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Research Article| Volume 104, ISSUE 1, P4-7, July 2021

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An introduction to risk evaluation and mitigation strategies

Open AccessPublished:April 24, 2021DOI:https://doi.org/10.1016/j.contraception.2021.04.018
An introduction to risk evaluation and mitigation strategies
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      Keywords

      A foundational principle of the United States Food and Drug Administration's (“FDA's” or “the Agency's”) new drug approval process is that a drug can be approved only if an applicant establishes the product to be safe and effective for its proposed indication and under the proposed conditions of use [

      Federal Food, Drug, and Cosmetic Act (“FDCA”), § 505, 21 U.S.C. § 355 (2020).

      ]. FDA has noted, however, that the Agency's approval of a drug as safe “does not suggest an absence of risk” [

      U.S. Food and Drug Administration. Guidance for Industry: REMS: FDA's Application of Statutory Factors in Determining When a REMS Is Necessary, https://www.fda.gov/media/100307/download [accessed 14 Apr. 2021].

      ]. Instead, “a drug is considered safe if it has an appropriate benefit-risk balance” [

      U.S. Food and Drug Administration. Guidance for Industry: REMS: FDA's Application of Statutory Factors in Determining When a REMS Is Necessary, https://www.fda.gov/media/100307/download [accessed 14 Apr. 2021].

      ].
      FDA's approval of prescribing information for a drug is a central way in which the Agency engages in risk management. Another risk management tool is FDA's authority to require a Risk Evaluation and Mitigation Strategy (“REMS”) when necessary. This article discusses REMS programs at a high level, beginning with the Agency's risk management programs that preceded its REMS authorities. We then detail FDA's authority to require REMS for new and previously approved drugs, the content that may be required, and shared REMS for brand and generic drugs. The article continues with a discussion of FDA's modification or release of REMS requirements. It then describes Mifeprex (mifepristone) as a real-world example of how these principles have been applied and concludes with a brief summary.

      FDA's predecessors to REMS

      The Food and Drug Administration Amendments Act of 2007 (commonly known as “FDAAA” and referred to in this article as “the 2007 statute”) amended the Federal Food, Drug, and Cosmetic Act to add a new section 505-1, which authorized FDA to require a REMS for a drug under certain circumstances. Although the statutory authority in section 505-1 was new, FDA had applied similar concepts before the 2007 statute's enactment.
      For example, in 1992, FDA established a process through which the Agency could accelerate approval of certain new drugs and biological products for serious or life-threatening illnesses [
      U.S. Food and Drug Administration
      New drug, antibiotic, and biological drug product regulations; accelerated approval, final rule.
      Fed. Reg. Dec. 11, 1992; 57: 58942
      ]. Under the Agency's accelerated approval regulations, which are referred to generally as “Subpart H,” FDA could require “postmarketing restrictions [on the product's distribution or use] as are needed to assure safe use” of a product shown to be effective [

      Approval With Restrictions to Assure Safe Use, 21 C.F.R. § 314.520 (2020).

      ,

      Approval With Restrictions to Assure Safe Use, 21 C.F.R. § 601.42 (2020).

      ]. These restrictions could limit the product's distribution to certain facilities or to physicians with special training or experience, or condition its distribution on the performance of specific medical procedures, though the Agency's regulations stated that any such restrictions would be “commensurate with the specific safety concerns presented by” the product [

      Approval With Restrictions to Assure Safe Use, 21 C.F.R. § 314.520 (2020).

      ,

      Approval With Restrictions to Assure Safe Use, 21 C.F.R. § 601.42 (2020).

      ].
      Risk Minimization Action Plans, also known as “RiskMAPs,” were another recent predecessor to REMS. A RiskMAP was a “strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits” [

      U.S. Food and Drug Administration. Guidance for Industry: Development and Use of Risk Minimization Action Plans, https://www.fda.gov/media/71268/download [accessed 14 Apr. 2021].

