US Risk Evaluation and Mitigation Strategies with Elements to Assure Safe Use: A Longitudinal Analysis of REMS Modifications (2008–2022)

Abstract

Introduction

Risk evaluation and mitigation strategies (REMS) are risk management healthcare interventions required by the US Food and Drug Administration (FDA) for certain prescription medicines with serious safety concerns to protect public health and ensure that the benefits outweigh its risks. REMS are expected to evolve over a drug’s lifecycle on the basis of new pharmacovigilance evidence and changing healthcare delivery context.

Objective

The aim of this study is to characterize the frequency and types of REMS modifications over time to inform health policy and pharmacovigilance practice.

Methods

A retrospective longitudinal case series study was conducted using publicly available data on program characteristics and change history from the FDA’s public website (REMS@FDA). All REMS programs with elements to assure safe use (ETASU; N = 100) approved by the FDA between 1 January 2008 and 31 December 2022 were linked longitudinally into “REMS Classes” based on common drug class and/or moiety (N = 67). Median follow-up per program was 7.4 (interquartile range [IQR] 2.3–11.6) years after the index REMS approval. Type of REMS modification was coded and categorized as major or minor using the FDA’s guidance to the industry. Frequency and type of modification and time to first major modification were assessed.

Results

The median number of new REMS Classes approved per year was four. In the last 5 years of observation (2017–2022), REMS were being exclusively introduced concurrently with product approval. The median number of modifications per year per REMS class was 1.2 (IQR 0.7–1.6), representing 671 modifications and 364 unique dates. The median time to first modification was 15.4 (IQR 6.9–25.8) months and did not vary by when the index REMS was approved. Of the REMS classes, 96% (n = 64) had at least one modification by end of observation. As the cumulative number of REMS classes increased over time, modifications to approved REMS classes outpaced the approval of new REMS classes 17:1. The most common types of modifications were changes to REMS goals and/or design (n = 221) and changes to REMS materials (n = 167). However, no clear patterns were observed to suggest a specific type of early modification was more common than another. Among the 32 REMS classes approved in the first 5 years following the FDA Amendments Act of 2007 (FDAAA; 2008–2012), approximately one half (n = 14) had evolved to a shared system REMS by end of observation and one third (n = 10) had been released (median time to release 7.0 years, IQR 4.7–7.2 years).

Conclusions

REMS modifications were common and demonstrated responsiveness to new evidence about the drug and adaptation to changing patterns of healthcare delivery within a learning health system.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40264-026-01654-w.

Key Points

Risk evaluation and mitigation strategies (REMS) are population-based drug safety programs required by the US Food and Drug Administration for certain prescription medicines to ensure that their benefits outweigh their risks.

In this 15-year longitudinal case series analysis of 671 program modifications for 67 unique REMS classes grouped by common drug moiety/drug class, annual modifications outpaced new program approvals 17:1 with no clear pattern observed to suggest a specific type of modification was more common than another or could be avoided.

Findings show REMS modifications are common over a drug’s life course and thus should be anticipated as part of a learning regulatory and pharmacovigilance health system.

Introduction

Risk evaluation and mitigation strategies (REMS) are drug safety programs that the US Food and Drug Administration (FDA) can require for certain prescription medicine with serious safety concerns to ensure that the drug’s benefits outweigh its risks [1]. Each REMS has defined goals to mitigate a specific serious risk or set of risks [2]. Programs can consist of one or more elements, including a medication guide for patients, a communication plan that disseminates safety information to healthcare professionals, and/or additional elements to assure safe use (ETASU). ETASU can require that healthcare providers who prescribe the drug and/or pharmacies who dispense the drug be specially certified, the drug only be dispensed in certain healthcare settings, the drug only be dispensed with evidence or other documentation of safe use conditions, patients using the drug be subject to certain monitoring, or each patient using the drug be enrolled in a registry. More recently, for drugs that pose a serious risk, the FDA may also require certain packaging or a safe disposal system as part of a REMS [3]. As reported on the FDA’s REMS Public Dashboard [4], there were 71 active REMS as of 10 June 2025, with 65 of the active REMS (91.5% of programs) requiring ETASU [5].

