Expert Commentary

Progesterone supplementation does not PROLONG pregnancy in women at risk for preterm birth: What do we do now?

OBG Manag. 2019 December;31(12):36-38

What is the future for 17P now that a required trial for the drug's efficacy showed that its use did not reduce preterm birth, neonatal morbidity, or fetal/early infant deaths—and an FDA advisory committee recommended withdrawal of the drug's approval?

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References

American College of Obstetricians and Gynecologists Committee on Practice Bulletins--Obstetrics. ACOG practice bulletin no. 127: Management of preterm labor. Obstet Gynecol. 2012;119:1308-1317.
Makena [package insert]. Waltham, MA: AMAG Pharmaceuticals, Inc; 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021945s012lbl.pdf. Accessed November 10, 2019.
US Food and Drug Administration. Code of Federal Regulations Title 21. Subpart H--Acceleratedapproval of new drugs for serious or life-threatening illnesses. April 1, 2019. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=314&showFR=1&subpartNode=21:5.0.1.1.4.8. Accessed November 10, 2019.
Meis PJ, Klebanoff M, Thom E, et al; for the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348:2379-2385.
Society for Maternal-Fetal Medicine Publications Committee. The choice of progestogen for the prevention of preterm birth in women with singleton pregnancy and prior preterm birth. Am J Obstet Gynecol. 2017;216:B11-B13.
Gallagher JR, Gudeman J, Heap K, et al. Understanding if, how, and why women with prior spontaneous preterm births are treated with progestogens: a national survey of obstetrician practice patterns. AJP Rep. 2018;8:e315-e324.
Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, et al. 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG study): a multicenter, international, randomized double-blind trial. Am J Perinatol. 2019. doi:10.1055/s-0039-3400227.
Society for Maternal-Fetal Medicine Publications Committee. SMFM statement: Use of 17-alpha hydroxyprogesterone caproate for prevention of recurrent preterm birth. https://els-jbs-prod-cdn.literatumonline.com/pb/assets/raw/Health%20Advance/journals/ymob/SMFM_Statement_PRO LONG-1572023839767.pdf. Accessed November 10, 2019.
American College of Obstetricians and Gynecologists. Practice advisory: Clinical guidance for integration of the findings of the PROLONG study: progestin's role in optimizing neonatal gestation. https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Advisories/Clinical-guidance-for-integration-of-the-findings-of-The-PROLONG-study-Progestins-Role-in-Optimizing?IsMobileSet=false. Accessed November 10, 2019.

Preterm birth (PTB) remains a significant public health concern and a major cause of newborn morbidity and mortality. In the United States, 1 in 10 babies are born preterm (< 37 weeks), and this rate has changed little in 30 years.¹

In 2011, the US Food and Drug Administration (FDA) approved progesterone supplementation—specifically, α-hydroxyprogesterone caproate (17P) injection (Makena)—to prevent recurrent PTB in women with a singleton pregnancy at high risk by virtue of a prior spontaneous PTB.² This was the first-ever FDA-approved drug for PTB prevention, and it was the first drug approved by the FDA for use in pregnancy in more than 15 years. The approval of 17P utilized the FDA's Subpart H Accelerated Approval Pathway, which applies to therapies that: 1) treat serious conditions with unmet need, and 2) demonstrate safety and efficacy on surrogate end points reasonably likely to predict clinical benefit.³

By voting their approval of 17P in 2011, the FDA affirmed that PTB was a serious condition with unmet need, that birth < 37 weeks was an accepted surrogate end point, and that there was compelling evidence of safety and benefit. The compelling evidence presented was a single, randomized, vehicle-controlled clinical trial conducted by the Maternal-Fetal Medicine Units (MFMU) Network, which showed significant reduction in recurrent PTB < 37 weeks (from 54.9% in the placebo group to 36.3% in the 17P group; P<.001; relative risk [RR], 0.66; 95% confidence interval [CI], 0.54-0.81).⁴

In 2017, the Society for Maternal-Fetal Medicine (SMFM) reaffirmed the use of 17P to prevent recurrent PTB and, that same year, it was estimated that 75% of eligible patients received 17P.^5,6 Importantly, Subpart H approval requires one or more follow-up clinical trials confirming safety and efficacy. And the FDA has the right—the responsibility—to revisit approval if such trials are either not performed or are unfavorable.

The recently published PROLONG study by Blackwell and colleagues is this required postapproval confirmatory trial conducted to verify the clinical benefit of 17P supplementation.⁷

Continue to: Study design, and stunning results...

Progesterone supplementation does not PROLONG pregnancy in women at risk for preterm birth: What do we do now?

References

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