FDA Withdraws Makena Approval for US Market

FDA approval for Makena, a drug used to reduce risk for preterm birth, has been formally withdrawn. The withdrawal also includes all generics (17-alpha hydroxyprogesterone caproate [17-OHPC]). Regarding any current medication in distribution, the FDA states that “Patients who have questions should talk to their healthcare provider.” Both ACOG and SMFM have addressed the situation.

ACOG

Intramuscular 17-OHPC is not recommended for the primary prevention of preterm birth in patients with a history of spontaneous preterm birth

In summary, at this time, the body of evidence is equivocal regarding the effectiveness of 17-OHPC, and the referenced FDA action will limit access to 17-OHPC for patients

SMFM

We agree with the FDA determination and discourage continued prescribing of 17-OHPC, including through compounding pharmacies

We agree with the FDA that there is no evidence of benefit with continued treatment

Patients currently receiving 17-OHPC can be counseled that the FDA’s Center for Drug Evaluation and Research (CDER) has not identified evidence of harm from discontinuation prior to 37 weeks of gestation

RESEARCH SUMMARY:

The authors of the PROLONG trial (Progestin’s Role in Optimizing Neonatal Gestation) reported on the use of 17α-hydroxyprogesterone caproate (17-OHPC) for the treatment of preterm birth (PTB)

In this study population, 250 mg 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death

On October 29, 2019, the FDA advisory committee recommended that the drug be withdrawn from the market (9 to 7 vote). On October 5, 2020, the Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market. At that time, the decision was made to hold further meetings and discussions. Based upon further follow-up, the CDER briefing materials for the Advisory Committee meeting (October 17-19, 2022) states

Makena has not been shown to improve neonatal outcomes from premature birth, is no longer shown to be effective for its approved use, and has known risks

The 1,708-person confirmatory trial designed to verify Makena’s clinical benefit instead failed to show that Makena has any benefit to newborns. Data from this trial, taken together with other evidence, also fail to show that Makena reduces the risk of recurrent preterm birth

For these and other reasons detailed herein, Makena should be withdrawn from the market

Background to PROLONG Trial

• A previous study, on behalf of the NICHD, demonstrated success of IM 17-OHPC in preventing PTB (see ‘Learn More – Primary Sources)
  • Meis et al. (NEJM, 2003): 250 mg IM 17-OHPC reduced recurrent preterm birth (PTB) in women with a prior spontaneous PTB (SPTB)
    • Relative risk [RR] 0.66 (95% CI, 0.54–0.81)
• The current PROLONG study was a ‘confirmatory trial’, performed with FDA input as a requirement for the FDA accelerated approval pathway

PROLONG Methods

• Double-blind randomized controlled trial (RCT)
• Participants
  • ≥18 years
  • Singleton pregnancy
  • Currently 16w0d to 20w6d
  • Previous history of singleton SPTB (birth between 20w0d and 36w6d following preterm labor or PROM)
• Groups (IM injection 1 in upper outer quadrant of the gluteus maximus) weekly until delivery or 36 weeks
  • 17-OHPC (250 mg)
  • Placebo
• Stratified by
  • Study site
  • GA at randomization
• Primary outcomes
  • PTB < 35 weeks
  • Composite neonatal morbidity and mortality index

PROLONG Results

• PTB < 35w0d (p=0.72)
  • 17-OHPC: 11.0%
  • Placebo: 11.5%
  • Relative risk (RR) 0.95 (95% CI, 0.71–1.26)
• Neonatal composite index (p=0.73)
  • 17-OHPC 5.6%
  • Placebo 5.0%
  • RR 1.12 (95% CI, 0.70–1.66)
  • Note: No differences seen in any of the individual components that were part of the composite index

KEY POINTS:

Sibai et al. Obstet Gynecol, 2020

Meis Trial

• Well designed and conducted
• Highly statistically significant results
  • Prespecified criterion threshold of alpha=0.015 was met regarding benefit of 17-OHPC
  • Preterm birth <37 weeks: Relative risk (RR) 0.66 (95% CI, 0.54 to 0.81; P<.001)
  • Preterm births <35 weeks: RR 0.67 (95% CI, 0.48 to 0.93)
  • Preterm birth <32 weeks: RR 0.58 (95% CI, 0.37–0.91)
• Subgroup analysis: Number of prior preterm birth | Race | Marital status | Smoking or substance use
  • Confirmed generalizability

Prolong Trial

• Population studied was very different from that of the Meis trial (non-US)
• Trial is underpowered based on observed event rates
  • For 90% power, PROLONG required 3,600 women for preterm birth <35 weeks and 6,000 women for neonatal composite outcome
• PROLONG not powered for subgroup analysis, but Meis et al. did look at US subgroup and found that while not statistically significant
  • Direction and magnitude of effect <32 weeks and neonatal composite index were similar to the Meis trial

Authors’ Conclusion

We assert PROLONG was underpowered, based on substantially lower observed preterm birth rates than anticipated, and therefore was a false-negative study, rather than the Meis trial being a false-positive study

Careful assessment of these two trials is critical as removal of 17α-hydroxyprogesterone caproate from the U.S. marketplace may have substantial effects on public health

Learn More – Primary Sources:

FDA Commissioner and Chief Scientist Announce Decision to Withdraw Approval of Makena

ACOG Practice Advisory: Updated Clinical Guidance for the Use of Progesterone Supplementation for the Prevention of Recurrent Preterm Birth

SMFM Special Statement: Response to the Food and Drug Administration’s withdrawal of 17-alpha hydroxyprogesterone caproate

17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial

Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. (NEJM, 2003)

Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement: MAKENA supplemental new drug application

FDA (October 2020): CDER proposes withdrawal of approval for Makena

Re-examining the Meis Trial for Evidence of False-Positive Results (Sibai et al. Obstetrics & Gynecology, 2020)

FDA Briefing Materials for Withdrawal of Makena Approval (2022)

FDA: UPDATED INFORMATION: October 17 – 19, 2022: Hearing Announcement involving the Obstetrics, Reproductive, and Urologic Drugs Advisory Committee