Voluntary Withdrawal of Makena from the US Market in Response to FDA Assessment

At the October 17-19 Obstetrics, Reproductive, and Urologic Drugs Advisory Meeting, the committee voted 14 to 1 that that Makena should be removed from the market while awaiting any further confirmatory studies. Although the final FDA decision has not been released, Covis, the maker of Makena, has sent a letter to the FDA stating that they are voluntarily seeking to withdraw the drug from the market and wish to work with the FDA to ensure an orderly wind-down.

At this time, ACOG has released a statement that “until further information is available, ACOG’s current practice guidance” for preterm birth remains in effect (see ‘Related ObG Topics’ below)

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On October 29, 2019, the FDA advisory committee recommended that the drug be withdrawn from the market (9 to 7 vote). On October 5, 2020, the Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market.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For these and other reasons detailed herein, Makena should be withdrawn from the market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 
• 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:

ACOG Statement on Announcement Regarding the Voluntary Removal of Makena (17-OHPC) from the Market

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

ACOG: Statement on FDA Committee Recommendation to Withdraw 17p Hydroxyprogesterone Caproate

Cervical Cerclage – Professional Recommendations

CLINICAL ACTIONS:

ACOG defines cervical insufficiency as “the inability of the uterine cervix to retain a pregnancy in the absence of the signs and symptoms of clinical contractions, or labor, or both in the second trimester.” In addition, ACOG separates out indication for cerclage in to 3 categories

• History: ≥1 of the following
  • Second trimester pregnancy losses related to painless cervical dilation and no history of labor or abruption
  • Previous second trimester cerclage for painless cervical dilation
• Physical Examination: Also known as ‘physical examination–indicated cerclage’, ‘rescue cerclage’ and ’emergency cerclage’
  • Patient presents with painless second trimester cervical dilation
• Ultrasound: Cervical length shortening and history of preterm birth
  • Singleton pregnancy
  • Prior spontaneous preterm birth (<34 weeks)
  • Cervical length:  <25 mm (at <24 weeks)

SMFM states that cerclages are effective in woman based on the following indications:

• History indicated: 3 or more PTBs or second-trimester losses.
• Ultrasound indicated: ≥1 early PTB (defined as delivery between 17w to 33w6d), and cervical length (CL) <25 mm on transvaginal ultrasound (TVUS) before 24 weeks

Timing of Cerclage Placement

• History-indicated cerclage
  • Place between 12 and 14 weeks after confirmation of pregnancy viability
• Ultrasound or exam-indicated cerclage
  • May be placed prior to 23 weeks

Risk Factors

• Prior PTB
• Repeated cervical dilation
• Cervical procedures (including cone and LEEP)
• Cervical laceration
• Urogenital abnormalities

SYNOPSIS:

Clinically, cervical insufficiency is painless dilation and recurrent mid-trimester losses without signs of preterm labor (PTL), PPROM, or infection. Patient history may include superimposed symptoms (i.e. bleeding, pressure), therefore a judicious review of records is advised.  Those with a history of prior preterm birth can benefit from cervical length screening to appropriate guide selected patients for cerclage.

KEY POINTS:

Ultrasound Indicated Cerclage with Prior History of Preterm Birth or Second Trimester Losses (SMFM)

• CL surveillance
  • Begin at 16 weeks
  • Perform every 2 weeks
  • CL measurement 25-29 mm: Perform weekly
• Offer cerclage when
  • CL <25 mm prior to 23w0d weeks and
  • History of spontaneous PTB at 17w0d to 33w6d
• 17–alpha hydroxyprogesterone caproate (17-OHPC)
  • Note: Cerclage placement or presence should not alter recommendations
• Evidence from research studies
  • There is no difference in efficacy of McDonald versus Shirodkar techniques

Special Circumstances

• Diagnosis of cervical insufficiency is unclear
  • Consider close screening starting at 16 weeks in place of history indicated cerclage placement
• Very early losses
  • Consider beginning screening <16 weeks if there is a history of very early second trimester losses

‘Emergency’ Cerclage (Exam indicated)

• There is literature, including a meta-analysis (Obstet Gynecol, 2015), to support ’emergency’ or ‘rescue’ cerclage
  • Neonatal survival
    • Cerclage: 71% survival
    • No cerclage: 43% survival
    • Relative risk 1.65 (95% CI 1.19–2.28)
  • Prolongation of pregnancy
    • Mean difference: 33.98 days (95% CI, 17.88 to 50.08)
  • Authors note significant limitations including quality of data and only 1 RCT included

After clinical examination to rule out uterine activity, or intraamniotic infection, or both, physical examination-indicated cerclage placement (if technically feasible) in patients with singleton gestations who have cervical change of the internal os may be beneficial

SMFM Choosing Wisely Campaign

• SMFM recommends the following after cerclage placement
  • Do not perform serial cervical length measurements
  • There is no evidence that cervical length monitoring following a cerclage improves outcomes, despite cervical shortening being associated with increased risk for preterm birth

Learn More – Primary Sources:

SMFM: Cervical cerclage for the woman with prior adverse pregnancy outcome

ACOG Practice Bulletin 142: Cerclage for the Management of Cervical Insufficiency

Physical Examination–Indicated Cerclage: A Systematic Review and Meta-analysis