Preterm Birth and 17OHP — Why the FDA Should Not Withdraw Approval

Abstract

n engl j med 383;24 nejm.org december 10, 2020 e130(1) I n the late 1990s, there was no drug approved by the Food and Drug Administration (FDA) with a labeled indication for preventing recurrent pre-term birth in women with a previous preterm birth. The risk of such recurrence was and is known to vary widely by study population, but it was consistently higher in Black women than in White women 1,2 and resulted in substantial neonatal morbidity and mortality. The absence of an approved medication to prevent recurrent preterm birth prompted the National Institute of Child Health and Human Development (NICHD) to sponsor the Maternal Fetal Medicine Units Network to study 17 alpha-hydroxyprogesterone cap-roate (17OHP) as a possible preventive agent for recurrent preterm birth among women with at least one previous spontaneous pre-term birth. The multisite study was done in the United States, and the results were published by Meis et al. in 2003. 3 The study participants were similar to women obtaining care at major U.S. academic medical centers: 59% non-Hispanic Black and 22 to 25% White, with an average age of approximately 26 years; 50% were married or living with a partner, 21.6% were smokers, and 8% reported consuming alcohol and 3% using street drugs during their pregnancies. The observed risk of recurrent preterm birth at less than 37 weeks' gestation in the placebo group was 55%. At the second planned interim analysis , with the primary outcome available for 70% of the planned sample, the prespecified stopping boundary was crossed and study enrollment was stopped for efficacy. The results demonstrated a 34% relative risk reduction for recurrent preterm birth (relative risk, 0.66) at less than 37 weeks, from 55% in the placebo group to 36% in the 17OHP group (absolute risk reduction, 18 percentage points) and a very similar relative risk reduction in births at less than 35 weeks. The study was accepted by the FDA through its accelerated approval process to allow a labeled indication for 17OHP for this use. Under the provisions of this process , the surrogate outcome measure of reduced risk of preterm birth was permissible because it was deemed "reasonably likely" that an adequate reduction in the preterm-birth rate would result in reductions in neonatal morbidity and mortality and because 17OHP was unlikely to cause harm to either mothers or fetuses. Although the study by Meis et al. was not designed or powered to detect differences in secondary outcomes, the point estimates and confi