HCR 553 Module 5 Major Assignment 2, Part A: A Product Pulled From the Market Example

Approved on a Promise: The Rise and Withdrawal of Makena and What It Teaches About Quality in Accelerated Approval

Student Name

MS in Clinical Research Management, Arizona State University

HCR 553: Quality Assurance and Clinical Research

Instructor Name

Month Day, Year

Approved on a Promise: The Rise and Withdrawal of Makena and What It Teaches About Quality in Accelerated Approval

Introduction

Few drugs are withdrawn for doing too little rather than too much harm, but Makena is one. It was the only FDA-approved drug to reduce the risk of preterm birth in women with a previous spontaneous preterm birth, and for a decade it was widely used. Its withdrawal in 2023 followed a failed confirmatory trial and a long regulatory process, and it shows how quality questions about evidence can take years to resolve.

The Product and Its Approval

Makena is a weekly intramuscular injection of hydroxyprogesterone caproate, a synthetic progestin. The FDA approved it in 2011 under the accelerated approval pathway, which allows approval based on a surrogate or intermediate endpoint reasonably likely to predict clinical benefit, on condition that a confirmatory trial follows. The evidence came largely from one trial run by a federally funded maternal-fetal medicine network: among 463 women with a prior spontaneous preterm birth, weekly injections reduced delivery before 37 weeks from 54.9% with placebo to 36.3% (Meis et al., 2003). The approval used delivery before 37 weeks as the endpoint likely to predict reductions in infant illness and death.

The Confirmatory Trial

The required confirmatory trial, PROLONG, randomized 1,708 women at 93 centers, 41 in the United States and 52 elsewhere, in a 2:1 ratio to the drug or placebo. It found no difference in preterm birth before 35 weeks, 11.0% with the drug against 11.5% with placebo, and no difference in a composite of serious newborn complications (Blackwell et al., 2020).

Why the Trials Disagreed

The populations differed sharply. The original trial enrolled women at very high risk in the United States, where more than half of the placebo group delivered before 37 weeks. PROLONG enrolled mostly women outside the United States with much lower baseline risk, so the trial may have had little room to show a benefit even if one existed in the highest-risk group. Supporters argued that the confirmatory trial did not test the population the drug was approved for; the FDA concluded that the original single trial was itself not strong enough to stand alone once a larger trial failed.

The Withdrawal

In 2020 the FDA's drug center proposed withdrawing approval. The manufacturer requested a hearing, which took place in 2022, and in April 2023 the Commissioner and the agency's Chief Scientist announced a final decision withdrawing approval of Makena and its generics (U.S. Food and Drug Administration, 2023). The process took years because, under the law at the time, withdrawal of an accelerated approval required a lengthy formal hearing. The Food and Drug Omnibus Reform Act of 2022 later gave the FDA faster procedures and the power to require confirmatory trials to be under way before approval.

Quality Lessons

1. A single trial is fragile evidence. Approval based on one study, however well run, leaves regulators exposed if a second study disagrees.

2. Confirmatory trials must be timely. PROLONG reported almost a decade after approval, during which the drug became standard care.

3. The confirmatory population must match the approved population. Enrolling mostly lower-risk women outside the United States made the result hard to apply to the patients who used the drug most.

4. Withdrawal must be possible without years of delay, so that patients do not receive drugs whose benefit is unproven.

Conclusion

Makena's withdrawal was not a safety recall but a judgment that the evidence of benefit had not held up. Its history shows that quality in drug regulation depends as much on the design and timing of confirmatory evidence as on the original approval.

References

Blackwell, S. C., Gyamfi-Bannerman, C., Biggio, J. R., Jr., Chauhan, S. P., Hughes, B. L., Louis, J. M., Manuck, T. A., Miller, H. S., Das, A. F., Saade, G. R., Nielsen, P., Baker, J., Yuzko, O. M., Reznichenko, G. I., Reznichenko, N. Y., Pekarev, O., Tatarova, N., Gudeman, J., Birch, R., . . . Krop, J. (2020). 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG study): A multicenter, international, randomized double-blind trial. American Journal of Perinatology, 37(2), 127-136. https://doi.org/10.1055/s-0039-3400227

Meis, P. J., Klebanoff, M., Thom, E., Dombrowski, M. P., Sibai, B., Moawad, A. H., Spong, C. Y., Hauth, J. C., Miodovnik, M., Varner, M. W., Leveno, K. J., Caritis, S. N., Iams, J. D., Wapner, R. J., Conway, D., O'Sullivan, M. J., Carpenter, M., Mercer, B., Ramin, S. M., . . . Gabbe, S. G. (2003). Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. New England Journal of Medicine, 348(24), 2379-2385. https://doi.org/10.1056/NEJMoa035140

U.S. Food and Drug Administration. (2023, April 6). FDA commissioner and chief scientist announce decision to withdraw approval of Makena [Press release]. https://www.fda.gov/news-events/press-announcements/fda-commissioner-and-chief-scientist-announce-decision-withdraw-approval-makena