WALTHAM, Mass., December 14, 2020 – AMAG Pharmaceuticals, Inc. has submitted its response to the FDA’s Notice of Opportunity for a Hearing (“NOOH”) regarding the Agency’s proposal to withdraw approval for Makena—also referred to as 17-OHPC—the only FDA-approved treatment, along with five generic versions, to reduce preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.
The submission of supporting documentation follows upon AMAG’s October 14, 2020 request for a hearing and provides detail on the company’s position in requesting a hearing, recognizing clinicians’ decade-long use of this treatment and the public health implications of withdrawing approval. The response sets out data, analyses, and information demonstrating why Makena should remain available as the only FDA-approved option for women in the U.S. who are at risk for preterm birth, including clinical study results that highlights the evidence of effectiveness of Makena among Black and other minority women.
AMAG—and its new owner, Covis Pharma Group, a leading pharmaceutical company that has a track record of working collaboratively with FDA and is focused on providing therapeutic solutions for patients with life-threatening conditions and chronic illnesses—stand ready to discuss data-driven next steps to maintain Makena as an option for physicians and patients, including developing a new randomized, controlled trial and further evaluating real-world data.
“We seek a hearing to ensure that higher risk women and their doctors retain access to the only safe and effective, FDA-approved treatment for preterm birth and remain committed to the science and clinical experience supporting the value of Makena for appropriate U.S. patients,” said Covis CEO Michael Porter. “We stand ready to work collaboratively with the Agency to address methods of more fully understanding and maintaining this important treatment option for this high-risk underrepresented, principally minority patient population. Preterm birth is an increasing health issue in the U.S., with preterm birth rates significantly higher than in other developed countries. We believe that a thorough review of the benefits of Makena, particularly among at-risk, disadvantaged communities, is required.”
Nearly a year after the divided Advisory Committee meeting and without an opportunity to discuss options for further data generation, FDA sent a NOOH to AMAG and generic manufacturers of 17-OHPC. At the Advisory Committee meeting, experts agreed that additional data would be useful in clarifying benefit or defining the population in whom the drug may provide the most benefit. AMAG agrees that additional data would be helpful and had hoped to discuss several possible avenues with FDA.
AMAG, and its new owner Covis, remain committed to conducting a further study of 17-OHPC. As described in the submission response, possible additional studies include: (1) a retrospective study using secondary real-world data sources, including electronic health record databases and claims databases; and (2) a prospective, primary data collection study with selected hospitals and healthcare networks, such as the Maternal-Fetal Medicine Units Network as well as non-academic sites. AMAG is also open to discussing another randomized clinical trial, better focused on the most at-risk, principally minority patient populations.
A summary of key arguments that warrant discussion at a public forum can be found in the full copy of the submission available here. While the FDA reviews the submission of supporting documentation, Makena remains approved and available and the product label remains unchanged.
AMAG is a commercial-stage biopharmaceutical company focused on bringing innovative products to patients with unmet medical needs. The company does this by leveraging its development and commercial expertise to invest in and grow its pharmaceutical products across a range of therapeutic areas. For additional company information, please visit www.amagpharma.com.
Covis is headquartered in Luxembourg with operations in Zug, Switzerland and is a global specialty pharmaceutical company that markets therapeutic solutions for patients with life-threatening conditions and chronic illnesses. Additional information is available at www.covispharma.com.
AMAG Pharmaceuticals Submission in Response To the Food And Drug Administration’s
Notice of Opportunity for a Hearing and Proposal To Withdraw Approval of Makena®
AMAG’s position that Makena (hydroxyprogesterone caproate injection) should remain on the market and available to patients during further study is supported by legal, scientific, and policy rationales. The full response provides six arguments that warrant discussion at a public forum in which FDA can fully evaluate the public health considerations presented:
- Makena has a favorable benefit-risk profile meriting further study rather than withdrawal
The Meis trial demonstrated the substantial benefit of Makena for women at higher risk of preterm birth—so much so that the trial was ended early and 17-OHPC became widely used. Given this, it became exceedingly difficult to construct a confirmatory study that mirrored the higher-risk population in the Meis trial. Ultimately, the confirmatory study, PROLONG, failed to confirm the benefit of 17-OHPC in a very different population of women than those studied in the Meis trial. The PROLONG patient population had significantly lower background rates of preterm birth risk with more than 75 percent of participants enrolled from outside of the U.S., including 61 percent from Russia and Ukraine.
