On January 4, the Food and Drug Administration (FDA) approved modifications to the Risk Evaluation and Mitigation Strategies (REMS) program for the medication abortion drug mifepristone. These modifications permit mifepristone to be dispensed by certified licensed health care providers and pharmacies, including retail pharmacies. The FDA had modified the REMS in 2021 to eliminate the "in-person dispensing" requirement, that is, that the drug be dispensed only in certain health care settings (specifically clinics, medical offices, and hospitals), and to add a requirement that pharmacies that dispense the drug by mail be certified.

These actions help fulfill President Joe Biden's commitment "to protect a woman's right to the FDA-approved ... medication that's been available for over 20 years" despite the US Supreme Court's 2022 Dobbs v. Jackson Women's Health Organization decision to reverse Roe v. Wade and were made pursuant to executive orders 14079 and 14076, directing the Department of Health and Human Services (HHS) to "consider actions to advance access to reproductive health care services." Should other chain and independent retail pharmacies join CVS and Walgreens in seeking certification to dispense mifepristone, the FDA's decision could greatly facilitate access to medical abortion.

The FDA's actions are not only a reaction to Dobbs but also the fruition of decades of unrelenting advocacy by reproductive health groups. They are also the latest in a series of incremental actions to expand access to mifepristone, with the FDA moving at a slow pace despite 40 years of global clinical evidence and literature that the "in-person" REMS requirements did not better assure patient safety. The decision may also signal broader flexibility toward using novel features of the health care marketplace to assure patient access to safe medications, both prescription (such as mifepristone) and non-prescription (over the counter).

US Access To Mifepristone

Mifepristone, or RU-486 as it was originally known, was first investigated in combination with a prostaglandin for the termination of early-stage pregnancies in 1982 and was first approved for this use in France in 1989. In the US, mifepristone was approved in 2000 under the accelerated approval pathway for use in combination with misoprostol for the termination of pregnancy through 49 days' pregnancy.

This approval was the result of a tortuous and politically fraught path to market, including the original manufacturer's reluctance to risk boycotts and retaliation in the "anti-abortion climate in the United States;" a hostile regulatory climate toward reproductive health drugs, such as Depo-Provera; a politically driven exemption of RU-486 from the FDA's policy permitting personal importation of drugs for non-commercial use, reversed only due to a change in administration; and a lengthy four years of FDA deliberations from time of submission to approval, notwithstanding strong support from physicians, a battery of completed clinical studies, and a decade of use in France, Sweden, and the United Kingdom.

As part of its approval, the FDA required confirmatory post-market studies as well as conditions of approval similar to those imposed abroad: that the drug be provided in-person and under the supervision of a qualified physician; distributed under controlled conditions; and dispensed with a patient Medication Guide (MedGuide). In-person administration was part of the submitted clinical studies, which in turn mirrored French requirements, but these requirements were imposed in the absence of data supporting their premise that restricting access in these ways would better assure patient safety.

The Mifepristone REMS

In 2007, responding to safety concerns surrounding the painkiller Vioxx and other prescription drugs, Congress enacted REMS authorities integrating the FDA's existing tools—from labeling and communication plans to restricted dispensing and patient registries—to manage safety issues with select drugs. The FDA has since required nearly 300 REMS, including for some products approved prior to 2007 deemed subject to "elements to assure safe use" under the REMS umbrella. Mifepristone's existing restrictions were deemed to constitute a REMS program in June 2011, despite a continuing lack of data substantiating the value of these restrictions in assuring safe use and availability.

Since mifepristone's approval in 2000, medication abortion has "transformed the practice of abortion care" in the US, according to the Guttmacher Institute, accounting in 2020, for 53 percent of all abortions. Since 2012, use of mifepristone and misoprostol in combination has also been the World Health Organization's recommended method for medical abortion.

As clinical experience with medical abortion expanded, guidelines around mifepristone's use were further relaxed to expand access. In response to a supplemental application from drug sponsor Danco Laboratories in 2016, the FDA amended mifepristone's approval to increase the period of use to 10 weeks gestation, reduce the necessary dosage and number of provider visits, expressly allow for administration by non-physician providers, and lift the restriction on sites of administration of misoprostol from in-clinic to newly include "at home or other location convenient for the woman."

During its 2016 review, the FDA assessed the mifepristone REMS program and determined that the patient MedGuide should be dispensed "to minimize the burden on the health care delivery system of complying with the REMS." Upon approval of a generic mifepristone in 2019, the FDA mandated a "shared system" REMS (a REMS that includes more than one product and is implemented jointly by two or more applicants) for all mifepristone products approved for medical abortion, maintaining existing requirements that:

  • In-person dispensing and administration occur at a clinic, hospital, or under direct supervision of a certified provider;
  • Prescribing providers be certified and qualified, including in the assessment of gestational age and the assurance of surgical intervention, and must sign a "Prescriber Agreement Form;" and
  • Patients be counseled on risks and benefits, and sign, with their provider, a "Patient Agreement Form."

Questioning The Mifepristone REMS

Long before Dobbs, the mifepristone REMS requirements, particularly the in-person dispensing mandate, came under increasing criticism for unduly restricting access. Studies demonstrated substantial disparities in access to abortion services, and that physical distance alone from providers can render such services inaccessible. The requirements were also criticized as persistent political exceptionalism in the regulation of reproductive health drugs, rather than being supported by data or research demonstrating their utility; the FDA's own 2016 review acknowledged that the established safety profile of mifepristone over 15 years of experience is well-characterized and stable, and known safety risks occur rarely.

