The burden of the Risk Evaluation and Mitigation Strategy (REMS) on providers and patients experiencing early pregnancy loss: a commentary

Early pregnancy loss (EPL) is a common complication in pregnancy and affects approximately 1 million women in the U.S. every year [1, 2]. Patient-centered care includes expectant, medical and procedural treatment options. Medical management offers an expedient and active treatment course that is less invasive and more private than uterine aspiration [3–7], and misoprostol alone has traditionally been used for medical management of EPL. However, treatment efficacy is substantially improved when mifepristone is used as a pretreatment to misoprostol [8–12]. Additionally, cost-effectiveness analyses demonstrate that the combination regimen has economic benefits for both patients and the health care sector [13, 14]. Based on these pivotal studies and the American College of Obstetrics and Gynecology (ACOG) recommendations, the combined mifepristone-misoprostol regimen has become the standard of care for medical management of EPL [8].

In practice, however, the incorporation of mifepristone into EPL management has challenges for providers. While implementation of new clinical guidelines is often protracted [15, 16], mifepristone’s use for this indication is additionally impeded by the FDA-mandated Risk Evaluation and Mitigation Strategy (REMS) [17, 18]. Providers must be licensed to prescribe mifepristone through a prescriber agreement form, in which they must attest to their ability to provide or arrange for surgical interventions should patients require it. This results in health care disparities in areas where such surgical interventions are not readily available, making mifepristone access even more critical. In addition, REMS restrictions prevent prescription sales in retail pharmacies and require certified clinicians to dispense mifepristone to patients in a clinic or hospital setting. In 2018, ACOG released a statement supporting efforts to remove the REMS for mifepristone in order to improve access for patients[19].

REMS restrictions place a major burden on patients seeking EPL management, as well as on their healthcare providers. Approximately 500,000 patients per year present to the emergency department (ED) in the U.S. with vaginal bleeding in pregnancy, often caused by EPL[20]. Emergency medicine physicians are unlikely to be registered to provide mifepristone and emergency departments are unlikely to stock mifepristone, thus leading to less effective care or care delays for these already burdened patients. Studies have demonstrated that patients who present to the ED for EPL care are more likely to be Black and underinsured, compared with patients who seek care in ambulatory settings [20, 21]. During the current COVID-19 pandemic, which disproportionately affects women from racial and ethnic minorities with severe disease and mortality [22, 23], we need to reduce rather than expand existing disparities among underserved EPL patients. Now is the time to lessen unnecessary in-person medical interactions, but REMS prevents us from taking these measures for patients with EPL.

In 2018, in preparation for performing implementation research, we conducted open-ended surveys with 26 obstetrician/gynecologists in Kansas (n=15) and Pennsylvania (n=11) about facilitators and barriers to mifepristone use for EPL care, in the hypothetical scenario in which no REMS restrictions existed. Providers were asked questions that included, “If administrative barriers were removed, what would make it difficult and easy for you to prescribe mifepristone for women experiencing a miscarriage?” and, “What would you like and dislike about prescribing mifepristone for miscarriage?”. We found that providers were enthusiastic about adopting the mifepristone regimen in order to provide effective evidence-based EPL care. They cited the superior efficacy of the mifepristone regimen as a significant benefit and a facilitator to implementation. Some providers responded that if no administrative hurdles existed, they would encounter no personal or logistical barriers to prescribing mifepristone, and many felt that widespread and easy availability in local pharmacies would facilitate their ability to prescribe the medication. As would be expected for a new clinical intervention, many providers stated a need for education of staff and providers about the clinical indications for mifepristone use in the EPL setting.

The FDA recognized that certain REMS restrictions increase the risk of COVID-19 transmission among healthcare providers and patients. At the start of the pandemic last year and in an effort to decrease risk of COVID-19 transmission, the FDA lifted REMS restrictions on certain medications [24], by allowing providers to determine the necessity of certain restrictions, including in-person medication dispensation. However, mifepristone was not included as one of these medications. Subsequently, on July 13, 2020, a federal court ruled that the FDA must temporarily suspend enforcement of the in-person requirement for mifepristone for medical abortion [25]; which initially was reinstated by a Supreme Court decision [26], however, the FDA announced on April 13, 2021 it will suspend this requirement for the duration of the COVID pandemic [27]. This, unfortunately, applies only to induced abortion and does not extend to the use of mifepristone for EPL.

Patients deserve immediate access to safe and effective EPL care. However, despite robust evidence [12] and updated guidelines [8] the routine use of mifepristone in medical management of EPL is limited by REMS restrictions and the politicization of reproductive health care. The FDA purports not to regulate the practice of medicine; however, the current REMS restrictions are altering how healthcare providers manage early pregnancy loss[27]. Increasing provider and patient education and ensuring widespread availability of mifepristone may facilitate the implementation of this evidence-based change in practice, but in order to truly increase access to patient-centered, evidence-based, equitable care, it is vital that mifepristone REMS restrictions be lifted.