But FDA experts and others said the data does not support such a view. In closing arguments, Peter Stein, director of the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research, agreed on the urgent need for a drug to reduce the incidence of preterm birth — a leading cause of infant mortality in the United States. But he said the data indicates that Makena is not that drug.
“Hope is a reason to keep looking for options that are effective,” he said. “Hope is not a reason to take a drug that is not shown to be effective, or keep it on the market.”
The recommendations of the panel of independent advisers are nonbinding, though the agency usually follows its advice. Withdrawing a drug from the market is a highly unusual step.
The three-day hearing was emotional both for members of the public, as well as those on the Obstetrics, Reproductive, and Urologic Drugs Advisory Committee.
Several health groups supported keeping Makena on the market while further study is done, worried that pulling it could deepen racial health inequities. “We believe that removing access will have a detrimental impact on the health of women and birthing people at risk of recurrent preterm births and will not impact all women equally,” said Martha Nolan, senior policy adviser at HealthyWomen, a nonprofit reproductive health group focused on helping women making informed decisions about their care.
Members of the panel, which is made up of maternal health experts, neonatologists, statisticians and other experts, related their distress at data from a large trial of Makena that showed no benefit for the drug when there are no good alternatives for women at high risk of delivering early.
“I’m so disappointed. … I wish we weren’t sitting here today,” one member said.
Another, Esther Eisenberg, a reproductive endocrinologist, said she supported withdrawing the drug, “but I’m very conflicted. This is a very very difficult question.”
Cassandra Henderson, a maternal-fetal medicine specialist in New York City who was the sole panel member who argued the large clinical trial showed promise for some patient subgroups and who voted to keep the drug on the market, said she was concerned about the low representation of minority women in the trial, as “we do know race is sort of a surrogate for racism and all the structural inequities.”
Drugmaker Covis Pharma and its backers have argued the study may have missed its benefits in high-risk populations in the United States because participants were largely Eastern European and only 7 percent Black. In a filing with the FDA, the drug company called the latter trial “flawed,” not only because of its racial demographics, but also because the population was low-risk and the women had access to national health-care systems that differ greatly from the complex piecemeal system in the United States.
Raghav Chari, chief innovation officer for Covis Pharma, had testified the company was willing to work with the agency to limit Makena’s use to “a higher-risk target population” only and would also agree to stop active promotion of the drug.
He called this a “practical approach” that would enable individual physicians in consultation with their patients to make decisions about whether using the drug might be helpful.
“We are not proposing that race biologically differentiates patients,” he said Wednesday. “At the same time, it is well-documented that preterm birth disproportionately impacts women who are Black and other minorities in the United States. These and other social determinants of risk are factors in defining the higher-risk population where Makena is most likely to be effective.”
But Joseph Alukal, a urologist who is director of men’s health at NewYork-Presbyterian/Columbia University Irving Medical Center, suggested the racial inequity argument “implies the drug is effective and implies the drug is safe” when we do not actually have an answer on that.
Makena was approved by the FDA in 2011 under an accelerated approval program for drugs that treat serious conditions for which there are no treatments. The drugmakers are then required to conduct studies confirming the drug’s benefits to continue selling the medication. But the debate over Makena’s effectiveness more than a decade after its approval underscores the complexities of that program, highlighting how it can take the agency years to pull a drug from the market even if officials believe it is ineffective.
In the case of Makena, the FDA’s Center for Drug Evaluation and Research proposed withdrawing it from the market in October 2020 — a move that followed an expert advisory panel’s 9-7 vote a year earlier to pull it from the market based on disappointing results from a large confirmatory study. But regulatory requirements, as well as the pandemic, have slowed the process.
The FDA’s Stein argued that leaving Makena on the market for a narrowed use would “upend the intention of the accelerated pathway.” He argued that “absent evidence of effectiveness, we are only left with risk. The benefit-risk balance for Makena is not favorable.”
Francesco Tallarico, Covis’s head of government affairs and policy, said the company was “obviously very disappointed” with the advisory committee’s vote. The company would “continue to have a dialogue” with the FDA before making decisions on whether to move forward with a new randomized controlled trial, he said.
A decision by the FDA won’t come immediately. Within 45 days of the transcript of the hearing being posted, the meeting’s presiding officer — Celia M. Witten, deputy director of the FDA’s Center for Biologics Evaluation and Research — will put out a report about the panel’s recommendations that also contain her own views.
Then, the evaluation and research center and Covis will have 45 days to comment. Afterward, FDA Commissioner Robert Califf and the agency’s chief scientist will review the information and make a decision, which they “plan to do … expeditiously,” said FDA spokesperson Shannon Hatch.