      ]. “Tools” that could be required in a RiskMAP included targeted education and outreach for healthcare practitioners and patients; “reminder systems” to help healthcare practitioners and patients minimize risk; and “performance-linked access systems” allowing a drug to be made available only if certain conditions are met (e.g., certification by pharmacies or practitioners). FDA recommended that tools allow for “the widest possible access to the product with the least burden to the healthcare system that is compatible with adequate risk minimization” and that applicants design RiskMAPs to be “accessible to patients in diverse locales, including non-urban settings” [

      U.S. Food and Drug Administration. Guidance for Industry: Development and Use of Risk Minimization Action Plans, https://www.fda.gov/media/71268/download [accessed 14 Apr. 2021].

      ].
      When the 2007 statute established FDA's current authority to require a REMS, the statute also addressed drugs approved before its enactment that were subject to predecessor requirements (e.g., RiskMAPs and requirements for drugs approved under Subpart H). Under the 2007 statute, drugs subject to predecessor requirements would be considered to have an approved REMS (which the statute referred to as a drug being “deemed to have in effect” an approved REMS) [

      Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, 121 Stat. 823, § 909(b)(1) (Sep. 27, 2007).

      ]. FDA subsequently published a Federal Register notice identifying the drugs and biological products “deemed to have in effect” an approved REMS and notifying application holders for these drugs of their obligation to submit a proposed REMS for approval [

      U.S. Food and Drug Administration. Identification of Drug and Biological Products Deemed to Have Risk Evaluation and Mitigation Strategies for Purposes of the Food and Drug Administration Amendments Act of 2007, Notice, 73 Fed. Reg. 16313 (Mar. 27, 2008).

      ].

      The current REMS framework

      FDA may decide a REMS is required for a product either before or after its approval. Before a drug's approval, the Agency may determine a REMS “is necessary to ensure that the benefits of the drug outweigh the risks” [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ]. After a drug's approval, FDA may require a REMS if it makes this determination based on “new safety information” [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ]. In this context, “new safety information” refers to information about a serious risk or an unexpected serious risk associated with use of the drug of which FDA becomes aware [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ].
      When making this determination, either before a drug's approval or after, FDA considers the following factors outlined in the statute: (1) the estimated size of the population likely to use the drug involved; (2) the seriousness of the disease or condition that is to be treated with the drug; (3) the expected benefit of the drug with respect to such disease or condition; (4) the expected or actual duration of treatment with the drug; (5) the seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug; and (6) whether the drug is a new molecular entity [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ,

      U.S. Food and Drug Administration. Guidance for Industry: REMS: FDA's Application of Statutory Factors in Determining When a REMS Is Necessary, https://www.fda.gov/media/100307/download [accessed 14 Apr. 2021].

      ]. Of the 48 novel drugs approved by FDA in 2019 and identified in an Agency report [
      U.S. Food and Drug Administration.
      New Drug Therapy Approvals. 2019; ([accessed 14 Apr. 2021])
      https://www.fda.gov/media/134493/download
      ], 2 of those drugs were approved with a REMS; of the 53 novel drugs approved by FDA in 2020 and identified in an Agency report [

      U.S. Food and Drug Administration. New drug therapy approvals 2020, https://www.fda.gov/media/144982/download [accessed 14 Apr. 2021].

      ], 1 of those drugs was approved with a REMS.
      The content of a REMS depends on the goals of each REMS. At a minimum, each REMS must include a timetable for submitting periodic assessments of the program [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ]. FDA can require additional REMS elements—such as a Medication Guide, a patient package insert, or a communication plan—as long as the Agency makes the requisite determination for each element [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ]. For example, a Medication Guide may be required if the Agency determines the drug “pose[s] a serious and significant health concern requiring distribution of FDA-approved patient information” [

      Scope and Purpose, 21 C.F.R. § 208.1 (2020).

      ]. FDA will require a Medication Guide if FDA determines that any of the following circumstances exists: (1) the drug product is one for which patient labeling could help prevent serious adverse effects; (2) the drug product has serious risks (relative to benefits) that patients should be made aware of because information concerning the risks could affect their decision to use the product; or (3) the drug product is important to health, and patient adherence to directions for use is crucial to its effectiveness [

      Scope and Purpose, 21 C.F.R. § 208.1 (2020).

