A Chronicle of the 17OHP-C Story to Prevent Recurrent Preterm Birth

Abstract Preterm birth is a substantial public health concern. In 2019, the United States preterm birth rate was 10.23%, which is the fifth straight year of increase in this rate. Moreover, preterm birth accounts for approximately one-in-six infant deaths, and surviving children often suffer developmental delay or long-term neurologic impairment. While the burden of preterm birth is clear, identifying strategies to reduce preterm birth has been challenging. On October 29, 2019, a United States Food and Drug Administration Advisory Committee voted 9 to 7 to withdraw interim accelerated approval of 17-alpha hydroxyprogesterone caproate for prevention of recurrent preterm birth because the called for confirmatory trial, known as the PROLONG trial, was not confirmatory. The PROLONG trial included subjects enrolled in the United States and Canada in an effort to ensure that at least 10% of patients would be from North America, however, this trial took nine years to complete and did not demonstrate significant treatment effects in the two primary outcomes of interest. Delivery before 35 weeks occurred in 11% (N=122/1130) of women given 17-alpha hydroxyprogesterone caproate compared to 11.5% (N=66/578) given placebo (RR 0.95; 95%CI: 0.71-1.26, P=0.72).9 Similarly, the co-primary outcome neonatal composite index occurred in 5.6% (N=61/1093) of women given 17-alpha hydroxyprogesterone caproate compared to 5.0% (N=28/559) given placebo (RR 1.12; 95%CI: 0.68-1.61, P=0.73). There was also a lack of efficacy for 17-alpha hydroxyprogesterone caproate treatment in the analysis of a variety of secondary outcomes. Like the Maternal-Fetal Medicine Units Network trial, the PROLONG trial was also flawed. Importantly, the Maternal-Fetal Medicine Unit Network trial was the sole justification for treating women in the United States with 17-alpha hydroxyprogesterone caproate for nearly two decades. And now, despite more than half a century, 17-alpha hydroxyprogesterone caproate still has not been shown to be clearly effective. So, in this context, how does the advising physician dependent upon scientific evidence advise a patient that 17-alpha hydroxyprogesterone caproate is effective when the evidence to support this advice has repeatedly been found to be inadequate? This Clinical Opinion is a critical appraisal of the two randomized trials examining the efficacy of 17OHP-C to prevent recurrent preterm birth and a chronicle of events in the regulatory process of drug approval to help answer this question. With this examination, these events illustrate the complexity of pharmaceutical regulation in the era of accelerated FDA approval and characterize the financial impact and influence in medicine. In this report, we also emphasize the value of observational studies in contemporary practice as well as identify other examples in medicine wherein FDA accelerated approval has been withdrawn. Importantly, the themes of the 17OHP-C story are not limited to obstetrics but also serve as a microcosm of issues within the United States healthcare system that ultimately contribute to the high cost of healthcare. In our opinion, the answer to the question is clear—the facts speak for themselves—and we believe 17-alpha hydroxyprogesterone caproate should not be endorsed for use to prevent recurrent preterm birth in the United States.