Today, AMAG Pharmaceuticals, Inc. submitted its response https://www.regulations.gov/document?D=FDA-2019-P-4683-0005 with the U.S. Food and Drug Administration (FDA) to a petition filed by Public Citizen’s Health Research Group (HRG).
AMAG respectfully disagrees with HRG’s request to withdraw FDA approval of Makena® (hydroxyprogesterone caproate injection) and the five FDA-approved generics (which could no longer be marketed if Makena’s NDA was withdrawn). The response provides six arguments to support the continued, positive benefit-risk profile of Makena.
- Preterm Birth is a Significant Public Health Issue
Preterm birth is the leading cause of neonatal mortality and morbidity in the U.S., and rates of preterm birth are on the rise in the U.S. Makena and its generics – often referred to as 17P or 17-OHPC, are the only FDA-approved treatment options indicated for reducing the risk of recurrent preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.
- FDA’s 2011 Approval of Makena was Appropriate Based on the Landmark Meis Study
Makena was granted accelerated approval in 2011 based on a clinical trial conducted by the Maternal-Fetal Medicine Units Network, sponsored by the National Institute of Child Health and Human Development, which was published by Meis et al. in the New England Journal of Medicine. The Meis study, which was conducted entirely in the U.S., demonstrated that 17P reduced the occurrence of recurrent preterm delivery by approximately one-third compared to placebo. The Meis study continues to provide substantial evidence that supports ongoing access to FDA-approved 17P for this high-risk, orphan population with no FDA-approved alternatives.
- The Results of PROLONG Do Not Invalidate the Results of the Meis Study
The recently completed PROLONG (Progestin’s Role in Optimizing Neonatal Gestation) study did not meet its two pre-specified co-primary endpoints. While PROLONG failed to confirm 17P’s efficacy, it does not invalidate the results and conclusions from the Meis study. PROLONG, although designed to replicate the Meis study, evaluated a markedly different, international patient population with significantly lower background rates of preterm birth risk with more than 75 percent of subjects being enrolled from outside of the U.S. This lower risk patient population was reflective of the reluctance of U.S. physicians to enroll high-risk patients in a placebo-controlled study rather than prescribe 17P. As a consequence, the rate of recurrent preterm birth was considerably lower than expected, which resulted in PROLONG being underpowered. This unexpectedly lower rate of preterm birth, driven by ex-U.S. enrollment, raises uncertainty about the applicability of PROLONG to the higher risk U.S. population.
Importantly, a favorable maternal and fetal safety profile of 17P was reaffirmed in PROLONG.
Following the release of the PROLONG data, both the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine issued statements, which support the use of 17P in appropriate patients.
- FDA Can Ensure Continued Access to 17P
As FDA has previously noted, they judiciously consider multiple factors, including safety, patient need, and the availability of other treatments when considering whether to withdraw a product approved under accelerated approval. As FDA has recognized, there are many reasons for the outcomes of a trial, including the population used. FDA considers the public’s best interest before removing a drug from the market and has long-standing flexibility when considering what constitutes substantial evidence. AMAG is committed to continuing a dialogue with the FDA on feasible ways to generate additional efficacy data while retaining current access for patients.
- Withdrawal Would Deprive Women and Their Physicians of the Option of Shared Decision-making
Removing the only FDA-approved treatment from the market would impact the shared decision-making for pregnant women and their providers. It would leave patients with no effective options or result in a return to compounded 17P with the associated potential efficacy and safety risks. In addition to these concerns, compounded medications lack appropriate labeling to inform patients and providers about potential risks and benefits.
- The U.S. has Substantial Health Disparities in Preterm Birth, Which Would Likely be Increased Without Access to FDA-Approved 17P
The demographic differences between the Meis and PROLONG populations underscore the impact that social determinants of health may have had on the results of both studies. The body of evidence most generalizable to U.S. patients is the Meis study due to its exclusively U.S. enrollment. Withdrawing the only FDA-approved intervention could have the unintended consequence of further exacerbating existing health disparities associated with preterm birth in the most vulnerable patient populations.
AMAG is committed to continue working with the FDA to determine the best path forward for patients and clinicians.
At this time, it is important to know that Makena’s approval and product label remain unchanged. Guidelines released on October 25, 2019 regarding 17P are available at: American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine. If you have been prescribed or are taking Makena and have questions about your prescription, please speak with your healthcare provider or contact Makena Care Connection® by calling 1-800-847-3418 (M–F, 8AM–8PM ET) or emailing email@example.com.
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