      ].
      FDA can also require a REMS to include additional elements, known as elements to assure safe use (“ETASU”), “because of [a drug's] inherent toxicity or potential harmfulness” [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ]. Before imposing an ETASU, FDA must make two determinations. First, the Agency must conclude that the drug is effective but associated with a serious adverse drug experience and can be approved only if (or would be withdrawn unless) the ETASU are required to mitigate the specific serious risk identified in the drug's labeling [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ]. Second, for a drug initially approved without ETASU, FDA must determine that other less burdensome elements, such as a Medication Guide or a communication plan, would not mitigate the serious risk [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ].
      ETASU must include one or more “goals” to mitigate a specific serious risk. To that end, the ETASU may impose certain requirements that health care providers, pharmacies, patients, and other stakeholders must satisfy [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ].
      Section 505-1 of the Federal Food, Drug, and Cosmetic Act requires that patient access and burden on the health care delivery system be weighed as factors when designing a REMS with ETASU. The statute states that ETASU must “not be unduly burdensome on patient access to the drug,” considering the specific serious risk being mitigated, and must “be commensurate with the specific serious risk listed in the labeling of the drug” [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ]. The statute highlights three categories of patients in particular: (1) patients with serious or life-threatening diseases or conditions; (2) patients with difficulty accessing healthcare, “such as patients in rural or medically underserved areas”; and (3) patients with functional limitations [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ]. In addition, section 505-1 specifies steps that must be taken to minimize burdens on the health care system “to the extent practicable” [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ]. These steps include conforming a drug's ETASU to the ETASU for other drugs with similar, serious risks and designing the ETASU “to be compatible with established distribution, procurement, and dispensing systems for drugs” [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ].
      Until a recent amendment of section 505-1, the REMS statute presumptively required generic drugs that are the subject of an abbreviated new drug application to use a single, shared system with the reference listed drug (usually a brand name drug) if that drug is subject to a REMS with ETASU [

      Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, 121 Stat. 823, § 909(b)(1) (Sep. 27, 2007).

      ,

      Further Consolidated Appropriations Act, 2020, Pub. L. No. 116–94, 133 Stat. 2534, § 610 (Dec. 20, 2019).

      ]. Now, under the amended statutory provision, an abbreviated new drug application in this situation may use a single, shared system with the reference listed drug or use a “different, comparable aspect of the” ETASU [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ,

      Further Consolidated Appropriations Act, 2020, Pub. L. No. 116–94, 133 Stat. 2534, § 610 (Dec. 20, 2019).

      ]. ETASU qualify as “different [but] comparable” if they use different methods or operational means but still achieve the same degree of safety as the original ETASU [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ,

      Further Consolidated Appropriations Act, 2020, Pub. L. No. 116–94, 133 Stat. 2534, § 610 (Dec. 20, 2019).

      ].

      REMS modifications

      There are two ways to add, modify, or remove any goal or element of an approved REMS. The first way occurs at the initiative of the person holding the approved application for the drug subject to the REMS, who must submit an “adequate rationale” along with the proposed change [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ]. The second way occurs when FDA requires a modification based, for instance, on a determination that one or more goals or elements should be added, modified, or removed from the approved REMS to ensure the drug's benefits outweigh its risks; minimize the health care delivery system's compliance burden; or accommodate different, comparable aspects of an abbreviated new drug application's ETASU [

      FDCA § 505-1, 21 U.S.C. § 355-1.

      ].
      For example, FDA originally determined a REMS with ETASU was necessary for Addyi (flibanserin) tablet “to ensure the benefits of the drug outweigh the increased risk of severe hypotension and syncope associated with Addyi due to an interaction with alcohol” [

      U.S. Food and Drug Administration. Approval for Addyi (flibanserin) tablets, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/022526Orig1s000Approv.pdf [accessed 14 Apr. 2021].

      ]. To mitigate this risk, the Addyi REMS included ETASU requiring that healthcare providers “have particular experience or training, or [be] specially certified” and that pharmacies, practitioners, and healthcare settings “that dispense the drug [be] specially certified” [

      U.S. Food and Drug Administration. Approval for Addyi (flibanserin) tablets, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/022526Orig1s000Approv.pdf [accessed 14 Apr. 2021].

