Following a 3 day meeting, the Food and Drug Administration’s (FDA) Obstetrics, Reproductive, and Urologic Drugs Advisory Committee voted to recommend that the FDA pursue withdrawal of Makena (hydroxyprogesterone caproate injection) from the US market.
Makena is indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The product was granted accelerated approval in 2011 based on data from a placebo-controlled trial that showed weekly injections of Makena reduced the rate of recurrent preterm delivery in high-risk women. The proportion of patients who delivered preterm at less than 37 weeks was 37.1% for the Makena arm and 54.9% for the control arm (treatment difference, -17.8% [95% CI, -28.0, -7.4]). No overall survival difference was observed in this trial due to the higher rate of miscarriages and stillbirths in the Makena arm.
As part of this approval, the Company was required to conduct a confirmatory trial (PROLONG; ClinicalTrials.gov Identifier: NCT01004029), which included 1710 patients randomly assigned to receive weekly injections of Makena or placebo. Results showed that the trial did not meet the coprimary endpoints. The incidence of preterm delivery at less than 35 weeks was 11.0% for the Makena-treated group and 11.5% for placebo (P =.72). In addition, no statistical differences in the rates of neonatal mortality and morbidity were observed between the groups (5.4% for Makena vs 5.2% for placebo; P =.84). According to the manufacturer, the difference in results was influenced by the study population, as the first trial included a higher risk population than the PROLONG study.
Over a 3 day period, an FDA panel of experts convened to discuss whether the drug should remain on the market given the findings of the confirmatory trial. On the question of whether results from the PROLONG trial verified the clinical benefit of Makena on neonatal morbidity and mortality from complication of preterm birth, all 15 members of the panel voted “no”.
The FDA committee was then asked to vote on whether the available evidence demonstrated that Makena was effective for its approved indication of reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. Among the 15 members, 1 voted “yes” 13 voted “no” and 1 member abstained.
Finally, the committee was asked to vote on whether Makena should remain on the market taking into consideration the benefit-risk profile. Concerns over the low level of minority women in the confirmatory trial led to a discussion of the type of studies that would be needed to prove clinical benefit in higher-risk populations. However, based on the totality of evidence, the majority (14 members) voted to remove Makena from the market.
“Put simply, Makena’s risks, which include, among other things, thromboembolic events, are unacceptable in light of the lack of evidence of clinical benefit. Failing to withdraw Makena would mean maintaining FDA approval of a drug that, based on all available evidence, has not been shown to be more effective than, but is riskier than, no treatment. This would be a disservice to patients at risk for recurrent PTB and would undermine the accelerated approval pathway,” the FDA committee stated in the briefing document.
Commenting on the vote, Raghav Chari, PhD, Chief Innovation Officer at Covis, said, “As presented during the hearing, we believe that Makena is effective in a higher-risk patient population. We will work collaboratively with the FDA to clarify the next steps in this process.”
Although not bound by the committee’s recommendations, the FDA does take them into consideration when making decisions on market withdrawal. Until the final decision has been made, Makena remains approved and the product labeling remains unchanged.
- October 17 to 19, 2022: Hearing announcement involving the Obstetrics, Reproductive, and Urologic Drugs Advisory Committee. October 17-19, 2022. https://www.fda.gov/advisory-committees/advisory-committee-calendar/updated-public-participation-information-october-17-19-2022-hearing-announcement-involving#:~:text=the%20hearing%20progresses.-,Webcast%20Information,-Persons%20wishing%20to
- Briefing materials supporting CDER’s proposal to withdraw approval of Makena. https://www.fda.gov/media/162246/download
- Covis Pharma reports on FDA advisory committee hearing for Makena®. News release. October 19, 2022. https://www.globenewswire.com/news-release/2022/10/19/2537830/0/en/Covis-Pharma-Reports-on-FDA-Advisory-Committee-Hearing-for-Makena.html
- Makena. Package insert. Covis Pharma. 2018. Accessed October 20, 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a1998c1d-8337-4f00-8dcb-af3b54d39b77&type=display