Peter Stein, director of the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research, acknowledged in closing arguments the 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 testified during three days of hearings about the urgent need for such a drug, but only if the data and science support it — and that’s not the case for Makena.
“Hope is a reason to keep looking for alternatives that are effective, whether we find them here or elsewhere,” he said. “Hope is not a reason to take a drug that has not been shown to be effective. or keep it on the market.”
The recommendations of the panel of independent advisers are non-binding, although the agency usually follows their advice. Pulling a drug off the market is a very 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 Urological Drugs Advisory Committee.
Several health groups have supported keeping Makena on the market while further studies are done, concerned that pulling it could exacerbate health disparities. “We believe that removing access will have a detrimental impact on the health of women and childbearing individuals at risk of repeated preterm births and will not affect all women equally,” said Martha Nolan, senior policy adviser at HealthyWomen, a nonprofit women’s health group focused on helping women to make informed decisions about their care.
Members of the panel, made up of maternal health experts, neonatologists, statisticians and other experts, spoke of the difficulty of the decision.
“I’m so disappointed … I wish we weren’t sitting here today,” one member said. Another expressed “deep sadness” at the large-scale trial against Makena that showed no benefit.
Esther Eisenberg, a reproductive endocrinologist, supported withdrawing the drug, “but I’m very conflicted. This is a very difficult question.”
Cassandra Henderson, a maternal-fetal medicine specialist in New York City who was the only panel member to say the large clinical trial showed promise in some patient subgroups and to vote to keep the drug on the market, said she was concerned about the low representation. of minority women in the trial, as “we know that race is kind of a surrogate for racism and all the structural inequalities.”
Drugmaker Covis Pharma and its supporters have argued that the study may have missed benefits in high-risk populations in the United States because participants were mostly Eastern European and only 7 percent responded. In a filing with the FDA, the drug company called the latter trial “flawed,” not only because of the racial demographics, but also because the population was low-risk and the women had access to national health care that differs greatly from the complex piecemeal system in the United States.
Raghav Chari, Chief Innovation Officer for Covis, had testified that the company was willing to work with the agency to limit Makena’s use to only “a higher-risk target group” and would also agree to stop actively marketing the drug.
He called this a “practical approach” that would enable individual doctors in consultation with their patients to make decisions about whether use of the drug might be helpful.
Chari said Covis is committed to conducting further studies to address questions about the drug’s potential risks and benefits, stressing that reducing preterm birth is a public health priority and an area of unmet need in drug development.
“We are not suggesting that race biologically separates patients,” he said Wednesday. “At the same time, it is well documented that preterm birth disproportionately affects black and other minority women in the United States. These and other social determinants of risk are factors in defining the higher-risk population in which 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 disparity argument “suggests that the drug is effective and suggests that the drug is safe” when we don’t actually have an answer to 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 it is not appropriate to allow Makena to remain on the market and that it would lead to “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 drug manufacturers are then required to carry out studies that confirm the substance’s benefits in order to continue selling the medicine. But the debate over Makena’s effectiveness more than a decade after it was approved underscores the complexity 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.
As for Makena, the FDA’s Center for Drug Evaluation and Research proposed pulling 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 limited use would “nullify the intent of the accelerated pathway.” He argued that “absent evidence of effectiveness, we are left with only risk. The benefit-risk balance for Makena is not favorable.”