Navigating the Latest Shifts in Mifepristone Regulations

Recent legal developments and ongoing litigation have made the regulation of mifepristone and misoprostol a critical issue for healthcare providers and policymakers. This article explores evolving FDA guidelines, recent court rulings, and state actions impacting the availability and administration of these medications, offering insights into a fast-moving legal landscape with significant implications for medical providers.

FDA Approval and Changes to Authorized Uses

Medication termination of a pregnancy is a protocol that involves taking oral medication to terminate a pregnancy. This can be accomplished through either taking mifepristone in combination with misoprostol or taking misoprostol alone. Relevantly here, in 2000, the U.S. Food and Drug Administration (FDA) originally approved Mifeprex (mifepristone), taken in a regimen with misoprostol, to end an intrauterine pregnancy through seven weeks of gestation. The FDA approved the drug with certain restrictions for patient safety.

Under current FDA guidelines, certain medications are available only under a risk evaluation and mitigation strategy (REMS) program. REMS are drug safety programs that the FDA has the authority to require for certain medications with serious safety concerns. REMS are “designed to reinforce medication use behaviors and actions that support the safe use of that medication.” REMS focus on preventing, monitoring, and managing a specific serious risk. However, the REMS program was not created until 2007. Therefore, as part of the Food and Drug Administration Amendments Act of 2007, Mifeprex was deemed to have, in effect, an approved REMS.

Subsequently, in 2016, the FDA approved a supplemental new drug application to approve Mifeprex for use up to 10 weeks of pregnancy rather than seven weeks of pregnancy. Under the 2016 supplemental new drug application, the FDA also modified the REMS to allow healthcare providers such as nurse practitioners to prescribe Mifeprex and reduced the number of required in-person visits from three to one. Then in 2019, the FDA approved a generic version of Mifeprex, mifepristone tablets, to be taken with misoprostol to terminate an intrauterine pregnancy through 10 weeks of pregnancy. The World Health Organization has subsequently approved the use of these two pills in combination to terminate an intrauterine pregnancy through 12 weeks of pregnancy.

In 2019, when mifepristone was approved as a generic form of Mifeprex, the FDA approved a single REMS program, the Mifepristone REMS Program, for the medical termination of intrauterine pregnancy through 70 days (10 weeks) of pregnancy. Then, in 2021, the FDA determined the Mifepristone REMS Program could be modified to reduce the burden on the healthcare delivery system. Relying on data gathered during the COVID-19 pandemic from pregnant women using mifepristone without an in-person visit, the FDA determined it would no longer enforce the initial in-person visit requirement. Immediately, four medical associations and several individual physicians filed suit against the FDA, seeking a preliminary injunction to either require the FDA to rescind its approval of the drug or to rescind the FDA’s 2016 and 2021 regulatory actions. Danco Laboratories, the sponsor of Mifeprex, subsequently intervened to defend the FDA’s actions.

Challenges to FDA Approval From Doctors and Healthcare Organizations

On April 7, 2023, the United States District Court for the Northern District of Texas issued an order to enjoin the FDA’s approval of mifepristone, which, in effect, removed the drug from the market. The FDA and Danco Laboratories immediately appealed the District Court’s decision to the Fifth Circuit.

On April 12, 2023, a three-judge panel of the Fifth Circuit issued an order partially staying the order from the District Court and allowed the FDA’s original 2000 approval of mifepristone to stand. The Fifth Circuit’s order allowed the drug to be sold under the more stringent 2000 regulatory framework requiring three in-person visits with the prescribing physician. The Justice Department and Danco Laboratories appealed the restrictions on mifepristone to the Supreme Court on April 14, 2023. The Supreme Court stayed the District Court’s order pending the outcome of the case on April 21, 2023. The Fifth Circuit then heard the case on May 17, 2023, and issued a ruling on August 16, 2023. The Fifth Circuit panel held that the plaintiffs had standing to challenge the FDA’s approval of mifepristone and, while they were unlikely to succeed on their challenge to the FDA’s 2000 and 2019 drug approvals, they were likely to succeed in showing that the FDA’s 2016 and 2021 actions were unlawful. The Supreme Court then granted certiorari and limited the controversy to the question of the plaintiff’s standing and the appropriateness of the FDA’s changes to the Mifeprex REMS Program in 2016 and Mifepristone REMS Program 2021.