      ]. The Addyi REMS also included a Medication Guide, among other elements. FDA later approved REMS modifications that included removal of the ETASU for Addyi. The Agency determined the ETASU were “no longer necessary” on the basis of information collected in two Phase 1 studies “show[ing] that the risk with alcohol is narrower than understood at the time of approval” [

      U.S. Food and Drug Administration. Supplement Approval for Addyi (flibanserin) Tablets, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/022526Orig1s009ltr.pdf [accessed 14 Apr. 2021].

      ]. As a result of this determination, FDA removed the ETASU “to minimize burden on the health care system” [

      U.S. Food and Drug Administration. Supplement Approval for Addyi (flibanserin) Tablets, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/022526Orig1s009ltr.pdf [accessed 14 Apr. 2021].

      ]. The Addyi REMS continue to include a Medication Guide as an element of the program, along with a timetable for submission of REMS assessments, to inform patients about the “risks of concomitant use of alcohol with ADDYI” [

      U.S. Food and Drug Administration. Supplement Approval for Addyi (flibanserin) Tablets, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/022526Orig1s009ltr.pdf [accessed 14 Apr. 2021].

      ].
      FDA also may decide to “release” a REMS entirely and has done so for a number of drugs [

      U.S. Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies, https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsData.page [accessed 14 Apr. 2021].

      ]. Consistent with the statutory language for when a REMS may be required, FDA has explained that it will release a REMS if the Agency determines that the measures “are no longer necessary to ensure a medication's benefits outweigh its risks” [

      U.S. Food and Drug Administration. Frequently Asked Questions (FAQs) About REMS (updated 26 Jan. 2018), https://www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/frequently-asked-questions-faqs-about-rems [accessed 14 Apr. 2021].

      ]. One example is the REMS with ETASU for Tikosyn (dofetilide), which was approved prior to the 2007 statute's enactment and was deemed to have in effect an approved REMS [

      U.S. Food and Drug Administration. Supplement Approval for Tikosyn (dofetilide) Capsules, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/020931s003ltr.pdf [accessed 14 Apr. 2021].

      ]. FDA subsequently approved a REMS with ETASU for Tikosyn “to ensure the benefits of the drug outweigh the risk of ventricular arrhythmias” [

      U.S. Food and Drug Administration. Supplement Approval for Tikosyn (dofetilide) Capsules, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/020931s003ltr.pdf [accessed 14 Apr. 2021].

      ]. As part of the REMS with ETASU, FDA required that Tikosyn be prescribed only by healthcare providers who had been educated about the safe use of Tikosyn, including inpatient initiation and creatinine monitoring [

      U.S. Food and Drug Administration. Supplement Approval for Tikosyn (dofetilide) Capsules, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/020931s003ltr.pdf [accessed 14 Apr. 2021].

      ]. FDA later approved a release of the REMS with ETASU after determining that ETASU were no longer necessary for Tikosyn and that maintaining the Medication Guide, which had been an element of the REMS, as part of the drug's approved labeling would be adequate [

      U.S. Food and Drug Administration. Supplement Approval/Release REMS Requirement for Tikosyn (dofetilide) Capsules, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/020931Orig1s012,s013ltr.pdf [accessed 14 Apr. 2021].

      ]. In particular, based on REMS assessments submitted for Tikosyn, the Agency determined that healthcare providers—including prescribers who had not been certified—“demonstrate[d] acceptable knowledge of the product's risks” and its safe use conditions, which could “be conveyed appropriately via the current product labeling” [

      U.S. Food and Drug Administration. Supplement Approval/Release REMS Requirement for Tikosyn (dofetilide) Capsules, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/020931Orig1s012,s013ltr.pdf [accessed 14 Apr. 2021].

      ]. FDA also explained that “the need for inpatient initiation and monitoring of Tikosyn [was] well-accepted in clinical practice (see, e.g., the 2014 AHA/ACC/HRS Guideline for the Management of Patients for Atrial Fibrillation)” [

      U.S. Food and Drug Administration. Supplement Approval/Release REMS Requirement for Tikosyn (dofetilide) Capsules, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/020931Orig1s012,s013ltr.pdf [accessed 14 Apr. 2021].

