Politics, Science, and the Future of FDA Drug Regulation: FDA’s Review of Mifepristone REMS as a Litmus Test

On September 19, 2025, US Department of Health and Human Services (HHS) Secretary Robert F. Kennedy Jr and US Food and Drug Administration (FDA) Commissioner Martin Makary announced that HHS would be conducting "a study on the safety of the current [Risk Evaluation and Mitigation Strategy (REMS)]" for mifepristone to "determine whether modifications are necessary." This announcement came in response to a letter from the attorneys general of 22 states, seeking a review of the mifepristone REMS. Secretary Kennedy and Commissioner Makary wrote that their decision was "informed by the lack of adequate consideration underlying the prior REMS approvals" and further justified their review in light of "recent studies raising concerns about the safety of mifepristone as currently administered" that the attorneys general had cited in their letter.

In this issue of JAMA, Dilek and colleagues 1 conduct a comprehensive document analysis of the process and evidence the FDA followed in establishing and modifying the mifepristone REMS from 2011 to 2023. 1 They review more than 5000 pages of more than 250 FDA internal documents obtained through a Freedom of Information Act (FOIA) request, further supplemented by publicly available information, and document the agency's approach. They highlight 5 key decision points, including times when the FDA decided to relax or remove certain restrictions and other times when the FDA decided to keep restrictions in place.

Dilek and colleagues find that the agency consistently took a cautious approach led by the agency's scientific staff, seemingly removed from ongoing ideological and political debates, and reliant not just on sponsor-submitted data but also on meta-analysis of independent studies of mifepristone's safety. For example, the authors report that in 2015-2016, when the FDA expanded mifepristone's approved indication for use through 70 days' gestation and removed some REMS restrictions, staff scientists based their decision-making on "published studies reflecting clinical practice, 16 years of accumulated postmarketing safety data, and the most recent sponsor-submitted REMS assessment report." After 2016, FDA scientific review teams continued to obtain and review safety data through spontaneous adverse event reporting, postmarket safety surveillance mechanisms, and other avenues. These findings thus challenge Kennedy and Makary's contention that the FDA has, in recent years, failed to apply "adequate consideration" to its REMS decisions.

The authors also identified 2 decision points where political appointees overrode staff scientists to veto changes to the REMS that would have increased access to mifepristone. These decisions-the first in 2015-2016 and the second in 2020-led to the maintenance of certain REMS requirements mandating patient communications and in-person dispensing during the COVID-19 pandemic, despite FDA staff scientists having concluded that such requirements were unnecessary.

Previous analyses of REMS programs have raised concerns about the effectiveness of such programs generally in improving patient safety. A 2013 investigation from the HHS Office of the Inspector General reviewed a sample of 49 REMS required by the FDA between 2008 and 2011 and found that nearly one-half of the sponsor assessments did not include all of the information requested by the agency, and less than one-fifth of REMS met all of the FDA's goals. 2 Studies have also demonstrated that medication guides and communication plans are largely ineffective in educating patients and prescribers about drug safety risks, [3][4][5] while others have raised concerns around how Elements to Assure Safe Use (ETASUs), such as prescriber or pharmacy certifications, patient registries, and prescriber training, are designed, implemented, and evaluated. 6 Moreover, REMS requirements have shifted over time: less restrictive REMS components, such as medication guides and communication plans, are now used less often, while more restrictive ETASUs have become more common. 7 The FDA's mostly opaque decision-making process in reevaluating and updating REMS programs has further obscured the effectiveness of these programs. 8 Using internal documents related to the mifepristone REMS that the FDA made publicly available through a FOIA request, but which were not previously public, Dilek and colleagues' review 1 offers unique insight into the agency's cautious and careful decision-making. Despite multiple reevaluations of the mifepristone REMS, political appointees' interference was rare and tended in the direction of caution. However, intense political scrutiny may have contributed to the agency's caution and thoroughness.

In this respect, the FDA's handling of mifepristone may not be characteristic of all REMS-regulated drugs. For instance, the FDA's review process for mifepristone's initial approval in 2000 lasted for 4 years, compared with an average of 15.6 months for 27 other new drugs approved that same year, even after the FDA convened an external advisory committee meeting in July 1996 that voted near unanimously that the available evidence demonstrated mifepristone's safety and efficacy. Political leadership may now play a more central role in the FDA's regulatory decision-making vis-à-vis mifepristone. In multiple congressional hearings earlier this year, Secretary Kennedy voiced concern over mifepristone's safety and support for reevaluation of the drug's REMS. In their letter responding to the state attorneys general, he and Commissioner Makary specifically mentioned "the in-person dispensing requirement" removed from the mifepristone REMS in 2023, signaling they may try to reinstate it.

At the same time, court orders may soon begin to constrain the FDA's freedom to revise the mifepristone REMS. Plaintiffs in competing, pending litigations, including State of Missouri v FDA and Purcell v Kennedy, variously ask federal judges to issue orders that could force the FDA to tighten or loosen the mifepristone REMS, freeze it as is, or remove it altogether. Conversely, a decision by the FDA to tighten the mifepristone REMS in coming months could undermine ongoing litigation that challenges state restrictions on the drug as preempted by federal law, such as Dr Amy Bryant's challenge to North Carolina's restrictions. 9 If the history of the FDA's management of mifepristone's REMS requirements is marked by caution-reliant on agency staff and experts and driven by scientific evidence rather than political interference-the current administration's first year suggests an opposite approach. For instance, HHS and the FDA recently joined the White House to suggest a causal link between acetaminophen use in pregnancy with autism, despite recent studies showing a lack of association. 10 Moreover, in the same press conference, Secretary Kennedy and Commissioner Makary announced that the FDA intends to approve leucovorin for treatment of a condition linked to autism, based not on any new clinical trial data but instead on a literature review and a case series of 40 patients with heterogeneous symptoms. Dilek and colleagues' findings and other studies show that it is highly unusual for political appointees to make such decisions without the input of multiple scientific review teams or against agency scientists' recommendations. 11 As HHS and the FDA conduct their promised review of the mifepristone REMS, they should adhere to the principles of "gold standard science" and "radical transparency" repeatedly invoked by current leadership.

Gold standard science will require continuing the approach the FDA has historically taken with the mifepristone REMS and ensuring that multiple scientific review teams conduct a comprehensive analysis of available information, including sponsor-submitted assessments, data from postmarket studies, and data derived from the FDA's existing safety surveillance systems. Gold standard science will also require that the FDA's scientific staff are at the helm of the analysis and protected from political interference. The FDA should also consider convening an advisory committee meeting, expressly inviting independent experts to publicly weigh the evidence and potential modifications of the REMS.

Radical transparency will require transparency from the start; patients and clinicians should not need to wait for documents to be made available in response to FOIA requests, which frequently take years to be completed, to understand the current FDA's decision-making on this essential drug. The FDA should make its evidence and internal discussion publicly available proactively, or at very least respond promptly to FOIA requests. Sharing this material will allow independent experts to interrogate the FDA's ongoing work. Taking these steps will ensure that the FDA not only continues to protect public health and patient safety but also maintains the trust of patients and the medical profession.