Nicole’s first child was born two months early. Pregnant with her second and fearing another preterm labor, she learned of a hormonal shot that could lower her risk.
“After I had my first baby, even the people in the [neonatal] ICU, they kept telling me, ‘If you ever have another baby, you're going to have to be on shots,’” Nicole said.
Nicole’s doctors told her the drug, called Makena, was her only option to prevent preterm labor, which is associated with a higher risk of death and disability for the baby. But none mentioned its approval was conditional, and that its effectiveness was in question.
“They told me the benefits outweigh the risks,” said Nicole, whose full name BioPharma Dive is withholding to protect her privacy.
Nicole took the drug as prescribed and delivered what she calls her “Makena baby” at 38 weeks, just shy of full term. She believes the drug is to blame for lasting bladder and hormonal issues that started during her second pregnancy. And she remains concerned about how the drug affected her child in utero.
While the causes of early labor aren’t well understood, certain factors are associated with it, including lifestyle, a short cervix and a prior history of preterm births. In 2021, roughly 1 out of every 10 births in the U.S. was preterm — the highest rate since at least 2007, according to the Centers for Disease Control and Prevention.
When Nicole took Makena, the drug had been on the market for nine years under an accelerated approval granted by the Food and Drug Administration for preterm birth prevention. The clearance was contingent on its maker confirming, in further testing, that Makena did in fact lower the risk of an early labor.
But in 2019 — years after that supporting evidence was due — results from a confirmatory clinical trial comparing Makena to a placebo showed the treatment didn’t work.
In the years since, Makena has become a controversial test case of the FDA’s authority to withdraw treatments that have failed in required follow-up testing. The agency’s advisers, as well as some physicians and women who were prescribed the drug, have pressured the FDA to act, citing Makena’s uncertain benefits and known risks.
“It calls into question what the FDA exists for in the first place if we’re going to keep drugs on the market after we learned that they didn’t work,” said Amy Romano, a midwife and CEO of consulting firm Primary Maternity Care who spoke at an October FDA hearing on Makena.
The drug’s current owner, private equity-backed Covis Pharma, has resisted, fighting the FDA’s attempt to remove Makena’s approval. Other physicians are conflicted, aware that, without Makena, at-risk women would be left with no treatment option.
A decision from the FDA’s top leadership — Commissioner Robert Califf and Chief Scientist Namandjé Bumpus — is expected soon, possibly by this month. Their verdict will decide Makena’s future and be closely watched by the pharmaceutical industry more broadly.
Known risk, uncertain benefit
Makena consists of a synthetic hormone known as hydroxyprogesterone caproate. Originally sold by Bristol Myers Squibb under a different name, the hormone has been used since the 1950s for several gynecological and obstetrical conditions other than preterm birth prevention. It was removed from market after Bristol Myers stopped selling it in the late 1990s.
But the hormone became available as Makena in 2011, when a company called KV Pharmaceutical won an accelerated FDA approval for its use in pregnant women with at least one prior preterm birth. The clearance was supported by a 2003 clinical trial run by the National Institutes of Health that showed women who received the injection had a roughly one-third lower rate of delivery before 37 weeks of gestation.
KV was required to complete a larger study confirming that benefit, a responsibility inherited by Amag Pharmaceuticals when that drugmaker acquired KV in 2014. However, progress was slow, and results didn’t become available until 2019. The data showed Makena did not reduce the rate of early labor, nor did it improve the infant’s health after a preterm birth, calling into question the drug’s place on the market.
“In our view, the drug should not have been approved [on the basis] of that  trial,” said Michael Carome, director of the advocacy group Public Citizen’s health research group.
“When you combine that information with the well-designed, larger post-market trial showing no benefit, it was clear to us that the drug should come off the market because it's not effective for its approved use,” Carome added. A frequent critic of both the FDA and the drug industry, Public Citizen has opposed Makena’s continued marketing.