      ].

      Mifepristone REMS

      Mifeprex (mifepristone) is an example of a drug that has been subject to additional requirements under FDA's evolving risk management authorities. FDA approved Mifeprex on September 28, 2000 for the medical termination of intrauterine pregnancy through 49 days'” pregnancy [

      U.S. Food and Drug Administration. Approval Letter for Mifeprex (mifepristone) Tablets (Sept. 28, 2000), https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2000/20687appltr.pdf [accessed 14 Apr. 2021].

      ]. At the time of approval, which predated the enactment of FDA's REMS authority, distribution of Mifeprex was restricted under FDA's Subpart H regulations (i.e., the accelerated approval regulations described in section 1). After the 2007 statute's enactment, FDA identified a number of drugs, including Mifeprex, as “deemed to have in effect an approved REMS” by virtue of having in effect elements to assure safe use [

      U.S. Food and Drug Administration. Identification of Drug and Biological Products Deemed to Have Risk Evaluation and Mitigation Strategies for Purposes of the Food and Drug Administration Amendments Act of 2007, Notice, 73 Fed. Reg. 16313 (Mar. 27, 2008).

      ]. FDA approved the Mifeprex REMS on June 8, 2011, explaining the Agency determined a REMS was necessary “to ensure the benefits of the drug outweigh the risks of serious complications by requiring prescribers to certify that they are qualified to prescribe MIFEPREX (mifepristone) and are able to assure patient access to appropriate medical facilities to manage any complications” [

      U.S. Food and Drug Administration. Supplement Approval Letter for Mifeprex (mifepristone) Tablets (June 8, 2011), https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/020687s014ltr.pdf [accessed 14 Apr. 2021].

      ].
      The original Mifeprex REMS consisted of a Medication Guide and a timetable for submitting REMS assessments, as well as ETASU and an implementation system for the required elements [

      Danco Laboratories, LLC. Risk Evaluation and Mitigation Strategy (REMS) for NDA 20-687 Mifeprex (mifepristone) Tablets, 200 mg, https://www.accessdata.fda.gov/drugsatfda_docs/rems/Mifeprex_2011-06-08_Full.pdf [accessed 14 Apr. 2021].

      ]. The ETASU included requirements that prescribers be specially certified, that Mifeprex be dispensed only in certain health care settings (i.e., clinics, medical offices, and hospitals); and that Mifeprex be dispensed only to patients with “documentation of safe use conditions” [

      Danco Laboratories, LLC. Risk Evaluation and Mitigation Strategy (REMS) for NDA 20-687 Mifeprex (mifepristone) Tablets, 200 mg, https://www.accessdata.fda.gov/drugsatfda_docs/rems/Mifeprex_2011-06-08_Full.pdf [accessed 14 Apr. 2021].

      ]. As part of this documentation, a patient was required to complete a Patient Agreement. This document specified (among other things) an understanding that the patient would take Mifeprex in the provider's office (on “Day 1”); take misoprostol, the second drug in the regimen, in the provider's office two days after taking Mifeprex (on “Day 3””); and return to the provider's office within about two weeks after taking Mifeprex for a follow-up visit (on about “Day 14”) [

      Danco Laboratories, LLC. Risk Evaluation and Mitigation Strategy (REMS) for NDA 20-687 Mifeprex (mifepristone) Tablets, 200 mg, https://www.accessdata.fda.gov/drugsatfda_docs/rems/Mifeprex_2011-06-08_Full.pdf [accessed 14 Apr. 2021].

      ].
      On March 29, 2016, FDA approved an efficacy supplement for Mifeprex, which (among other things) extended the gestational age during which the drug can be used from 49 days to 70 days and removed language stating that the patient must take the medication in the provider's office and must return for an in-person follow-up visit. [

      U.S. Food and Drug Administration. Supplement Approval Letter for Mifeprex (mifepristone) Tablets (Mar. 29, 2016), https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/020687Orig1s020ltr.pdf [accessed 14 Apr. 2021].

      ,

      U.S. Food and Drug Administration. Cross-Discipline Team Leader Review for Mifeprex (mifepristone) Oral Tablets, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/020687Orig1s020CrossR.pdf [accessed 14 Apr. 2021].