The plaintiffs argued that the FDA’s relaxed regulation of mifepristone could (1) cause downstream conscience injuries to the individual doctor plaintiffs and the specific members of the plaintiff medical associations who are also doctors, (2) cause downstream economic injuries to the doctors, and (3) cause injuries to the medical associations themselves, which asserted their own organizational standing. On the first point, the Supreme Court found that “federal law fully protects doctors against being required to provide abortions or other medical treatment against their conscience—and therefore breaks any chain of causation between the FDA’s relaxed regulation of mifepristone and any asserted conscience injuries.” To the second point, the Supreme Court found that “the law has never permitted doctors to challenge the government’s loosening of general public safety requirements simply because more individuals might then show up at emergency rooms or in doctors’ offices with follow-on injuries.” The court pointed out that such a holding would allow doctors to challenge essentially any “general public safety requirements,” defeating the purpose of the standing doctrine.

The court highlighted the fact that “doctors have never had standing to challenge the FDA’s drug approval simply on the theory that use of the drugs by others may cause more visits to doctors.” Justice Kavanaugh further wrote, “doctors who object to what the law allows others to do may always take their concerns to the Executive or Legislative Branches and seek greater regulatory or legislative restrictions on certain activities.” The Supreme Court found that the medical association plaintiffs did not have organizational standing, reversed the Fifth Circuit’s judgment, and remanded the case for further proceedings.

Challenges to Authorized Uses from States

While Alliance for Hippocratic Medicine v. FDA was playing out in federal court, the Mifepristone REMS Program was further modified by the FDA on Jan. 3, 2023, to make the following changes:

• Mifepristone must be prescribed by a healthcare provider who meets certain qualifications and is certified under the Mifepristone REMS Program.
• In order to become certified, healthcare providers must complete a prescriber agreement form.
• The agreement form must be reviewed and signed by both the patient and the healthcare provider wherein the risks of the mifepristone regime are fully explained to the patient before the drug is prescribed.
• The patient must be provided a copy of the patient agreement form and mifepristone medication guide (FDA-approved information for patients).
• Mifepristone may only be dispensed by or under the supervision of a certified prescriber, or by a certified pharmacy on a prescription issued by a certified prescriber.
• To become certified to dispense mifepristone, pharmacies must complete a pharmacy agreement form.
• Certified pharmacies must be able to ship mifepristone using a shipping service that provides tracking information.

These January 3, 2023, REMS program modifications, in effect, allowed certain retail pharmacies to dispense and ship Mifeprex and mifepristone tablets. Subsequently, on February 23, 2023, the state of Washington and nine other states filed suit against the FDA, arguing the agency should have gone further to make mifepristone more accessible. Specifically, the plaintiffs sought a preliminary injunction “affirming FDA’s original conclusion that mifepristone is safe and effective” and enjoining the “unnecessary and burdensome January 2023 restrictions.” The plaintiffs filed on behalf of themselves and as parens patriae in protecting the health and well-being of their residents. Shortly thereafter, in March 2023, a coalition of other states, led by Idaho, filed a motion to intervene, arguing their interests were not properly represented by the FDA defendants. The coalition of states led by Idaho argued that the FDA should reinstate the in-person dispensing rule and remove the ability for retail pharmacies to dispense the drug.

On April 7, 2023, the United States District Court for the Eastern District of Washington granted the plaintiff’s motion for a preliminary injunction in part to enjoin the FDA from “altering the status or rights of the parties under the operative Mifepristone REMS Program until a determination on the merits.” The plaintiffs had asserted that they were likely to succeed on the merits of the claim that the FDA’s 2023 changes to the Mifepristone REMS Program violated the Administrative Procedure Act (APA). The FDA had disagreed and argued that the plaintiffs lacked standing and had not exhausted their administrative remedies. Upon examination of the plaintiff’s asserted claim regarding the 2023 REMS change, the court determined that it was “not the Court’s role to review the scientific evidence and decide whether mifepristone’s benefits outweigh its risks without REMS and/or ETASU [elements that are necessary to assure safe use].” However, the court went on to find that. based on the present record, the FDA did not assess whether mifepristone qualifies for REMS and ETASU based on the criteria set forth under 21 U.S.C. § 355-1(a)(1),(f)(1). And moreover, the record demonstrated potentially internally inconsistent FDA findings regarding mifepristone’s safety profile. Therefore, the court found that there were serious issues going to the merits of the plaintiff’s APA claims.

