Premature birth drug Makena reignites debate over health care equity

A controversial preterm birth drug is renewing a debate among doctors about whether keeping fast-selling drugs on the market without clear clinical benefit is exacerbating racial health disparities.

In the coming months, the Food and Drug Administration is expected to decide whether to withdraw Covis Pharma’s Makena, which the FDA approved through its fast track in 2011. If it is pulled from the market, it would mark the first withdrawal of a drug’s fast track approval in more than Ten years.

Makena is designed to reduce the risk of preterm birth in patients who have previously had an unexplained birth before 37 weeks of pregnancy.

Taking the drug off the market would be particularly harmful to black patients, who face disproportionately higher rates of preterm birth, the drugmaker and patient advocacy groups said. Some of the groups received funding from previous producers of Covis and Makena.

But prescribing a treatment with little evidence that it works can expose minority groups to financial costs and exacerbated health risks, doctors and bioethicists say.

“What patients need is not just an approved product, they need products that will actually be clinically useful,” said Holly Fernandez Lynch, assistant professor of bioethics and law at the University of Pennsylvania.

“We don’t want to just put products on the market hoping they work, because that’s really not what patients need,” she added.

Makena’s pending decision comes amid broader pressure to change the FDA’s accelerated approval pathway, which is designed to speed access to drugs by relying on biomarkers or a surrogate endpoint as a laboratory measure to predict a drug’s clinical benefit .

Lawmakers are seeking to add to the year-end government spending package provisions that would give the FDA more tools to pull fast-track drugs that lack proven clinical benefit.

The defense of Covis

The FDA’s Center for Drug Evaluation and Research first proposed in October 2020 that Makena be removed from the market because a required post-marketing study failed to confirm clinical benefit.

A panel of independent FDA advisers voted overwhelmingly on Oct. 19 to recommend pulling the drug.

Covis acknowledged that its confirmatory trial did not show a clear clinical benefit. But the drug should remain on the market to allow for follow-up studies among groups at higher risk of preterm birth, including black women, Covis said.

A small 2003 clinical trial funded by the US National Institute of Child Health and Human Development showed some promise that 17 alpha-hydroxyprogesterone caproate, later approved as Makena, could help reduce the risk of preterm birth among women who have had a previous unexpected birth. The study, widely known as the Meis trial, was conducted in the US with nearly 60% of black participants and has been cited by Makena’s supporters as an indication that the drug may be useful for higher-risk groups.

Yolanda Lawson, an associate attending physician at Baylor University Medical Center and president-elect of the National Medical Association, spoke in support of keeping Makena on the market during advisory committee hearings in October. She said in an interview that the results of the Meis trial showed “proven benefit” for higher-risk groups.

“Being in practice, I can think of at least three patients who lost babies, never even had a live birth, but with the use of the drug and other measures they were able to have full-term, healthy babies,” Lawson said.

Covis also argued in the hearings that removing Makena from the market would fuel uncertainty about the drug’s safety, making it harder to recruit trial participants, particularly minority groups with a historical distrust of medical research due to decades of past abuse.

“It can definitely create doubt and suspicion” among patients about whether the drug is safe, Lawson said.

“Spin Campaign”

Doctors and bioethicists who support removing Makena from the market say they don’t buy Covis’ argument and that allowing doctors to continue prescribing the drug could put patients at risk with little chance of benefit.

Using health care equity as an argument for keeping a drug on the market is “an unethical use of the term,” said Adrian Fugh-Berman, a professor of pharmacology and physiology at Georgetown University.

“Something that is low-risk is not risk-free,” added Fugh-Berman, director of Georgetown’s PharmedOut Project, which aims to promote evidence-based prescribing and education about medical product marketing practices.

“Any level of risk is only worth it if the drug actually has a benefit, and this has no benefit,” she said. Known side effects of the drug include migraines, blood clots, and hypertension.

Adam S. Urato, a Massachusetts-based maternal-fetal medicine physician, was one of the people behind the 2019 citizen petition to the FDA requesting Makena be withdrawn. He said in an interview that health care providers like him “don’t want to give pregnant women drugs or do things to them that haven’t been proven to be safe and effective and have a clinical health benefit.”

“Health equity is a laudable goal, and we want everyone to do well,” Urato said. But health care equity can also “be used as a spin campaign, primarily to increase sales and profits or to keep drugs on the market.”

Covis Pharma did not respond to multiple requests for comment.

Path changes

Both the FDA and lawmakers have pushed for legislative changes to minimize the time between when a drug enters the market and when studies demonstrating clinical benefit are completed.

“It took the FDA two years after the initial recommended withdrawal to get to this stage,” said Fernandez Lynch at Makena. “We need a really expedited recall path once we’ve decided that the product should no longer be on the market.”

Part of promoting the success of the fast track should also be ensuring that confirmatory trial populations are representative of the makeup of the disease population, Fernandez Lynch said.

Fugh-Berman said recent efforts by Congress to rework expedited approval, which was included in the House-approved user fee package (HR 7667) but dropped from the final language, “will not be enough.” She pointed to a set of additional recommendations included in a September white paper from PharmedOut, such as making randomized, controlled trials the default under the accelerated approval program and allowing automatic withdrawal of approval when post-marketing requirements are not met by a certain date.

“The whole expedited approval process needs to be overhauled to protect patients,” she said.

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