      ]. When reviewing the efficacy supplement, FDA “also evaluated the current REMS program [at that time] to determine whether each Mifeprex REMS element remain[ed] necessary to ensure the drug benefits outweigh the risks” [

      U.S. Food and Drug Administration. Risk Evaluation and Mitigation Strategy (REMS) Memorandum for Mifeprex (mifepristone) Oral Tablets, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/020687Orig1s020RiskR.pdf [accessed 14 Apr. 2021].

      ]. As part of this evaluation, FDA considered information from a recent assessment of the program's effectiveness, safety data collected for Mifeprex since its approval in 2000, and “experience from current clinical practice” [

      U.S. Food and Drug Administration. Risk Evaluation and Mitigation Strategy (REMS) Memorandum for Mifeprex (mifepristone) Oral Tablets, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/020687Orig1s020RiskR.pdf [accessed 14 Apr. 2021].

      ]. FDA subsequently approved REMS modifications that included removal of the Medication Guide as a REMS element, though it continues to be part of the FDA-approved labeling that must be provided to a patient [

      U.S. Food and Drug Administration. Supplement Approval Letter for Mifeprex (mifepristone) Tablets (Mar. 29, 2016), https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/020687Orig1s020ltr.pdf [accessed 14 Apr. 2021].

      ]. Another example of a modification to the Mifeprex REMS in 2016 was changing the provider reporting requirement to mandate reporting only of deaths (whereas the reporting of ongoing pregnancies, hospitalizations, transfusions, or other serious adverse events had previously also been required) [

      U.S. Food and Drug Administration. Cross-Discipline Team Leader Review for Mifeprex (mifepristone) Oral Tablets, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/020687Orig1s020CrossR.pdf [accessed 14 Apr. 2021].

      ]. The modified Mifeprex REMS still requires, however, that Mifeprex be dispensed in person to patients only in clinics, medical offices, or hospitals by or under the supervision of a prescriber certified to participate in the Mifeprex REMS [

      Danco Laboratories, LLC. Risk Evaluation and Mitigation Strategy (REMS) for NDA 020687 Mifeprex (mifepristone) Tablets, 200 mg, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/020687Orig1s020RemsR.pdf [accessed 14 Apr. 2021].

      ]. The modified REMS also continues to require that patients complete the Patient Agreement [

      Danco Laboratories, LLC. Risk Evaluation and Mitigation Strategy (REMS) for NDA 020687 Mifeprex (mifepristone) Tablets, 200 mg, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/020687Orig1s020RemsR.pdf [accessed 14 Apr. 2021].

      ].
      FDA approved another modification to the Mifeprex REMS, on April 11, 2019, to establish a single, shared system REMS that applies to both Mifeprex and a generic mifepristone product approved by FDA on the same day [

      U.S. Food and Drug Administration. Supplement Approval Letter for Mifeprex (mifepristone) Tablets (Apr. 11, 2019), https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/020687Orig1s022ltr.pdf [accessed 14 Apr. 2021].

      ]. The single, shared system REMS is referred to as the Mifepristone REMS and features the same elements as the Mifeprex REMS modified in March 2016.
      Most recently, FDA decided to exercise enforcement discretion during the COVID-19 public health emergency with respect to certain Mifepristone REMS requirements. Specifically, as long as the other REMS requirements are met, FDA does not intend to enforce the requirements that the medication be dispensed to patients only in person, including in-person requirements related to the Patient Agreement, and will exercise enforcement discretion with respect to the dispensing of mifepristone through the mail by or under the supervision of a certified prescriber and through a mail-order pharmacy when such dispensing is done under the supervision of a certified prescriber [

      U.S. Food and Drug Administration. Letter to the American College of Obstetricians and Gynecologists (Apr. 12, 2021), https://www.aclu.org/sites/default/files/field_document/fda_acting_commissioner_letter_to_acog_april_12_2021.pdf [accessed 14 Apr. 2021].

      ,

      U.S. Food and Drug Administration. Questions and Answers on Mifeprex (updated Apr. 13, 2021), https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/questions-and-answers-mifeprex [accessed 14 Apr. 2021].

