Peter Stein, director of the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research, acknowledged in closing arguments clinicians’ arguments about the need for an effective drug to reduce the incidence of preterm birth — a leading cause of infant mortality in the United States. He said the agency agrees with clinicians who tested during three days of hearings on the urgent need for such a drug, but only if the data and science support it — and that is not the case for Makena.
“Hope is a reason to keep looking for options that are effective, whether we find them here or elsewhere,” 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, although 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 the panel members of the Obstetrics, Reproductive, and Urologic Drugs Advisory Committee.
Several health groups have supported keeping Makena on the market while further study is done, worried that pulling it could deepen 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, nonprofit women’s health group focused on helping women make informed decisions about their care.
Members of the panel, which is made up of maternal health experts, neonatologists, statisticians and other experts, related the difficulty of their decision.
“I’m so disappointed … I wish we weren’t sitting here today,” one member said. Another expressed “deep sadness” about the large trial of Makena that showed no benefit.
Esther Eisenberg, a reproductive endocrinologist, 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 that the study may have missed its benefits in high-risk populations in the United States because participants were largely Eastern Europe 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, had tested 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.
Chari said Covis is committed to conducting additional studies to address questions about the drug’s potential risks and benefits, emphasizing that reducing preterm birth is a public health priority and an area of unmet need in drug development.
“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 Columbia/NewYork-Presbyterian, 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.
Mark Hudak, a neonatologist at the University of Florida College of Medicine, said he is “sensitive to the disparity issues that have been raised.” However, he said allowing Makena to remain on the market is not appropriate and would result in “complete regulatory chaos.”
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’s 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.”
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