The FDA has the regulatory authority to modify REMS programs [1]. For example, the FDA can require a modification to address new safety information or reduce burden on the healthcare delivery system or to accommodate different, comparable aspects of ETASU for an abbreviated new drug application (i.e., generic drug). A company can also submit a modification at any time. Given that some REMS may exist for the entire lifespan of the drug, there are also provisions to accommodate availability of multiple generic medications and reduce patient and healthcare system burden by developing Shared System REMS or a comparable REMS [6]. A REMS may also be released if it is no longer necessary to ensure the benefits outweigh the risks, for example, when it is determined that a product’s prescribing information becomes sufficient to communicate risks [7, 8].

Since the Food and Drug Administration Amendments Act of 2007 (FDAAA) was enacted and REMS were authorized, the FDA has taken steps to provide predictability to developers by standardizing REMS and improving their integration into the US healthcare system [9]. The FDA has issued guidance to the industry on content and format [10], assessment and reporting [11], modifications [12], development of shared systems [6, 13], and most recently the use of a REMS logic model to link program design with assessment [14]. FDA reauthorization goals (2023–2027) continue to emphasize enhancement and modernization of the FDA drug safety system, including adopting new scientific approaches for improving safety surveillance and modernizing REMS assessments [15].

The longitudinal dynamic nature of REMS as public health interventions implemented in real-world healthcare delivery systems has not been qualified or quantified. By statute, FDAAA requires the FDA to minimize healthcare system and patient-access burden when implementing REMS. The goal is safe access, not just restriction, with ongoing assessment and program modification as a means to reduce burdens to what are minimally necessary. Nonetheless, each change to a program also represents regulatory administrative burden in terms of costs, time, and resources industry and stakeholders expend to monitor and modify risk management activities.

The objective of this case series study was to evaluate the natural history of REMS with ETASU and describe the frequency and characteristics of program modifications in the 15 years after FDAAA was enacted. We hypothesized that the types of drugs requiring a REMS might change over time as well as the type of modifications as industry and regulators became more familiar with the design and implementation of these programs as norms were established. The overarching aim is to inform regulatory policy and strategies to improve REMS efficiency.

Methods

Source Data

REMS characteristics and revision/modification history were obtained from the REMS Data Files found on the FDA’s public website REMS@FDA [16]. Files provided dates and details on all modifications and revisions to each REMS ever approved and included information about current REMS as well as REMS that are no longer active (online resource eAppendix 1). Data were publicly available for download directly from the FDA website as CSV files and merged using the REMS identification number (REMSID) as the linking variable (download date 27 April 2023). Data on REMS goals, requirements, materials, REMS approval letters, and update history were also available for active REMS on the FDA website [17].

Study data were collected and managed using Research Electronic Data Capture (REDCap) tools hosted at the Colorado Clinical and Translational Sciences Institute [18]. REDCap is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry, (2) audit trails for tracking data manipulation and export procedures, (3) automated export procedures for data downloads to common statistical packages, and (4) procedures for importing data from external sources.

Study Cohort

The sample was restricted to unique REMS with ETASU approved in the 15-year period following enactment of FDAAA through 31 December 2022 (N = 100) (online resource eFig. S1).

Each REMS identification number (REMSID) in the FDA’s regulatory database corresponds to a unique REMS tied to a specific company (e.g., in the case of a new drug or biologics license application) or set of companies (e.g., in the case of a set of abbreviated new drug applications for the same generic ingredient). Related REMS, from an epidemiologic natural history perspective, were grouped by common drug class and/or moiety to facilitate longitudinal analysis, herein referred to as a “REMS class” (online resource eTable S1). To illustrate, the three individually approved REMS for lenalidiomide—(1) Revlimid REMS (single branded drug), (2) lenalidomide REMS (single generic drug), and (3) parallel system lenalidomide REMS (linking multiple generic drugs)—were grouped as one REMS class to evaluate the evolution of risk management over time for the same active ingredient. The index REMS approval date was the date of the first REMS program approved within each REMS class. REMS class status (active, released by the FDA, or inactive due to drug discontinuation) at the end of the observation period was recorded. A total of 100 unique REMS programs with an ETASU were consolidated into 67 REMS classes, 54 of which were active through 31 December 2022. Follow-up time was defined as time from index REMS approval date to 31 December 2022, date of REMS Class release, or date of REMS class inactivation, whichever came first.

