A Food and Drug Administration advisory committee in a rare move on Wednesday voted 14-1 to pull the only available drug aimed at lowering the risk of premature births from the market, citing a lack of evidence that the medication shows any benefit.  

The Obstetrics, Reproductive and Urologic Drugs Advisory Committee’s recommendation is nonbinding, and FDA Commissioner Robert Califf will make the final decision in conjunction with Chief Scientist Namandjé Bumpus. But the agency typically follows the advice of its advisory committees, and top FDA officials argued forcefully against the drug, Makena, in presentations earlier this week.

The drugmaker’s attempts to find benefit in the data ultimately failed to persuade the committee. Members voting against the drug included Annie Ellis, a patient representative who emotionally recounted her own experience with risk of preterm birth, including crawling out of bed against her doctor’s orders to care for her three-year-old. 

“Sometimes when I see a lot of mathematical gymnastics being used to cut things in different ways and try to squeeze out a subset that has benefits, I have concerns,” she said, adding that she had to vote with her head rather than her heart.

Cassandra Henderson, a maternal medicine consultant with Rockwood Partners DPP, was the lone yes vote, noting the company’s initial trial showed some benefit and expressing concern that compounding pharmacies, which adapt drugs that are not commercially available and are largely outside of the FDA’s purview, would continue to offer riskier versions of the drug.

“I worry about that and I think if this is taken off the market my concern is that compounding will increase,” she said.

Accelerated approvals

The recommendation caps a marathon three-day hearing that effectively turned a conference room into an courtroom, with both the FDA and the drug’s current sponsor, Covis Pharma, questioning the other’s arguments. The FDA has been trying to yank the drug since 2019.

It’s also the latest example of higher scrutiny on drugs approved through the FDA’s accelerated approval pathway, which greenlights medications for unmet medical needs based on their likelihood to show a clinical benefit. Markers such as progress shown through X-rays or improvements in survival rates are used to assess accelerated approvals. 

Drugmakers are then required to conduct confirmatory trials proving the drug’s effectiveness. But those trials often take years to materialize, if they do at all. A September report from the Health and Human Services Office of the Inspector General found that one-third of the 278 accelerated approvals since the pathway’s inception in 1992 have incomplete follow-up studies. 

Makena’s confirmatory trial took 10 years — more than five years late, according to OIG. Medicaid has spent $700 million on the drug since its approval in 2011. 

The drug was approved based on results from a single trial. A larger confirmatory trial failed to prove the drug improved the length of pregnancy or the health of premature babies. 

Racial equity

But Covis argues the drug does benefit high-risk women. A number of patients, provider groups and consumer groups testified in support of keeping the drug on the market, since Makena is the only drug available to lower the risk of preterm births. 

Covis also framed the issue as a question of racial equity, given the higher risk in Black women. Makena’s supporters included Yolanda Lawson, the president-elect of the National Medical Association, a group that represents African American physicians. 

“If Makena is no longer available, the implications for high-risk women could be dire,” she testified. “It is my clinical perspective that Makena remains an important treatment option for higher-risk patients and should remain available to these women.”

The causes of premature births are not well understood, but it is known that infants born prematurely are at greater risk of breathing problems and conditions like cerebral palsy. 

FDA’s Center for Drug Evaluation and Research Director Patrizia Cavazzoni acknowledged the high U.S. rate of premature births, which affects one in 10 babies, in arguing to pull the drug.

“We once thought Makena was likely to be part of the answer to that problem,” she said. “Unfortunately, we no longer do.” 

Covis offered to narrow the drug’s label to high-risk women, reduce commercial promotions and voluntarily yank the drug if an additional trial failed to meet its goals.

“In all cases, if any of these indicate that the pre-specified goals cannot or have not been achieved, we will work with the FDA to withdraw the product from the market,” Chief Innovation Officer Raghav Chari said.

But the committee largely dismissed the company’s arguments that withdrawing the drug would make doctors and patients hesitant to enroll women in further trials. Even Merck executive Michelle Fox, the industry’s non-voting committee representative, voiced concerns about leaving the drug on the market given the FDA’s vocal stance against it.

“I don’t feel that it’s appropriate to continue to have the FDA state that they’re going to leave a drug on the market that they continue to state is ineffective, so that women can take it while the sponsor goes back to figure out if it actually works,” she said.  

An FDA advisory committee previously split over pulling the drug in 2019, recommending 9-7 for withdrawal. But Covis noted that five of the six OB-GYNs on the committee at the time voted to keep it on the market. 

The company argued the confirmatory trial was flawed and did not fully capture the drug’s effect on the highest-risk women, including Black women, thanks to high enrollment in countries like Ukraine and Russia. But committee member and New York University Department of Surgery Associate Vice Chair for Research Mara McAdams-DeMarco called that a “disingenuous argument.” 

“The rates of preterm birth were undoubtedly known prior to the start of the trial by the sponsor,” she said. “These things that are being brought up now as flaws were in fact identifiable during the design phase of the study.” 

FDA officials pointed to a slate of real-world and other external studies on the drug since its approval as evidence that Makena’s initial study was simply a “false positive.”

“There are a lot of randomized, double blind, placebo-controlled trials here,” said Laura Lee Johnson, a director in the FDA’s Office of Biostatistics. “A lot of real-world data, and a lot of different populations.”

Covis executives — including external counsel Rebecca Wood, FDA’s former chief counsel — argued the studies differed from Makena’s approved indications in various ways. They noted that one particular study showing a possible link to higher risks of cancer in children was focused on a different drug with the same active ingredient.

The drug also comes with risks, such as depression and blood clots, although the FDA’s main concern centers on effectiveness. 

“Absent evidence of effectiveness, we are only left with risk,” said Office of New Drugs Director Peter Stein.

Stein said attempts to reanalyze the data after the fact for evidence of benefit is helpful for further study, but simply amounts to “speculation and post hoc data dredging.” 

The FDA expressed concern that keeping the drug on the market would stymie further study on more effective treatments because it would hinder enrollment in new clinical trials.

“I hope that further studies of Makena and other potential treatments will be successful,” Stein said.