The uncertainty around Makena’s benefit has put greater scrutiny on its risks. While neither the 2003 study nor the confirmatory trial raised major red flags for the drug’s safety, Makena still comes with side effects and, in the 2003 trial, was associated with a greater number of miscarriages and stillbirths.
“If there are no benefits to something, there are only risks. And there are risks,” said Romano, who called for the drug’s withdrawal at the recent FDA meeting.
Romano’s view is shared by Adam Urato, a maternal-fetal specialist based in Framingham, Massachusetts. “We've basically been injecting pregnant women for 20 years with a synthetic hormone that doesn't work, and carries risks to the moms and babies,” said Urato, an industry critic who urged Makena’s withdrawal.
A regulatory spotlight
Many of Romano’s and Urato’s concerns were debated at a meeting of expert advisers convened by the FDA last fall. The hearing was the latest step in a yearslong regulatory battle between the agency and Makena's owners over the drug's study failure.
The agency first tried to remove Makena from the market in October 2020, one year after an earlier meeting of the same advisory committee voted 9-7 in favor of the FDA withdrawing the drug’s approval.
By then, Makena had yet another new owner, Covis, which was just finalizing an acquisition of Amag. The companies disputed the FDA’s proposal and requested a second hearing, drawing out the process and leading to the meeting that was held over three days this past October.
There, doctors, experts and patients testified both against and for Makena, which Covis argued should remain on the market in more limited fashion while it runs another trial.
“I think that's probably where Makena should be for the moment,” said Aaron Caughey, an obstetrician and gynecologist who specializes in maternal-fetal medicine at Oregon Health & Science University.
A member of the FDA panel last October, Caughey voted against recommending Makena remain on the market as is, calling for further study of the drug in high-risk populations. However, in an interview, he added that, while Makena's evidence doesn't appear to meet the FDA's approval standards, many drugs are prescribed by doctors off-label for specific use in certain individuals.
“I would offer it and discuss with patients the evidence that we have, which is imperfect at the current time, and allow it to be what we call a ‘shared medical decision-making opportunity’ between the patient and the provider.”
The FDA argued keeping Makena on the market while Covis conducted another trial would be “infeasible,” as it would be difficult to give women a placebo in a study of a drug that’s still commercially available. Results would not be available for some time, either, as Covis estimated a trial enrolling 400 participants would take four to six years to complete.
Covis, as well as those who spoke in favor of Makena, also cited its status as the only available medicine to reduce the risk of preterm birth, the incidence of which has steadily been increasing in the U.S.
“This is the one safe and effective drug, and you’re going to pull it from the market, and not allow access to it by some of the most vulnerable patient populations,” said Sally Greenberg, CEO of the advocacy group National Consumers League and who testified in support of Makena at the October meeting.
Ultimately, the FDA’s advisers weren’t swayed. They voted 14-1 to recommend the FDA pull Makena from market, lending support for the agency to do so. Final documents from both Covis and the FDA office that reviewed Makena are due to be filed by March 6, after which Califf and Bumpus will make the agency’s decision.
If there are no benefits to something, there are only risks. And there are risks.
CEO, Primary Maternity Care
An argument for equity
In arguing for keeping Makena available, Covis pointed to a potentially greater benefit in Black women, for whom preterm birth is more common than White or Hispanic women.
The company’s position was built around data from the 2003 trial that led to Makena’s approval. Two hundred and seventy three of the 310 participants in that study who received the drug were non-Hispanic Black.
The confirmatory study, by contrast, was conducted in Europe and enrolled mostly white women. As a result, Covis believes the trial wasn’t reflective of Makena’s benefit among higher-risk individuals.
“These patient populations are underserved and don't get the necessary attention and research needed to ensure that they have safe pregnancies,” said Greenberg. “This is a population that suffers from access to health care, and that makes it doubly difficult to ensure they have access to safe and effective drug treatments.”
But, in the October meeting, advisers were skeptical of Covis’ claims. There were no subgroups of women who benefited from Makena in confirmatory testing, according to the FDA, including among the Black women enrolled in the trials.