Descriptive Variables

Descriptive information was abstracted and categorized using information from the products’ prescribing information and FDA data files, including the date of index REMS approval, indicated duration of use (acute/short-term or chronic/maintenance), whether the product was an opioid, and the risk(s) targeted by the REMS. The FDA’s public Orphan Drug Designations and Approvals database was queried and an orphan drug indicator variable created [19]. Orphan drug designation is granted by the FDA to a drug or biological product to prevent, diagnose, or treat a rare disease or condition, defined as affecting fewer than 200,000 patients.

REMS requirements were also abstracted and categorized. Categories were medication guide, communication plan, and five ETASU components: implementation system, dispenser certification, prescriber training, prescriber certification, and patient enrollment. An implementation system is a mechanism (such as call center to facilitate enrollment or establishment of an electronic database of certified healthcare settings) for drug makers to monitor and evaluate certification of pharmacies and hospitals, healthcare settings, and safe use conditions as the means of improving their implementation. Dispenser certification requires a dispenser to become certified to be able to dispense the drug. Prescriber training indicates that the REMS program provides training to prescribers as part of its ETASU. Prescriber certification requires prescribers to become certified to be able to prescribe the drug. Patient enrollment requires patients to be enrolled in the REMS program.

Clinical context-of-use characteristics included the setting in which the product would be used (i.e., home, clinic/outpatient, emergency department/inpatient), indication for use, and whether it was approved for pediatric use. Additionally, an indicator variable called “indication–risk concordance” was created to flag whether or not the medical specialty typically prescribing the drug was also the medical specialty with familiarity in managing the adverse event necessitating REMS mitigation.

REMS characteristics included cataloging the type and number of REMS requirements at any time during the observation period. Consistent with the FDA’s REMS Logic Model guidance, which refers to levels of prevention [14], the public health intent of the REMS goals was classified as primary prevention (avoid risk), secondary prevention (early detection of risk), tertiary prevention (treatment of risk, including long-term negative impact), or reliance on benefit–risk informed decision-making alone when prevention was not possible (online resource eTable S2). More than one prevention level could be identified.

REMS Modifications and Revisions

Definitions for REMS changes were derived from the FDA’s guidance [12] and used to categorize each change (online resource eAppendix 2). Major modifications include the addition, removal, or change to a REMS goal; the addition or removal of an element of the REMS; a change to a medication guide; substantial modification of a REMS element such as a change to the medication guide; or conversion of a REMS for an individual drug to a shared system REMS involving multiple manufacturers. Minor modifications include the addition of a new strength or dosage regimen of the drug, change to a manufacturer’s logo or graphics, or change to an existing healthcare provider or patient enrollment form. Examples of revisions include changes in the application holder name or address to reflect transfer of application ownership, editorial changes such as changes to the application holders internal tracking information, and correction of grammatical or typographical errors.

Each REMS change had a reported change date, and using the guidance examples was classified as a revision, minor modification, or major modification on the basis of the history update descriptions provided in the FDA’s public REMS data files. Major modifications were subcategorized on the basis of whether the change affected REMS goals and design, program content and materials, assessment, or program sustainability. A single change date could involve one or more revisions with minor and/or major modifications.

Statistical Analysis

REMS characteristics were summarized using median and interquartile range (IQR) for continuous variables and frequency and percentages for categorical variables. The Kaplan–Meier method was used to estimate time to first modification. Kaplan–Meier curves provided point estimates, and comparisons between strata were made using the log-rank test. Data stratification was performed by year of index REMS approval, timing of index REMS approval relative to market approval, and year of index REMS approval for the subset of REMS classes whose index REMS approval occurred with market authorization.

Continuous variables were compared using a Wilcoxon test. Categorical data were analyzed via Pearson χ² test or Fisher exact test. Potential trends over time regarding the characteristics of REMS classes and types and frequency of modifications were also examined by segmenting the analyses into three equal time periods based on index year for REMS class approval: 2008–2012, 2013–2017, 2018–2022. The Cochran–Armitage test for trend and the Jonckheere–Terpstra test were used to evaluate trends over time for dichotomous and continuous variables, respectively. No adjustments were made for multiple comparisons, as this analysis was exploratory in nature. p < 0.05 was considered statistically significant, and all statistical tests were two-sided.