The Dobbs decision and resulting state laws banning or severely restricting abortion have added critical urgency to these critiques, and to the longstanding calls of the American College of Obstetricians and Gynecologists (ACOG), American Academy of Family Physicians (AAFP), American Medical Association (AMA) and other organizations to eliminate all mifepristone REMS requirements. But it was the onset of the global COVID-19 pandemic that provided the public health impetus to begin effectuating these reforms.

Challenging The Mifepristone REMS

In March 2020, the FDA announced it would exercise enforcement discretion during the COVID-19 public health emergency by refraining from enforcing REMS requirements for mandatory laboratory testing or imaging studies. In April, numerous organizations urged the FDA to similarly suspend the mifepristone REMS requirement of in-person administration on the same public health grounds. In May, the ACOG and other parties, supported by amici curiae briefs from national health organizations and 23 state attorneys general, successfully filed suit in US district court to enjoin the Trump administration from enforcing the in-person requirements. The District Court concluded that these requirements likely placed a "substantial obstacle" to women securing abortions during the pandemic, allowing for mail delivery of mifepristone nationwide.

The Trump administration appealed and fought the injunction throughout 2020, and in January 2021, the US Supreme Court granted an emergency stay of the injunction. But in April, under the Biden administration, the FDA wrote to the ACOG and the Society for Maternal-Fetal Medicine in response to their April 2020 letter, concluding on the basis of a literature and adverse event review that it would exercise enforcement discretion during the public health emergency toward mifepristone in-person dispensing and patient requirements, as well as the dispensing of mifepristone by mail under a certified provider's supervision following a telehealth consultation.

In May 2021, the change in administration, the ACOG lawsuit, and a pending 2017 lawsuit filed by the American Civil Liberties Union, persuaded Acting Commissioner Janet Woodcock and Center for Drug Evaluation and Research Director Patrizia Cavazzoni to undertake a comprehensive review of the mifepristone REMS. That month, a major study of Canadian mifepristone use without REMS-type restrictions in more than 84,000 medical abortions was published, concluding that "the abortion rate remained relatively stable, the proportion of abortions provided by medication increased rapidly, and adverse events and complications remained stable." In December 2021, the FDA completed its review and decided to make its COVID-19-related changes permanent, including newly allowing certified pharmacies to dispense mifepristone by mail.

In December 2022, a pro-life organization filed a citizen petition requesting a reversal of these 2016 and 2021 mifepristone REMS modifications, reversion to the 2011 REMS, and restriction of use of the drug to 49 days gestation. The petition specifically requested that the FDA require in-person administration after three office visits, including an ultrasound to rule out ectopic pregnancy and to determine gestational age, and sought contraindications for patients who do not have convenient access to emergency medical care and for telehealth limitation to "women in absolute need under extreme circumstances." On January 3, the FDA denied this petition, a day later approving the latest mifepristone REMS modifications.

Next Steps And Challenges To Mifepristone Access

Under its revised REMS restrictions, mifepristone continues to be prescribed and distributed in a "closed system:" It may only be prescribed by certified providers and dispensed by such provider or by certified pharmacies, either in person or by mail. Patients are still required to review and sign a form after mifepristone's risks and benefits are explained to them.

The FDA's January 4 decision is the culmination of a glacial relaxation of the conservative regulation of mifepristone, especially given the preponderance of positive clinical evidence, global regulatory experience, and post-market safety data available in support of dispensing with the in-person REMS requirements. Indeed, the FDA has taken pains to stress that this action was initiated prior to Dobbs. If maintenance of these restrictions is attributable in part to strict oversight by politically conservative administrations as well as to a desire to avoid litigation and congressional oversight during more progressive administrations, that questionable equilibrium simply became unsustainable between changes in clinical practice during the COVID-19 pandemic and the seismic impact of the Dobbs decision.

The REMS modifications are defensible not only scientifically and clinically, but also legally, as the FDA is entitled to substantial deference from the courts in implementing REMS requirements, which for mifepristone required reviews of post-market safety data, the scientific literature, and statutorily required REMS assessments by sponsors intended to answer "whether the REMS is meeting its goals and what if any, modification may be needed."

The key question remains how aggressive or successful states will be in seeking to restrict or criminalize access to mifepristone, in contravention of the FDA's judgment and statutory authority. Texas and Indiana ban medical abortion at specific gestational dates, while 18 states require in-person administration of mifepristone by a prescribing physician (consistent with the FDA's previous REMS requirements) that precludes telemedicine medical abortions, according to the Guttmacher Institute. It remains to be seen whether the Biden administration will seek to preempt state laws such as Texas' and Indiana's, as advocated by Democratic senators Elizabeth Warren (D-MA), Mazie Hirono (D-Hawaii), and Tammy Baldwin (D-WI).

The generic mifepristone manufacturer, GenBioPro, may also refile its suit challenging Mississippi's restricting access to mifepristone (on the basis of its abortion ban) in a favorable jurisdiction, which it had voluntarily dismissed in August 2022. The FDA will also continue to be asked to remove mifepristone's remaining patient and provider certification REMS requirements and even switch mifepristone from prescription to over-the-counter status, while it continues to police off-label prescribing of mifepristone to women who are not pregnant but seek access to the drug in the event that they later become pregnant.

Finally, the FDA's decision is significant not only for reproductive health but as another step in a historic evolution away from reliance on physicians to regulate access to prescription drugs toward broader and more effective use of pharmacists; allied health professionals; electronic health records and other forms of real-world data; and the explosive proliferation and validation of digital technologies and platforms to inform patients, monitor health, and assure compliance. This trend has important implications not only for prescription drugs but also for over-the-counter drugs, medical technologies, and digital health, which, if mifepristone is any guide, will undoubtedly far outpace the FDA's tempo for regulatory reform.

Originally Published by Health Affairs Forefront

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