Accelerated Approval of 17α-Hydroxyprogesterone Caproate

Abstract

Before 2011, 17α-hydroxyprogesterone caproate (17P) was used to prevent recurrent preterm birth in women with singleton pregnancies and was compounded at a low cost (∼$15 per injection). In 2011, the U.S. Food and Drug Administration (FDA) approved a commercial version of 17P (trade name “Makena”) through their Accelerated Approval Program, and the price of 17P subsequently increased by nearly 100-fold. This approval was largely based on a methodologically limited, placebo-controlled trial, which found that although 17P significantly reduced preterm births, the placebo group had significantly more participants with a history of preterm birth, potentially confounding the results. The FDA required a confirmatory trial for continued approval that demonstrated clinical benefit. Eight years after accelerated approval, the confirmatory trial, PROLONG (Progestin's Role in Optimizing Neonatal Gestation), found no evidence of an effect of Makena for reducing recurrent preterm birth or perinatal mortality. Trial completion triggered an automatic review of Makena by an advisory committee, which voted 9–7 to recommend revoking approval of Makena for preterm birth. Although the FDA created the Accelerated Approval Program to introduce therapies for serious conditions that lacked treatment options, Makena is an example of the limitations of this program. We encourage the FDA to re-evaluate their program and consider improvements, such as shorter timeframes to complete confirmatory trials, potentially revoking approval if the studies are not completed within a predefined timeframe, and to hold manufacturers responsible, in part, for the costs of therapy if they cannot prove a clinical benefit.

Resistance to Change

“…A large multicenter international study under the direction of the Pregnancy Research Branch of NIH based at Wayne State University demonstrated significant efficacy of such suppositories [69][70][71][72][73][74][75]. Despite that, the US Preventative Services Task Force (USPTF) refused to endorse their use after performing a very unconventional and convoluted statistical analysis in which the USPTF ignored significant components of the study data and focused on only a subset (following the findings of one US-based center rather than the findings of three European centers) [69][70][71][72][73][74][75]. Concurrently, a company produced Makena and obtained FDA approval for weekly injections of 17α-hydroxyprogesterone caproate under an Accelerated Approval Program -set up to permit rapid development of drugs that addressed serious medical problems.…”

“…Assessment of PTB treatments requires multiple levels of queries. First, the idea that a serious problem like PTB, with risks in part determined by a multitude of social determinants of health, could be treated as a single problem amenable to any single therapy is certainly not a given [69][70][71][72][73][74][75]. Second, the variability in quality of compounded treatments (which are not as tightly controlled as pharmaceutical company products but in which physicians had considerable confidence) needed to be understood.…”

“…Furthermore, the study ran almost 5 years longer than the average for such studies. The FDA emphasized the need for standardization, cited the recall problems of compounded 17-OHPC, and downplayed the utility of vaginal suppositories [76][77][78]. These approaches conflicted with the confidence that many physicians had developed in these treatments.…”