Analyses were conducted with SAS, version 9.4 (SAS Institute Inc). R statistical software version 4.2.3 (R Project for Statistical Computing) and the survival and survminer packages were used for plotting survival curves. The study was approved by the Colorado Multiple Institutional Review Board (protocol #18-1871).

Results

REMS Characteristics

Table 1 presents characteristics of the REMS, grouped by drug class, stratified by year of index REMS approval. The median number of new REMS classes approved per year was four. REMS classes had a median of 5 (IQR 3.0–5.0) REMS requirements out of the 7 assessed. The median number of modifications per year per REMS Class was 1.2 (IQR 0.7–1.6), representing 671 modifications and 364 unique dates.

Table 1.

Characteristics of REMS with ETASU by year of index REMS approval

	REMS with ETASU, grouped by common drug class, N (%)a
	All years	By year of index REMS approval
	2008–2022 (N = 67)	2008–2012 (n = 32)	2013–2017 (n = 18)	2018–2022 (n = 17)	p-Valueg
Status as of 31 December 2022
Active	54 (81)	22 (69)	15 (83)	17 (100)	0.008
REMS Shared Systemb	17 (31)	12 (55)	5 (33)	0	< 0.001
Released	10 (15)	10 (31)	0	0	< 0.001
Inactive, drug(s) discontinued	3 (4)	0	3 (17)	0	0.72
Timing of index REMS approval
Deemed, marketed product with pre-existing risk mitigation	14 (21)	11 (34)	3 (17)	0	0.005
Market introduction, concurrent with product approval	43 (64)	12 (38)	14 (78)	17 (100)	< 0.001
Postmarketing, marketed product, new risk mitigation	10 (15)	9 (28)	1 (6)	0	0.005
Public health intent of REMS goalsc
Primary prevention: prevent risk	20 (30)	11 (34)	8 (44)	1 (6)	0.08
Secondary prevention: monitor and detect risk early	24 (36)	6 (19)	8 (44)	10 (59)	0.005
Tertiary prevention: manage risk and understand (registry)	22 (33)	6 (19)	4 (22)	12 (71)	< 0.001
No prevention; ensure benefit–risk informed consent	17 (25)	14 (44)	3 (17)	0	< 0.001
Product characteristics
Orphan disease indication	42 (63)	17 (53)	12 (67)	13 (76)	0.13
Opioid-related analgesicd	7 (10)	3 (9)	3 (17)	1 (6)	> 0.99
Typical duration of use
Acute/short term (< 12 months)	18 (27)	6 (19)	3 (17)	9 (53)	0.02
Maintenance/as needed (12 months or longer)	42 (63)	21 (66)	13 (72)	8 (47)	0.29
Both options viable	7 (10)	5 (16)	2 (11)	0	0.15
Clinical care context
Approved for use in pediatrics	15 (22)	10 (31)	3 (17)	2 (12)	0.11
Site(s) of product use
Inpatient/emergency department	17 (25)	6 (19)	3 (17)	8 (47)	0.06
Clinic/outpatient	28 (42)	12 (38)	8 (44)	8 (47)	0.55
Home	41 (61)	22 (69)	10 (56)	9 (53)	0.29
Product indication–risk concordancee	25 (37)	16 (50)	2 (11)	7 (41)	0.36
REMS requirementsf
Medication guide	33 (49)	26 (81)	5 (28)	2 (12)	< 0.001
Communication plan	23 (34)	15 (47)	3 (17)	5 (29)	0.16
Elements to assure safe use (ETASU)
Implementation system	61 (91)	27 (84)	18 (100)	16 (94)	0.21
Dispenser certification	56 (84)	22 (69)	18 (100)	16 (94)	0.008
Prescriber training	54 (81)	25 (78)	14 (78)	15 (88)	0.47
Prescriber certification	47 (70)	22 (69)	14 (78)	11 (65)	> 0.99
Patient enrollment	33 (49)	13 (41)	10 (56)	10 (59)	0.24
Count of REMS elements, median (IQR)	5.0 (3.0–5.0)	4.0 (3.0–5.0)	5.0 (4.0–6.0)	5.0 (3.0–6.0)	0.09

REMS were grouped into “REMS classes” by common drug class/moiety of the active ingredient of the medication. The year of index REMS is the year of first REMS approval within a given REMS class

REMS risk evaluation and mitigation strategies, IQR interquartile range

^aData are presented as N (%) unless otherwise noted

^bDenominator = active drug classes

^cMore than one public health intent possible per program; column percentage may add up to more than 100.

