October 17, 2022
Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Ealena Callender, an OB/GYN with a master’s in public health and a Senior Fellow at the National Center for Health Research. Our research center is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.
In OB/GYN, preterm delivery is one of the most difficult challenges we face. The causes are complicated and not well-understood. But the associated harms are clear and devastating. We all want an effective intervention that will reduce the number of babies delivered too early and lead to better maternal and fetal outcomes. Unfortunately, current data do not indicate that Makena is the solution we have been seeking.
We strongly encourage this Advisory Committee to recommend withdrawing approval of Makena and removing the drug from the market. The reason is simple: The confirmatory trial failed to verify clinical benefit, and there is not substantial scientific evidence to establish the drug’s effectiveness for its approved use.
Patients must have confidence that FDA-approved drugs are safe and effective. Allowing this drug to remain on the market would undermine the legitimacy of FDA approval and harm patients who rely on the drug. If the FDA does not withdraw approval of a drug after research shows that it is not effective, what does FDA approval mean? Who can patients and doctors trust?
Makena was approved by the accelerated approval pathway in 2011 with the condition that the company complete further research to confirm clinical benefit. The subsequent trial – a multicenter, randomized, controlled, double-blind trial – failed to show that the drug either decreases the frequency of preterm birth or decreases neonatal complications associated with preterm birth. Moreover, the study found no difference in fetal or early-infant death and no difference in maternal outcomes. In the simplest terms, the company has not met the conditions of approval and therefore, approval should be withdrawn.
Preterm birth is a serious problem in the U.S. and throughout the world. Some have cited the fact that Makena is currently the only FDA-approved drug to help reduce preterm birth as justification for keeping it on the market. But that only makes sense if it has benefits that outweigh the risks. Makena’s label warns of multiple adverse reactions such as nausea and diarrhea and an increased risk of thromboembolic events, decreased glucose tolerance, fluid retention, and depression. Based on current evidence, treatment with Makena exposes women to many risks but no proven benefit.
The rate of preterm birth in the U.S. is 10.1% today1. Among Black women in the U.S., the rate is 51% higher than for all other women1. We reject the argument that Makena should remain on the market for this high-risk population, given that there is no scientific evidence that Makena is more effective in Black women. On the contrary, both trials showed similar results for Black and non-Black women.
Although the confirmatory trial had a lower percentage of Black participants compared to the initial trial, even the initial study population was not representative of Makena’s intended population. In 2006, the FDA expressed concern that the number of extremely high-risk patients in the initial trial may have overestimated Makena’s efficacy. The original trial paper states, “our results may not be generalizable to women whose risk factors for preterm delivery are different from those of the women in this trial2” and “the women in this study had particularly high risk. They were also strongly motivated, and compliance was excellent.2” We can’t conclude that Makena is more effective for Black women or women at particularly high risk because the initial study was not designed to show this.
Preterm birth is a complex condition for which there is no scientific consensus about the exact etiology or the contribution of individual risk factors. Some 20% of preterm births are induced for complications in the mother or fetus, such as hypertensive disorders, gestational diabetes, and poor fetal growth3. Another 25 to 30% of preterm births are spontaneous and unexplained3. Makena is indicated only for women who have had a prior preterm birth — but most preterm deliveries occur in women with no history of a prior preterm delivery2.
While Makena is the only FDA-approved drug indicated to prevent preterm birth for the prevention of preterm birth, it is by no means the only plausible method to address this complicated condition. An interdisciplinary approach is required to further understand the myriad factors that lead to preterm birth and to develop new approaches for prevention.
We know that improvements in the management of hypertensive disorders and diabetes will help decrease the need for medically-indicated preterm deliveries. Recent advances in the fields of immunobiology and genomics may lead to novel therapies. And, many experts agree that improving strategies to reduce the health impact of systemic racism would lead to better outcomes for Black women in the U.S.
Meanwhile, clinicians may use mechanical therapies including cerclage and cervical pessary or vaginal progesterone, for which studies have found clear evidence of benefit. And of course, if Makena or another drug is proven to be effective, we would all welcome that.
For the last 11 years, it has been the responsibility of the sponsor to prove that Makena is safe and effective, and the company has failed to meet those conditions of accelerated approval. If the drug has a different level of efficacy for Black women, high-risk women, or any other subset of women, the company must have better data to support this claim. At this point, it would be very difficult to enroll patients in a new randomized controlled trial while the drug remains approved and on the market.
We strongly encourage this committee to recommend withdrawal of Makena’s accelerated approval and require that Makena is removed from the market. It is then the obligation of the sponsor to conduct well-designed research to try to prove its claim that Makena provides a clinically meaningful benefit for patients.
On October 19th, the FDA Advisory Committee for Obstetric, Reproductive and Urologic Drugs voted 14-1 that Makena is not effective at reducing the risk of preterm birth and that it should be removed from the market.
- March of Dimes. March of Dimes Report Card: 2021. Accessed October 14, 2022. https://www.marchofdimes.org/materials/March_of_Dimes_US_2021_Report_Card_11152021.pdf
- Meis PJ, Klebanoff M, Thom E, et al. Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Caproate. N Engl J Med. 2003;348(24):2379-2385. doi:10.1056/NEJMoa035140
- Zierden HC, Shapiro RL, DeLong K, Carter DM, Ensign LM. Next generation strategies for preventing preterm birth. Adv Drug Deliv Rev. 2021;174:190-209. doi:10.1016/j.addr.2021.04.021