FDA Panel Backs Pulling Makena From Market for Preterm Birth

Troy Brown, RN

October 30, 2019

The US Food and Drug Administration's (FDA's) Bone, Reproductive and Urologic Drugs Advisory Committee voted by a narrow margin to recommend withdrawing hydroxyprogesterone caproate (17P) injection (Makena, AMAG Pharmaceuticals) 250 mg/mL from the market for the prevention of preterm birth (PTB).

The panel voted unanimously (0 yes, 16 no) on Wednesday that the findings from a confirmatory trial did not verify the clinical benefit of 17P on neonatal outcomes. The committee voted (3 yes, 13 no) that the findings of two studies together did not provide substantial evidence of 17P's effectiveness for reducing the risk for recurrent PTB.

The FDA approved 17P under an accelerated approval pathway in 2011 after one clinical trial demonstrated efficacy for reducing the risk for PTB in women with a singleton pregnancy and a history of singleton spontaneous preterm birth. As a condition of that approval, the FDA required a confirmatory trial and that trial failed to demonstrate a clinical benefit to newborns.

The panel was tasked with recommending withdrawal of 17P, leaving it on the market under the accelerated approval pathway and requiring a new confirmatory trial, or leaving it on the market and not requiring a new confirmatory trial.

A number of committee members expressed regret about removing a drug from the market when it is already widely used and is recommended by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM); however, the panel was instructed not to make that a part of their deliberations.

PTB is defined as birth before 37 weeks of gestation; approximately 10% of all childbirths and 8% of singleton pregnancies end in PTB. Infants born prematurely have an increased risk for neonatal mortality and significant morbidity, and for long-term physical developmental disability, the FDA explains in its briefing document.

"Even if they do get to leave the [neonatal intensive care unit], many do not see their first birthdays," Michelle Owens, MD, professor and medical director, department of obstetrics and gynecology, University of Mississippi School of Medicine, University of Mississippi Medical Center, Jackson, said during a company presentation at the meeting.

"While long-term complications are rare, they are profound," she said.

No drugs are currently approved for reducing neonatal morbidity or mortality or long-term health problems resulting from PTB.

Accelerated Approval Pathway

In August 2006, an FDA advisory committee voted 19 no, 2 yes not to recommend 17P for approval, in large part because they said the surrogate endpoint was not adequate for establishing efficacy. The FDA recommended that the company submit a draft protocol and evidence that an additional adequate and well-controlled trial was feasible.

On February 4, 2011, 17P received approval under the accelerated approval pathway of the Federal Food, Drug, and Cosmetic Act. In the preapproval clinical trial (Trial 002), 17P reduced the proportion of women who gave birth at fewer than 37 weeks' gestation — a surrogate endpoint deemed reasonably likely by the FDA to predict a clinical benefit to the newborn.

In a required postapproval confirmatory clinical trial completed in late 2018, there was no statistical significance between patients treated with 17P or placebo with respect to the coprimary outcomes of reduced risk for recurrent preterm birth or improved neonatal mortality and morbidity.

Approval Study

Trial 002 — the Meis study, used for the drug's approval in 2011 — was a multicenter, double-blind, placebo-controlled clinical trial that began in 1999 and ended in 2002. The study included 463 women with a singleton pregnancy and one or more prior spontaneous PTBs (sPTBs) from 19 university-based clinical centers in the Maternal-Fetal Medicine Units Network in the United States.

The study's primary and secondary efficacy endpoints were the proportion of pregnant women who delivered prior to 37 weeks' gestation and those who delivered prior to 35 or 32 weeks.

Women in the 17P group received 17P 250 mg intramuscularly once per week beginning at 16 weeks 0 days to 20 weeks 6 days through 36 weeks' gestation or birth.

There were 310 women in the 17P group and 153 women in the placebo group. 17P reduced the proportion of women who gave birth prior to 37 weeks' gestation from 55% (placebo) to 37% (17P) (treatment difference, -17.8%; 95% confidence interval [CI], -28% to -7.4%), independent of race, number of previous preterm deliveries, and gestational age of the previous PTB.

The proportions of women who gave birth at < 35 and < 32 weeks' gestation were also lower among women who received 17P compared with placebo: -9.4% (95% CI, -19.0% to -0.4%) for delivery < 35 weeks' gestation and -7.7% (95% CI, -16.1% to -0.3%) for delivery < 32 weeks' gestation.

Several factors may limit the generalizability of the study findings to the broader US population: approximately 60% of the study participants were self-identified blacks; participants were recruited from only academic centers, one of which provided 25% of participants; and the high rate of recurrent preterm birth seen in the placebo group (55%) was noteworthy.

The FDA required the applicant to conduct with due diligence, and submit data from, a confirmatory efficacy and safety trial as a condition of accelerated approval.

Confirmatory Study

Trial 003 — the PROLONG confirmatory study — was a multicenter, international, randomized, double-blind, placebo-controlled study that confirmed safety but not efficacy. Sean C. Blackwell, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, McGovern Medical School-UTHealth, Houston, and colleagues published the study findings online October 25 in the American Journal of Perinatology.

The Society for Maternal-Fetal Medicine said in an October 25 news release, "Based on the evidence of effectiveness in the Meis study, which is the trial with the largest number of US patients, and given the lack of demonstrated safety concerns, SMFM believes that it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial."

In a practice advisory, ACOG said on October 25, "ACOG is not changing our clinical recommendations at this time and continues to recommend offering hydroxyprogesterone caproate as outlined in Practice Bulletin #130, Prediction and Prevention of Preterm Birth."

The PROLONG study included women with eligibility criteria similar to those in the Meis study and was conducted from 2009 to 2018. Coprimary efficacy outcomes were delivery before 35 weeks gestation and a neonatal morbidity/mortality composite index.

"The inclusion of a clinical endpoint (the neonatal composite index) addressed the accelerated approval’s regulations of verifying that initial findings based on a surrogate endpoint (gestational age at delivery) lead to direct clinical benefit," the FDA explains in its briefing document.

Trial 003 included 1708 women from nine countries; 26%, 25%, and 23% of participants were from Russia, Ukraine, and the United States, respectively. The researchers had data for 1651 liveborn neonates.

The treatment effect for the coprimary outcomes of proportion of women who delivered prior to 35 weeks (11% Makena vs 12% placebo; P = .72) or neonatal composite index (5.4% Makena vs 5.2% placebo; P = .84) was not statistically significant.

Secondary outcomes did not differ for other gestational ages at birth (< 37 weeks [23% Makena vs 22% placebo; P = .57), < 32 weeks gestation [4.8% Makena vs 5.2% placebo; P = .70]), or for the individual components of the neonatal index.

The two populations were very different, several panel members pointed out, with those in the PROLONG trial having a lower baseline risk.

"I thought the idea of removal of the drug was…not feasible. Our patients know it's there, and if I don't find them some sort of progesterone, they'll find someone who will," temporary voting member Kimberly Hickey, MD, Maternal Fetal Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, said of her vote to leave it on the market under the accelerated approval pathway and require a new confirmatory trial.

"I do not believe that substantial evidence has been established, given the conflicting results of the two studies," temporary voting member Daniel Gillen, PhD, professor and chair, Statistics, University of California, Irvine, said of his vote to recommend withdrawing 17P.

There are "many, many, repercussions to the withdrawal and I don't make that choice lightly," he added.

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