An analysis of internal Food and Drug Administration documents by researchers at the Johns Hopkins Bloomberg School of Public Health finds that the agency generally followed cautious and evidence-based recommendations from staff scientists regulating the abortion drug mifepristone over a critical 12-year period.
The findings were published online January 12 in JAMA.
For their study, the researchers reviewed 264 internal FDA documents totaling 5,239 pages related to the FDA’s safety program for mifepristone from June 2011 to January 2023. The FDA approved mifepristone for early pregnancy termination in 2000. Today mifepristone, in combination with another drug, misoprostol, is the most widely used abortion regimen in the U.S. and is also widely used throughout the world.
The documents focused on staff scientists’ deliberations and leadership decisions regarding the FDA’s Risk Evaluation and Mitigation Strategies (REMS)—a safety program for select drugs that helps ensure a drug’s benefits outweigh its risks—as well as considerations during the COVID-19 pandemic. The researchers obtained the documents through a Freedom of Information Act (FOIA) request.
In their review, the researchers found that FDA decisions were based on safety considerations. They did not find evidence of ideological bias in internal discussions among FDA scientists.
Two limited instances of political intervention were identified in which senior FDA leadership decisions diverged from staff scientists’ recommendations. First, in 2016, FDA leadership required retention of a patient agreement form despite staff support for its removal; later, staff scientists supported retention of the form. In 2020, FDA leadership did not adopt staff scientists’ recommendation to suspend in-person dispensing during the COVID-19 pandemic; a court forced the agency to do so. These instances were discrete and time-limited.
Mifepristone has been the focus of extensive debate and court challenges, as disagreement over abortion health policy continues. Last September, federal health officials announced that they were going to review the FDA’s 2023 decision to stop requiring in-person dispensing of mifepristone at health care providers’ offices or clinics. This decision allowed patients to fill mifepristone prescriptions at certified pharmacies or by mail order.
Mifepristone ends a pregnancy by blocking the effects of the hormone progesterone, and misoprostol induces strong uterine contractions. When the FDA approved the mifepristone-misoprostol regimen in 2000, it imposed restrictions in light of the risk of side effects such as heavy uterine bleeding. The drug had to be prescribed in person by doctors, and patients had to receive the drug in person and sign an agreement form acknowledging its risks.
“We hope these findings will help keep a focus on what should remain a scientifically based approach to drug regulation,” says study corresponding author G. Caleb Alexander, MD, a professor at the Johns Hopkins Bloomberg School of Public Health and a founding co-director of the Center for Drug Safety and Effectiveness at the Bloomberg School.
Alexander and his team began this project in 2019 with FOIA requests for relevant FDA documents. The researchers coded the documents focusing on the agency’s reasoning for establishing, maintaining, or modifying approaches for regulating mifepristone. The qualitative analysis was also informed by publicly available information.
The researchers identified five key moments in the FDA’s regulation of mifepristone from 2011 to 2023:
- June 2011: The FDA deliberated whether to bring mifepristone under its new Risk Evaluation and Mitigation Strategies framework for drugs with potential safety issues. The agency opted to set up a REMS program for mifepristone, with in-person dispensing requirements that closely mirrored those in place since the product was first approved in 2000.
- October 2013: At the request of a senior FDA official, staff scientists conducted a formal reassessment of whether mifepristone’s REMS was still necessary. FDA scientists concluded that the drug’s safety profile was unchanged and identified reasons both to remove and to retain restrictions. Ultimately, the agency decided to maintain the REMS designation, reflecting a cautious approach despite consistent findings of safety.
- May 2015: At the request of mifepristone’s U.S. manufacturer, Danco Laboratories, the FDA reviewed a number of changes related to the drug’s labeling. After a comprehensive review of clinical studies and more than 16 years of safety data, the FDA concluded that the revised regimen was safe and effective, with serious adverse events remaining rare. The agency streamlined parts of the REMS but retained the requirement of a patient agreement form after FDA leadership determined it provided added assurance of informed patient care without limiting access.
- 2020–2021, COVID-19 Pandemic: During widespread clinic closures, the FDA was sued over its requirement that mifepristone be dispensed in person and accompanied by a patient signature. Although the agency opposed the lawsuit, FDA staff scientists concluded internally that the product could be safely dispensed remotely during the public health emergency. A federal judge temporarily suspended the requirements; the Supreme Court reinstated them in 2021. The FDA nevertheless chose to continue enforcement discretion, citing evidence—including studies from the suspension period—showing no increase in safety concerns.
- November 2021: As part of a review of mifepristone’s REMS requirements, FDA staff scientists discussed replacing the in-person dispensing requirement with a pharmacy certification system. The FDA, citing multiple studies and the lack of increased safety concerns during the period when the in-person dispensing requirement was not enforced, implemented this change in January 2023, supporting access by allowing mail-order and retail dispensing from certified pharmacies.
“Our review sheds light on the FDA’s decision-making process over a pivotal period and with respect to a drug that has long been subject to debate,” says study co-author Joanne Rosen, JD, MA, practice professor at the Bloomberg School and co-director of the Bloomberg School’s Center for Law and the Public’s Health. “We hope our findings that the agency acted cautiously, incrementally, and with a commitment to well-grounded scientific evidence will provide reassurance to the public and serve as a model for future agency review.”
The authors note that their analysis has several limitations. Some FDA documents obtained through FOIA were redacted, including entire pages; some internal FDA discussions may not have been captured in the documents the researchers did receive; and the analysis may not fully capture the complexity of agency decision-making.
“The U.S. Food and Drug Administration’s Regulation of Mifepristone” was co-authored by Sophie Dilek, Joanne Rosen, Anna Levashkevich, Joshua Sharfstein, and G. Caleb Alexander.
Disclosures: Alexander is a founding co-director of an FDA-funded Center of Excellence in Regulatory Science and Innovation, past chair of FDA’s Peripheral and Central Nervous System Advisory Committee, and a co-founding principal and equity holder in Stage Analytics.
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Journal
JAMA