Why was 17α-hydroxyprogesterone caproate (17-OHPC) removed from the market?

Why 17α-hydroxyprogesterone caproate (17-OHPC) Was Removed from the Market

17α-hydroxyprogesterone caproate (17-OHPC) was removed from the market by the FDA in April 2023 due to lack of evidence that it reduces the risk of recurrent spontaneous preterm birth, following a confirmatory trial that failed to demonstrate efficacy. 1

Background and Initial Approval

• 17-OHPC was initially approved by the FDA through an accelerated approval pathway based on a 2003 Maternal-Fetal Medicine Units Network trial that showed a 34% reduction in recurrent preterm birth at <37 weeks gestation 2
• The medication was recommended for women with singleton pregnancies and prior spontaneous preterm birth (SPTB), administered as 250 mg IM weekly from 16-20 weeks until 36 weeks gestation 2
• The Society for Maternal-Fetal Medicine (SMFM) had previously endorsed 17-OHPC as the preferred progestogen for prevention of recurrent preterm birth in women with singleton pregnancies and prior SPTB 2

Evidence Leading to Market Withdrawal

• The FDA required a confirmatory trial (PROLONG study) as a condition of the accelerated approval, which took 9 years to complete 3
• The PROLONG trial failed to demonstrate efficacy of 17-OHPC in preventing preterm birth:
  • Delivery before 35 weeks occurred in 11% of women given 17-OHPC versus 11.5% given placebo (RR 0.95; 95% CI 0.71-1.26; P=0.72) 3
  • The neonatal composite index occurred in 5.6% of women given 17-OHPC versus 5.0% given placebo (RR 1.12; 95% CI 0.68-1.61; P=0.73) 3
• An FDA advisory committee voted 9 to 7 in October 2019 to pursue withdrawal of 17-OHPC from the market 4, 3
• The FDA officially withdrew approval for all formulations of 17-OHPC (both intramuscular and subcutaneous) on April 5,2023, including both brand name (Makena) and generic versions 1

Clinical Implications of the Withdrawal

• SMFM agreed with the FDA determination and now discourages continued prescribing of 17-OHPC, including through compounding pharmacies 1
• The FDA determined it would be inappropriate to delay the withdrawal to allow patients currently receiving 17-OHPC to finish treatment, as there was no evidence of benefit with continued treatment 1
• Patients who were receiving 17-OHPC at the time of withdrawal were advised that the FDA's Center for Drug Evaluation and Research had not identified evidence of harm from discontinuation before 37 weeks of gestation 1

Current Alternatives for Preterm Birth Prevention

• Vaginal progesterone is now being considered as an alternative for prevention of recurrent spontaneous preterm birth in singleton pregnancies 5, 6
• SMFM recommends that discussion of vaginal progesterone for primary prevention of recurrent preterm birth should include a shared decision-making process 1
• Cervical cerclage remains an option for women with a cervical length ≤25 mm at <24 weeks gestation 1, 5
• Other strategies being explored include low-dose aspirin and interventions outside the progesterone-aspirin-cerclage paradigm 6

Lessons Learned

• This case highlights challenges in pharmaceutical regulations in the era of accelerated FDA approval 3
• The 17-OHPC story demonstrates the importance of confirmatory trials following accelerated approval and the need for rigorous evidence before widespread adoption of interventions 3
• The withdrawal emphasizes the need for continuous reassessment of treatment strategies for preterm birth prevention based on the most current evidence 6