      ]. The decision was based on a “careful scientific review” of clinical outcomes data and adverse event reports associated with the use of mifepristone [29]. The clinical outcome data did not show an increase in serious safety concerns when the in-person dispensing requirement was modified, and the adverse event reports did not indicate that deviating from or noncompliance with the REMS requirements contributed to the adverse events [

      U.S. Food and Drug Administration. Letter to the American College of Obstetricians and Gynecologists (Apr. 12, 2021), https://www.aclu.org/sites/default/files/field_document/fda_acting_commissioner_letter_to_acog_april_12_2021.pdf [accessed 14 Apr. 2021].

      ]. FDA also accounted for the possibility that “in-person dispensing . . . may present additional COVID-related risks to patients and healthcare personnel because it may involve a clinic visit solely for this purpose” [

      U.S. Food and Drug Administration. Letter to the American College of Obstetricians and Gynecologists (Apr. 12, 2021), https://www.aclu.org/sites/default/files/field_document/fda_acting_commissioner_letter_to_acog_april_12_2021.pdf [accessed 14 Apr. 2021].

      ].

      Conclusion

      The ability to require a REMS is one of FDA's authorities for ensuring a positive benefit-risk profile for a drug. FDA was applying REMS-like concepts to drugs before it had its current REMS authorities, and those drugs were later deemed to have an approved REMS in effect. The Agency may determine a REMS is necessary based on safety data collected before or after a drug's approval. Once a REMS has been approved, FDA may determine the REMS can be modified or released on the basis of information collected through the application holder's periodic REMS assessment reports and/or other evidence about the drug's safe use conditions. FDA has also created single, shared systems REMS that apply to brand drugs and generic drugs. Mifeprex is an example of a drug that was deemed to have an approved REMS in effect, was subsequently modified but retains most of its requirements, and now has a single, shared system REMS that applies to both Mifeprex and a generic mifepristone product.

      Declaration of Competing Interest

      The authors declare no conflict of interest.

      Funding

      This work was supported by the EMAA Project.

      References

      1. Federal Food, Drug, and Cosmetic Act (“FDCA”), § 505, 21 U.S.C. § 355 (2020).

        View in Article

      2. U.S. Food and Drug Administration. Guidance for Industry: REMS: FDA's Application of Statutory Factors in Determining When a REMS Is Necessary, https://www.fda.gov/media/100307/download [accessed 14 Apr. 2021].

        View in Article
        • U.S. Food and Drug Administration
        New drug, antibiotic, and biological drug product regulations; accelerated approval, final rule.
        Fed. Reg. Dec. 11, 1992; 57: 58942
        View in Article

      4. Approval With Restrictions to Assure Safe Use, 21 C.F.R. § 314.520 (2020).

        View in Article

      5. Approval With Restrictions to Assure Safe Use, 21 C.F.R. § 601.42 (2020).

        View in Article

      6. U.S. Food and Drug Administration. Guidance for Industry: Development and Use of Risk Minimization Action Plans, https://www.fda.gov/media/71268/download [accessed 14 Apr. 2021].

        View in Article

      7. Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, 121 Stat. 823, § 909(b)(1) (Sep. 27, 2007).

        View in Article

      8. U.S. Food and Drug Administration. Identification of Drug and Biological Products Deemed to Have Risk Evaluation and Mitigation Strategies for Purposes of the Food and Drug Administration Amendments Act of 2007, Notice, 73 Fed. Reg. 16313 (Mar. 27, 2008).

        View in Article

      9. FDCA § 505-1, 21 U.S.C. § 355-1.

        View in Article
      10. U.S. Food and Drug Administration.
        New Drug Therapy Approvals. 2019; ([accessed 14 Apr. 2021])
        https://www.fda.gov/media/134493/download
        View in Article

      11. U.S. Food and Drug Administration. New drug therapy approvals 2020, https://www.fda.gov/media/144982/download [accessed 14 Apr. 2021].

