In late October, an FDA Advisory Committee voted resoundingly against continuing FDA approval of 17α-hydroxyprogesterone caproate (17-OHPC; Makena), a medication indicated to reduce the risk of preterm labor in pregnant people. In documents prepared by FDA scientists ahead of the committee hearing, the conclusion was that the drug "should be withdrawn from the market." Similarly, an FDA Advisory Committee voted 3 years ago to withdraw the drug in the U.S., citing a showing the drug offered no benefit over placebo. Yet, the manufacturer has thus far been unwilling to voluntarily withdraw the drug, and so it remains unclear when (or even if) the FDA will follow through on the recommendations of its scientists and advisers.
Much of the current regulatory concern about 17-OHPC is centered on the drug's original FDA approval under the accelerated approval program and the ways in which 17-OHPC's subsequent clinical trials, as part of the program, cast doubt on the drug's safety and efficacy. Under accelerated approval, the FDA can approve drugs based on changes to surrogate measures that are reasonably likely to predict actual meaningful clinical endpoints, such as how a patient feels, functions, or survives. Manufacturers are required to conduct a post-approval study to confirm the drug's effect on clinical endpoints. However, recent studies have highlighted that confirmatory studies are often delayed (about between 2013 and 2016), frequently evaluate surrogate measures, and may not lead to drug withdrawal in a timely fashion when the confirmatory trials are negative.
The History of 17-OHPC
The 17-OHPC case exemplifies many of the ways that accelerated approval can go wrong. The drug, 17 alpha-hydroxyprogesterone, was first FDA-approved in 1956 under the brand-name Delalutin for prevention of "habitual and recurrent abortion." The drug fell out of favor for this indication, but received a new FDA-approval 55 years later in 2011 for preventing preterm birth, based on a 2003 trial. Although the trial did not show clinical benefit for neonatal health, the drug was approved via accelerated approval due to the substantial public health need for treatments for preterm labor and the promising surrogate results.
As part of the accelerated approval pathway, 17-OHPC's manufacturer was required to perform a confirmatory trial to assess its safety and efficacy with respect to neonatal health. The confirmatory trial was slow to proceed, and 17-OHPC expanded into wide use. The , finally completed in 2019, had enrolled 1,708 women and found no effect on the neonatal morbidity index. Interestingly, it also directly contradicted the key findings of the 2003 study, showing no differences in the frequency of preterm labor at less than 35 weeks.
In addition to the new trial findings, meta-analyses found 17-OHPC was at preventing preterm birth at less than 32, 35, and 37 weeks' gestation, and to another alternative of care, vaginal progesterone, in reducing the rate of preterm birth for mothers at less than 32, 34, and 37 weeks' gestation. (Meta-analysis research into vaginal progesterone's use is still ongoing, with a muddying the waters on vaginal progesterone's efficacy in preventing preterm birth.) Furthermore, 17-OHPC was also linked with in newborns exposed in utero.
Further investigation suggests that differences between the 2019 and 2003 study findings may be linked to in the design of the earlier trial. The randomization in the 2003 study appears to have been flawed, as participants in the placebo group were at higher risk of preterm labor than those in the 17-OHPC group, and the placebo group had a far higher preterm birth rate than expected at 55% (only of U.S. live births are preterm).
The Manufacturer Pushes Back
Covis Pharma insists that the drug in part because the 2003 trial had a larger percentage of Black participants than the confirmatory trial and because of post hoc analysis of patient data. There were major differences in patient populations and maternal risk factors of those enrolled in the 2003 trial and 2019 study. The smaller 2003 trial enrolled a high percentage of non-Hispanic Black patients (59%) compared to the 2019 trial, which enrolled only 7%. The bulk of the 2019 trial patients were white (88%) with most enrolling from Eastern European trial sites. The manufacturer claims these population differences are enough to explain the differences in the trial results. As the , the 2019 trial is "not a negative study but instead, because of key differences in enrollment of the study population, was inherently incapable of confirming the [2003] trial findings."
It is worth asking why the manufacturer would have pursued a study that, by its own admission, it now claims was incapable of confirming the drug's safety and benefit. More importantly, there are analytic reasons to believe that demographics of the 2019 study do not invalidate its negative finding. For example, the FDA performed to assess whether demographic or socioeconomic characteristics were effect modifiers, and concluded that race was unlikely to explain the differences.
Covis Pharma has also cited data from routine clinical use of the drug showing an association between its use and benefits for Black mothers with prior deliveries at less than 34 weeks. However, we must evaluate this claim with an abundance of caution. The 2019 study enrolled from a patient population in which 46% had at least one previous spontaneous preterm birth at less than 34 weeks -- an incredibly high percentage of women represented with that birth history -- suggesting race is likely not the factor that predisposed these mothers to preterm birth. Additionally, there are no physiological mechanisms or other biological reasons to believe 17-OHPC would differ in impact based on race. Emerging has shown that there is wide, varied genomic variability within U.S. racial categories that generally makes race a for genetic similarity.
Perhaps most important in evaluating the manufacturer's claim, we must consider the precedent that would be set if a manufacturer could subvert a negative clinical trial finding by citing its own analysis of observational data. This approach goes against the very basis of FDA drug approval.
Economic incentives are likely at play here. While Covis Pharma is fighting to keep the drug on the market because of its alleged clinical benefit for the underserved, the company's pricing decisions appear antithetical to this goal. Prior to FDA approval of 17-OHPC in 2011, the active ingredient 17 alpha-hydroxyprogesterone had been available as a compounded product (the active ingredient was off-patent, having been approved 55 years earlier). However, upon the discovery of 17-OHPC's potential use for prevention of preterm birth, the drug was granted brand-name status in 2011, and the manufacturer raised the price to . It is especially revealing that prices remain high despite health equity rhetoric. In November 2022, according to and , the annual price of brand-name Makena was still about $10,000 per year.
A Call for Greater FDA Authority
Today, as we rapidly approach the end of 2022, 17-OHPC remains on the market. The FDA must take the necessary steps to change this. The case sheds light on areas for reform in the FDA's accelerated approval pathway, particularly its reliance on confirmatory trials as a regulatory tool. An enforceable requirement for manufacturers to fulfill confirmatory trial obligations is essential, and if trials aren't completed or the drugs are deemed unsafe or ineffective, FDA needs to be able to more efficiently pull drugs from the market. There likewise needs to be assurance mechanisms that all confirmatory trials are properly designed to test real clinical endpoints and have patient populations comparable to the original trial's populations.
Achieving equity in healthcare delivery and the pharmaceutical market is a necessary goal. But, as the ongoing experience with 17-OHPC shows, pharmacoequity is not achieved through specious claims about racial equity or through prices that only exacerbate existing disparities in access to care.
is a third-year medical student at the University of Chicago Pritzker School of Medicine, and a member of the Program On Regulation, Therapeutics, And Law (PORTAL). is a third-year medical student at the University of Chicago Pritzker School of Medicine. is the director of the Program On Regulation, Therapeutics, And Law (PORTAL) in the Division of Pharmacoepidemiology and Pharmacoeconomics in the Department of Medicine at Brigham and Women's Hospital/Harvard Medical School.