^dOpioid-related analgesic products are medications used for pain management or for counteracting opioid overdose or withdrawal: Dsuvia, Ionsys, buprenorphine transmucosal products for opioid dependence, opioid analgesic, Probuphine, Sublocade, and transmucosal immediate-release fentanyl.

^eConcordance = the body/organ system of the risk is clinically managed by the same medical professional that also manages the indication

^fMore than one REMS requirement possible per program; column percentage may add to more than 100. The FDA’s expanded REMS authority under the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (SUPPORT) Act (2018) also allows the agency to require interventions (e.g., packaging, disposal systems) to mitigate a serious risk. None of the REMS during the study period had a packaging or disposal requirement

^gp values are from the Cochran–Armitage trend test or the Jonckheere–Terpstra test

Among the 32 REMS classes approved in the first 5 years following FDAAA (2008–2012), approximately one half (n = 14) evolved to a shared system REMS by end of observation, and one third (n = 10) had been released (median time to release 7.0 years, IQR 4.7–7.2 years). In the last 5 years of the observation period (2018–2022), REMS classes were exclusively introduced concurrently with product approval. Early REMS goals (2008–2012) centered on primary risk prevention. Later REMS goals (2018–2022) emphasized secondary and tertiary prevention and management, including use of patient registries.

The majority, 63% (42) of REMS classes, involved drugs with an orphan disease designation. Over time, drugs with REMS were increasingly associated with short-term acute indications and inpatient/emergency department care settings. Only 37% (25) of REMS classes had product indication–risk concordance in which the prescriber’s medical specialty was also the specialty most experienced in managing the adverse event.

Frequency of REMS Approvals and Modifications Over Time

Figure 1 presents the time trend of the number of new REMS class approvals and modifications by year. As the cumulative number of REMS classes increased over time, modifications to approved REMS classes outpaced the approval of new REMS classes 17:1. Early years were characterized by a higher number of new approvals per year (2008–2012: median 5, range 5–11; 2013–2022: median 3, range 2–5; p = 0.005) and a lower number of modifications per year (2008–2012: median 14, range 0–32; 2013–2022: median 60, range 46–71; p = 0.002). In contrast, the ratio of modifications to new approvals was ten times higher in the later years versus early years (median 1.6, range 0–6.2 versus median 16.7, range 11.8–31; p = 0.002) indicative of the dynamic nature of postmarketing surveillance and clinical development.

Fig. 1.

Frequency of new REMS classes with ETASU approved per year compared with REMS modifications. REMS were grouped into “REMS classes” by common drug class/moiety of the active ingredient of the medication. The year of index REMS is the year of first REMS approval within a given REMS class. Reported values reflect counts on 31 December of each year. The ratio is defined as the number of REMS modification types compared with the number of new REMS classes approved each year. REMS risk evaluation and mitigation strategies, ETASU elements to assure safe use

Characteristics of REMS Modifications Over Time

The majority of REMS modifications represented a major modification (518 of 671). Overall, the most common types of modifications were changes to REMS goals and/or design (n = 221) and changes to REMS materials (n = 167). Within modifications “Affecting REMS Program Goals and Design,” the most common were those for adding or removing elements (52 of 221, 23.5%), modifying serious risk information (44 of 221, 19.9%), and modifying medication guides (43 of 221, 19.5%). Minor modifications primarily involved updates to the REMS websites to improve clinical workflows, such as converting paper-based downloadable forms to digital formats. The opioid-related REMS classes had the most modifications with the seven REMS classes related to the opioid crisis (Fig. 5) having 68 major modifications, or roughly one in eight of the total.

Fig. 5.