        View in Article

      12. Scope and Purpose, 21 C.F.R. § 208.1 (2020).

        View in Article

      13. Further Consolidated Appropriations Act, 2020, Pub. L. No. 116–94, 133 Stat. 2534, § 610 (Dec. 20, 2019).

        View in Article

      14. U.S. Food and Drug Administration. Approval for Addyi (flibanserin) tablets, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/022526Orig1s000Approv.pdf [accessed 14 Apr. 2021].

        View in Article

      15. U.S. Food and Drug Administration. Supplement Approval for Addyi (flibanserin) Tablets, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/022526Orig1s009ltr.pdf [accessed 14 Apr. 2021].

        View in Article

      16. U.S. Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies, https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsData.page [accessed 14 Apr. 2021].

        View in Article

      17. U.S. Food and Drug Administration. Frequently Asked Questions (FAQs) About REMS (updated 26 Jan. 2018), https://www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/frequently-asked-questions-faqs-about-rems [accessed 14 Apr. 2021].

        View in Article

      18. U.S. Food and Drug Administration. Supplement Approval for Tikosyn (dofetilide) Capsules, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/020931s003ltr.pdf [accessed 14 Apr. 2021].

        View in Article

      19. U.S. Food and Drug Administration. Supplement Approval/Release REMS Requirement for Tikosyn (dofetilide) Capsules, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/020931Orig1s012,s013ltr.pdf [accessed 14 Apr. 2021].

        View in Article

      20. U.S. Food and Drug Administration. Approval Letter for Mifeprex (mifepristone) Tablets (Sept. 28, 2000), https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2000/20687appltr.pdf [accessed 14 Apr. 2021].

        View in Article

      21. U.S. Food and Drug Administration. Supplement Approval Letter for Mifeprex (mifepristone) Tablets (June 8, 2011), https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/020687s014ltr.pdf [accessed 14 Apr. 2021].

        View in Article

      22. Danco Laboratories, LLC. Risk Evaluation and Mitigation Strategy (REMS) for NDA 20-687 Mifeprex (mifepristone) Tablets, 200 mg, https://www.accessdata.fda.gov/drugsatfda_docs/rems/Mifeprex_2011-06-08_Full.pdf [accessed 14 Apr. 2021].

        View in Article

      23. U.S. Food and Drug Administration. Supplement Approval Letter for Mifeprex (mifepristone) Tablets (Mar. 29, 2016), https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/020687Orig1s020ltr.pdf [accessed 14 Apr. 2021].

        View in Article

      24. U.S. Food and Drug Administration. Risk Evaluation and Mitigation Strategy (REMS) Memorandum for Mifeprex (mifepristone) Oral Tablets, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/020687Orig1s020RiskR.pdf [accessed 14 Apr. 2021].

        View in Article

      25. U.S. Food and Drug Administration. Cross-Discipline Team Leader Review for Mifeprex (mifepristone) Oral Tablets, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/020687Orig1s020CrossR.pdf [accessed 14 Apr. 2021].

        View in Article

      26. Danco Laboratories, LLC. Risk Evaluation and Mitigation Strategy (REMS) for NDA 020687 Mifeprex (mifepristone) Tablets, 200 mg, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/020687Orig1s020RemsR.pdf [accessed 14 Apr. 2021].

        View in Article

      27. U.S. Food and Drug Administration. Supplement Approval Letter for Mifeprex (mifepristone) Tablets (Apr. 11, 2019), https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/020687Orig1s022ltr.pdf [accessed 14 Apr. 2021].

        View in Article

      28. U.S. Food and Drug Administration. Letter to the American College of Obstetricians and Gynecologists (Apr. 12, 2021), https://www.aclu.org/sites/default/files/field_document/fda_acting_commissioner_letter_to_acog_april_12_2021.pdf [accessed 14 Apr. 2021].

        View in Article

      29. U.S. Food and Drug Administration. Questions and Answers on Mifeprex (updated Apr. 13, 2021), https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/questions-and-answers-mifeprex [accessed 14 Apr. 2021].

        View in Article

      Article info

      Publication history

      Published online: April 24, 2021
      Accepted: April 16, 2021
      Received in revised form: April 15, 2021
      Received: February 10, 2021

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      DOI: https://doi.org/10.1016/j.contraception.2021.04.018

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