The PROLONG data do not and could not rule out the benefits seen in the Meis trial and, to the contrary, show a trend toward reduction of preterm birth for U.S. PROLONG patients—while also reaffirming Makena’s overall safety profile. There were no new negative safety signals in the PROLONG trial. As such, the overall benefit-risk profile for Makena supports that the drug should remain on the market and available to patients, while further study is conducted on efficacy in higher-risk subpopulations.
- The medical and patient community continue to support 17-OHPC as a treatment option
Clinicians should not be denied the ability to make an informed treatment determination in favor of using Makena for certain patients. Major professional societies including the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) continue to support the use of 17-OHPC to prevent recurrent preterm birth in appropriate patients. In the wake of the NOOH, FDA has received comments from practitioners and patients reporting their positive experiences with Makena. In addition, a number of leading organizations have expressed concerns through comments submitted to FDA’s docket, including the Association of Women’s Health, Obstetric and Neonatal Nurses, HealthyWomen, March of Dimes and National Consumers League.
- Withdrawal of Makena would leave an underserved and vulnerable, largely minority patient population without a treatment option
Withdrawal of Makena and generic equivalents on the basis of the PROLONG study will have significant public health consequences to Black and minority women at higher risk of preterm birth. It is well recognized that conditions and efficacy of treatments can vary significantly by minority subpopulation. These populations may be ill-served by studies that are inadequately representative, such as PROLONG, particularly where there are trends that suggest increased efficacy in these groups. FDA’s proposal to withdraw Makena is misplaced based on the flawed inclusion parameters of PROLONG and the potential outsize impact it will have on populations that were underrepresented in the clinical research.
It would be fundamentally inappropriate to deprive access to high-risk pregnant women because of a vastly different population enrolled in PROLONG. Neither compounding nor generic Delalutin—a 17-OHPC product not labeled for use in pregnant women—could fill the void. If Makena is withdrawn, the law requires FDA also to bar compounding of 17-OHPC. But even assuming that compounding were possible (for example, based on generic Delalutin), it is a false option. Compounding, especially of sterile products, has a troubled history in the U.S. and has led to numerous identified safety risks for patients. Proposing compounded versions of Makena, which many physicians have indicated they would resort to, as a solution to meet the needs of physicians and patients wishing to have access to a 17-OHPC product would introduce significant safety risks in the treatment of pregnant women, and stands in contrast to FDA’s policy on the safety and traceability of pharmaceutical products.
- Precedent and practice support maintaining approval for Makena while additional data are developed
When pre-approval data provides compelling evidence of an important clinical benefit for at-risk populations, withdrawal is not appropriate unless the post-approval data establish that there is no longer a reasonable likelihood of clinical benefit and there is no meaningful way to further study or characterize the potential benefit to patients. Through its prior actions, FDA has endorsed this view particularly where there are identifiable populations that would be placed at risk if a drug were withdrawn. FDA has not withdrawn drugs in prior instances where a confirmatory study has failed but there are indications of efficacy in a subpopulation, a positive safety profile, and no other available treatment options. In such cases, the Agency has taken affirmative steps to work with the sponsor to generate additional data, rather than deprive a vulnerable patient population of a possible treatment.
- FDA should maintain the approval status of Makena while follow-up studies are undertaken
FDA should reengage in discussions with AMAG and its new owner Covis about a proper path forward to keep Makena on the market while additional studies—such as an alternative real-world evidence study, a prospective observational study or a placebo-controlled, randomized clinical trial—are undertaken. In addition, there are important questions that merit discussion about the appropriate clinical endpoints that would be most indicative of benefit to women at high-risk of preterm birth.
- AMAG is entitled to a hearing
AMAG has demonstrated ample factual questions suitable for a hearing, and public health and policy concerns militate in favor of granting a hearing. The submission and accompanying documents also present new information that FDA has not previously had the opportunity to consider. A public hearing would allow a full and fair consideration of the parties who have made public statements and submitted concerns to the FDA docket. Additionally, FDA and the public would benefit from an advisory committee with greater hands-on experience in the treatment of high-risk pregnancies and the use of Makena in U.S. populations, including minority and socio-economically disadvantaged women.
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