Caughey, of OHSU, is similarly wary of attributing differences in Makena’s benefit by race.
“There's no evidence to suggest Black women have a different biology than the majority of the population, white women or other racial-ethnic groups,” Caughey said. “Rather what is suspected, both in the U.S. and in other countries, is the effects of systemic racism and structural racism, both impact health in general.”
Another debate: compounding
Until Makena’s 2011 approval, the drug ingredient that comprises it, hydroxyprogesterone caproate, was available at compounding pharmacies, a regulatory gray zone that doesn’t fall under the same kind of pharmaceutical oversight as branded medicines.
The FDA’s approval changed that, as the agency urges physicians prescribe the formulations that it approves. In practice, though, the agency initially declined to take action against pharmacies that continued to compound hydroxyprogesterone caproate. KV Pharmaceutical, which drew criticism for pricing Makena far higher than what compounded versions cost, later sued the FDA to limit their availability.
After it acquired KV in late 2014, Amag introduced a more convenient formulation that was meant to supplant use of compounded hydroxyprogesterone caproate — and boost sales.
Between 2015 and 2019, Amag recorded hundreds of millions of dollars in Makena sales each year, a significant portion of which was through state Medicaid programs. Currently, the average retail cost of a once weekly Makena injection is about $1,500, according to the telemedicine company GoodRx.
At the October meeting, Covis argued withdrawal of Makena would spur doctors to once again turn to compounded alternatives, which, it claimed, would result in greater safety risks for patients.
“With respect to compounding generally, FDA has recognized that the unnecessary use of compounded drugs unnecessarily exposes patients to potentially serious health risks,” Rebecca Wood, a partner at the law firm of Sidley Austin representing Covis said at the October meeting.
But the FDA countered that the use of Makena has fallen by nearly half since the publication of the negative confirmatory trial results. A withdrawal would likely cause prescriptions to drop further and the agency has said that, following a market removal, pharmacies would be barred from compounding the drug for use in preterm birth prevention.
A call to action?
That Makena has for years been the only treatment available to lower the risk of preterm birth is part of a broader problem, according to some.
“Preterm birth is the major contributor to perinatal mortality, babies dying and babies having long-term medical conditions,” said Caughey. “So why we wouldn’t want to invest much, much more into understanding and prevention, I don’t fully understand.”
Reproductive medicine, often organized within pharmaceutical companies’ women’s health divisions, has historically received less investment than other therapeutic areas. Maternal-fetal medicine draws even less money.
“There almost needs to be more investment in pregnancy and pregnancy-related conditions than other things because it’s been under-invested in for so long,” Caughey said.
The debate over Makena has also revealed how little scientists know about preterm birth and its causes.
“Preterm birth is multifactorial, and the idea that we can come up with a silver bullet medication that's going to address all of preterm birth — that's pretty far-fetched, given what a complex disorder it is,” Urato said.
Progesterone, the hormone that’s the chemical root of synthetic hydroxyprogesterone caproate, is known to support pregnancy and low levels are associated with miscarriages. Forms of it are also used in birth control pills.
“Other than knowing that progesterone is a hormone that’s produced in pregnancy and that we think is related to the maintenance of pregnancy, we don't fully understand how,” said Caughey. “The lack of understanding of mechanistic stories is part of the problem in pregnancy writ large. We don't really understand what causes preterm birth.”
In the meantime, women in Nicole's position will be searching for answers. Nicole remembers asking if there was anything else she could do to prevent another early delivery. “[The doctor] told me this was the only thing that can prevent preterm labor,” Nicole said.
In Urato’s view, proper prevention requires more than just a drug, even if another is developed besides Makena. Systemic issues such as lack of investment in research, health equity and how pregnant people are treated in the U.S. matter, too.
“I think lessons need to be learned,” Urato said. “We shouldn't miss this as an opportunity to draw lessons about what happened here and about what really went wrong in the [healthcare] system.”