The District Court went on to deny Idaho’s motion to intervene as of right, and dismissed for lack of jurisdiction the portion of the appeal concerning the District Court’s denial of the permissive intervention, in the State of Washington’s lawsuit challenging the FDA’s imposition of safe-use restrictions on the drug. Then on July 24, 2024, the United States Court of Appeals for the Ninth Circuit ruled on whether the coalition of states led by Idaho would be allowed to intervene. The circuit judge wrote that given the “deep and obvious conflict between the parties’ objectives,” Idaho would need to independently satisfy Article III standing requirements to join the suit.

The Court of Appeals next considered whether Idaho established standing to challenge the FDA’s elimination of the in-person dispensing requirement. To support its basis for standing, Idaho first alleged that elimination of the in-person dispensing requirement would cause the state economic injury in the form of increased costs to the state’s Medicaid system.

In responding, the court referenced Alliance for Hippocratic Medicine to determine that the causal chain between the FDA’s regulation of mifepristone and downstream medical outcomes is highly attenuated. Specifically, the court wrote, “even assuming for sake of argument” that the 2023 REMS will “cause more pregnant women to require emergency abortions,” that “an alleged uptick in Medicaid costs is exactly the kind of ‘indirect effect[] on…. state spending’ that the Supreme Court has rejected as a basis for standing.” The Appeals Court ultimately determined that the state could not establish standing based on the alleged costs to the state’s finances because the asserted casual chain was too attenuated. The Appeals Court went on to find that nothing in the 2023 Mifepristone REMS Program would injure Idaho’s sovereign interests by impairing its ability to regulate mifepristone or promote maternal and fetal health. Ultimately, the circuit affirmed the District Court’s order denying Idaho’s motion to intervene.

How State Regulations May Impact Medication Access

Parallel to the litigation happening at the federal level, several states have been weighing options at the state level to either expand or restrict access to mifepristone. As an example, effective October 1, 2024, mifepristone and misoprostol will both be listed as controlled dangerous substances under Schedule IV of Louisiana’s Uniform Controlled Dangerous Substances Law. This new law will make it illegal in Louisiana for any person to knowingly or intentionally possess either drug, unless it was obtained directly or pursuant to a valid prescription or order from a practitioner. Those persons found in violation of this statute will be subject to possible “imprisonment, with or without hard labor” for a minimum of one year but no longer than five years. Importantly, it will not be illegal for pregnant women to possess mifepristone or misoprostol for their own consumption.

Furthermore, prescribing these pills is not per se illegal. Lawful prescriptions for mifepristone and misoprostol may still be prescribed, filled, and administered in accordance with La. Rev. Stat. 14:87.9(C)(6). Thus, physicians and pharmacies will be able to continue prescribing and dispensing these drugs to patients in accordance with authorized procedures.

The Current Legal Landscape of Mifepristone and Misoprostol

Rulings in FDA v. Alliance for Hippocratic Medicine and Washington v. FDA have thus far hinged on the standing of the plaintiffs bringing the cases. This is not to say these cases have not been instructive as to how courts may address challenges to the FDA’s regulation of mifepristone. Both cases have highlighted the changes in the Mifeprex and mifepristone REMS program over the years. Both cases, and Washington v. FDA in particular, have additionally analyzed the FDA’s rationale for changes to the Mifepristone REMS Program. Additionally, this last year has seen movement at the state level as well, as states have begun weighing in on whether specific medications such as mifepristone should be more widely available or whether distribution should be more strictly controlled, as seen under the new Louisiana law. As the next several months play out, more movement is likely in this area.