulation. But in practice, the FDA initially declined to take action against pharmacies that continued to compound hydroxyprogesterone caproate. KV Pharmaceutical, criticized for pricing Makena far above the compounded version, later sued the FDA to restrict the availability of compounded products.
After acquiring KV in late 2014, Amag introduced a more convenient formulation designed to replace the use of compounded hydroxyprogesterone caproate and boost sales.
Between 2015 and 2019, Amag recorded hundreds of millions of dollars in annual Makena sales, a significant portion of which came from state Medicaid programs. According to data from the telehealth company GoodRx, the average retail price of a weekly Makena injection is currently about $1,500.
At the October meeting, Covis argued that withdrawal would prompt doctors to turn again to compounded alternatives, claiming this would pose greater safety risks to patients.
"Regarding compounded formulations, the FDA has recognized that unnecessary use of compounded drugs can unnecessarily expose patients to potentially serious health risks," said Rebecca Wood, a partner at Sidley Austin representing Covis, at the October meeting.
But the FDA countered that Makena's use has already declined by nearly half since the negative confirmatory trial results were published. Withdrawal could lead to further declines in prescriptions, and the FDA stated that pharmacies would be prohibited from compounding the drug for preterm birth prevention after withdrawal.
A call to action?
Some argue that Makena's status for years as the only available drug to reduce the risk of preterm birth itself reflects a broader problem.
"Preterm birth is a major contributor to perinatal death, infant death, and long-term infant illness," Caughey said. "So why we are not willing to invest more resources in understanding and preventing it, I do not fully understand."
Reproductive medicine, typically housed under women's health at pharmaceutical companies, has historically received less investment than other therapeutic areas. Maternal-fetal medicine receives even less funding.
"Investment in pregnancy and pregnancy-related conditions should almost be greater than in other areas because it has been chronically underfunded," Caughey said.
The debate over Makena also reveals how little the scientific community knows about preterm birth and its causes.
"Preterm birth is multifactorial, and thinking we can find a 'silver bullet' drug to address all preterm births—given its complexity—is quite unrealistic," Urato said.
Progesterone, the chemical basis for synthetic hydroxyprogesterone caproate, is known to support pregnancy, and low levels are associated with miscarriage. Some forms of it are also used in birth control pills.
"Beyond knowing that progesterone is a hormone produced during pregnancy and that we think it is involved in maintaining pregnancy, we do not fully understand its mechanisms," Caughey said. "This lack of mechanistic understanding is part of a broader problem in the pregnancy field. We do not really know what causes preterm birth."
Meanwhile, women in Nicole's situation will continue to seek answers. Nicole remembers asking whether there were other ways to prevent another preterm birth. "The doctor told me this was the only drug that could prevent preterm birth," Nicole said.
In Urato's view, even if another drug beyond Makena were developed, proper prevention would require more than just medication. Systemic issues such as underinvestment in research, health equity, and how the U.S. treats pregnant women are equally important.
"I think there are lessons to be learned," Urato said. "We should not miss this opportunity to reflect on what happened here and where exactly things went wrong in the (healthcare) system."