Withdrawing Approval of Makena — A Proposal from the FDA Center for Drug Evaluation and Research

Chang, Christina Y.; Nguyen, Christine; Wesley, Barbara; Guo, Jia; Johnson, Laura Lee; Joffe, Hylton V.

doi:10.1056/nejmp2031055

Cited by 31 publications

(25 citation statements)

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“…The EPPPIC protocol is published 13 , the statistical analysis plan and data dictionary are available on request. The trial investigators who shared IPD for the purposes of the EPPPIC IPD meta-analysis retain ownership of their trial data and any requests for access to IPD should be made directly to them.…”

Section: Author Contributionsmentioning

confidence: 99%

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Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials

Stewart¹,

Simmonds

Duley³

et al. 2021

The Lancet

144

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BackgroundPreterm birth is a global health priority. Using a progestogen during high-risk pregnancy could reduce PTB and adverse neonatal outcomes. MethodsSystematic review of randomised trials comparing vaginal progesterone, intramuscular 17hydroxyprogesterone caproate (17-OHPC), or oral progesterone with control, or with each other, in asymptomatic women at risk of preterm birth. We identified published and unpublished trials that completed primary data collection before July 30, 2016 (12 months before data collection began) by searching MEDLINE, Embase, CINAHL, the Maternity and Infant Care Database, and relevant trial registers between inception and July 30, 2019. Trials of progestogen to prevent early miscarriage or immediately-threatened preterm birth were excluded. Individual participant data were requested from investigators of eligible trials. Outcomes included preterm birth, early preterm birth, and mid-trimester birth. Adverse neonatal sequelae associated with early births were assessed using a composite of serious neonatal complications, and individually. Adverse maternal outcomes were investigated as a composite and individually. Individual participant data were checked and risk of bias assessed independently by two researchers. Primary meta-analyses used one-stage generalised linear mixed models that incorporated random effects to allow for heterogeneity across trials. FindingsInitial searches identified 47 eligible trials. Individual participant data were available for 30 of these trials. An additional trial was later included in a targeted update. Data were therefore available from a total of 31 trials (11,644 women and 16,185 offspring). Trials in singleton pregnancies included mostly women with previous spontaneous preterm birth or short cervix. Preterm birth before 34 weeks was reduced in such women who received vaginal progesterone (nine trials, 769 women; relative risk [RR] 0•78, 95% CI 0•68-0•90), 17-OHPC (five trials, 3,053 women; 0•83, 0•68-1•01), and oral progesterone (two trials, 183 women; 0•60, 0•41-0•90). Results for other birth and neonatal outcomes were consistently favourable, but less certain. A possible increase in maternal complications was suggested, but this was uncertain. We identified no consistent evidence of treatment interaction with any participant characteristics examined, although analyses within subpopulations questioned efficacy in women who did not have a short cervix. Trials in multifetal pregnancies mostly included women without additional risk factors. For twins, vaginal progesterone did not reduce preterm birth before 34 weeks (eight trials, 2046 women: RR 1•01, 95% CI 0•84-1•20) nor did 17-OHPC for twins or triplets (eight trials, 2253 women: 1•04, 0•92-1•18). Preterm premature rupture of membranes was increased with 17-OHPC exposure in multifetal gestations (rupture <34 weeks RR 1•59, 95% CI 1•15-2•22), but we found no consistent evidence of benefit or harm for other outcomes with either vaginal progesterone or 17-OHPC InterpretationVaginal progesterone and 17...

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Section: Author Contributionsmentioning

confidence: 99%

“…In October 2020 the FDA proposed that the synthetic drug should be removed from the market for indication to prevent recurrent spontaneous preterm birth. 13…”

Section: Introductionmentioning

confidence: 99%

Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials

Stewart¹,

Simmonds

Duley³

et al. 2021

The Lancet

144

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“…The approval of 17-OHPC for use as a preventative agent marked the first drug approved for use in pregnancy in over 15 years [184]. However, significant controversy surrounds the use of P4 to prevent recurrent spontaneous PTB, and the FDA has proposed the withdrawal of this approval after post-market studies failed to verify clinical benefit [189]. Additional studies of P4 for use in tocolysis are ongoing (Table 2).…”

Section: Progesterone (P4) Analogsmentioning

confidence: 99%

Landscape of Preterm Birth Therapeutics and a Path Forward

Coler

Shynlova

Boros-Rausch

et al. 2021

JCM

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Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear efficacy. Tocolytic agents are drugs that briefly delay PTB, typically to allow antenatal corticosteroid administration for accelerating fetal lung maturity or to transfer patients to high-level care facilities. Globally, there is an unmet need for better tocolytic agents, particularly in low- and middle-income countries. Although most tocolytics, such as betamimetics and indomethacin, suppress downstream mediators of the parturition pathway, newer therapeutics are being designed to selectively target inflammatory checkpoints with the goal of providing broader and more effective tocolysis. However, the relatively small market for new PTB therapeutics and formidable regulatory hurdles have led to minimal pharmaceutical interest and a stagnant drug pipeline. In this review, we present the current landscape of PTB therapeutics, assessing the history of drug development, mechanisms of action, adverse effects, and the updated literature on drug efficacy. We also review the regulatory hurdles and other obstacles impairing novel tocolytic development. Ultimately, we present possible steps to expedite drug development and meet the growing need for effective preterm birth therapeutics.

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“…In 2019, however, the required confirmatory trial failed to reproduce these findings on the surrogate end point of preterm birth or to improve neonatal outcomes. 9 In October 2020, the FDA proposed withdrawing hydroxyprogesterone caproate injection's approval, 9 as is permitted by the accelerated approval statute, but the drug's sponsor has not agreed and is seeking an agency hearing. 17…”

Section: Discussionmentioning

confidence: 99%

Recent Trends in Medicaid Spending and Use of Drugs With US Food and Drug Administration Accelerated Approval

et al. 2021

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IMPORTANCEState Medicaid programs have reported concerns about rising drug prices and spending, particularly regarding drugs entering the market through the accelerated approval program under the US Food and Drug Administration (FDA). The accelerated approval program enables the FDA to approve drugs on the basis of unverified surrogate end points, meaning that clinical benefits for these products are uncertain at the time of approval. However, state Medicaid programs are legally required to cover these drugs. Little is known about the set of products with accelerated approval over time, their use among Medicaid beneficiaries, or the magnitude of their financial influence on state Medicaid programs. OBJECTIVE To identify the number and class of drugs approved through the FDA's accelerated approval pathway and analyze state Medicaid programs' use and spending on these drugs from 2015 through 2019. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional study, biannual FDA reports were

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Withdrawing Approval of Makena — A Proposal from the FDA Center for Drug Evaluation and Research

Cited by 31 publications

References 1 publication

Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials

Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials

Landscape of Preterm Birth Therapeutics and a Path Forward

Recent Trends in Medicaid Spending and Use of Drugs With US Food and Drug Administration Accelerated Approval

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