Illustrative example of the natural history of REMS modifications over time. Use case: postmarket and at-approval REMS, for multiple related REMS classes with ETASU associated with mitigating the opioid epidemic. Drug classes related to the opioid epidemic are opioid-related analgesic products used for pain management or for counteracting opioid overdose or withdrawal: Dsuvia, Ionsys, buprenorphine transmucosal products for opioid dependence, opioid analgesics, Probuphine, Sublocade, and transmucosal immediate-release fentanyl. In the 1910s, the first synthetic opioids were developed or put into use in medical practice. In August 1947, methadone was approved by the FDA. “In the 1960s and 1970s, the FDA approved short-acting combination products such as oxycodone/acetaminophen (Percocet, 1976). In the late 1980s and early 1990s, the FDA approved long-acting formulations of older opioid products, such as morphine (MS Contin in 1985) and oxycodone extended-release (ER) (OxyContin, 1995). Most recently, starting around 2010, the FDA has approved a cohort of opioids with supposedly abuse-deterrent properties, including tapentadol ER (Nucynta ER, 2011) and hydromorphone ER (Exalgo ER, 2010)" [43]. For details on specific product history for the TIRF class, see https://www.fda.gov/media/115101/download. REMS risk evaluation and mitigation strategies, ETASU elements to assure safe use, RiskMAP risk mapping, assessment and planning; TIRF transmucosal immediate-release fentanyl, OA opioid analgesic, BTOD buprenorphine transmucosal products for opioid dependence; Shared, single shared system

Table 2 describes REMS class changes stratified by year of index REMS approval. Median follow-up per class grouping was 7.4 (IQR 4.2–11.6) years with REMS classes approved in the earlier period having significantly longer follow-up. On average REMS classes had 1.2 (IQR 0.7–1.6) modifications per year resulting in 671 modifications made over the 15-year observation period; 96% (64) of REMS classes had at least 1 modification. However, no clear patterns were observed to suggest a specific type of early modification was more common than another.

Table 2.

Summary of changes for REMS classes with ETASUs

		All years	By year of index REMS approval
		2008–2022	2008–2012	2013–2017	2018–2022	p valuec
Years of follow-up, median (IQR)	7.4 (4.2–11.6)		11.7 (7.9–12.7)	7.6 (5.3–8.8)	2.9 (1.8–4.0)	< 0.001
Modification time course, median (IQR)
Per year of follow-up		1.2 (0.7–1.6)	1.3 (0.8–1.7)	1.2 (0.6–1.7)	1.0 (0.4–1.5)	0.12
Months to first modification		15.4 (6.9–25.8)	17.3 (10.0–29.1)	10.4 (7.1–20.2)	9.9 (3.6–21.0)	0.13
Number of REMS classes		N = 67	n = 32	n = 18	n = 17
Change per REMS class, N (%)
One or more changes (revision or modification)		65 (97)	32 (100)	18 (100)	15 (88)	0.06
One or more modifications (major or minor)		64 (96)	32 (100)	18 (100)	14 (82)	0.01
Number of changes		N = 800	n = 534	n = 197	n = 69
Type of change, N (%)a
Revision		129 (16)	73 (14)	36 (18)	20 (29)	0.001
Minor modification		153 (19)	103 (19)	35 (18)	15 (22)	0.94
Major modification		518 (65)	358 (67)	126 (64)	34 (49)	0.01
Characteristics of major modifications, N (%)b
Affecting REMS program goals and design		221 (28)	165 (31)	46 (23)	10 (14)	0.001
Modifying goal		13 (2)	10 (2)	3 (2)	0	0.39
Modifying serious risk information		44 (6)	32 (6)	10 (5)	2 (3)	0.34
Modifying indication		31 (4)	15 (3)	11 (6)	5 (7)	0.02
Modifying drug administration		32 (4)	22 (4)	7 (4)	3 (4)	> 0.99
Modifying patient laboratory testing		6 (1)	4 (1)	2 (1)	0	0.78
Removing/adding elements		52 (7)	43 (8)	9 (5)	0	0.005
Modifying medication guide		43 (5)	39 (7)	4 (2)	0	< 0.001
Affecting REMS assessment		43 (5)	30 (6)	9 (5)	4 (6)	0.81
Affecting REMS materials (content)		167 (21)	108 (20)	42 (21)	17 (25)	0.42
Affecting REMS program sustainability		41 (5)	29 (5)	12 (6)	0	0.22
Proposed release of REMS requirement		10 (1)	10 (2)	0	0	0.04
Converting or adding to a shared system		28 (4)	19 (4)	9 (5)	0	0.46
Inactivation, drug discontinuation		3 (0)	0	3 (2)	0	0.14

REMS were grouped into “REMS classes” by common drug class/moiety of the active ingredient of the medication. The year of index REMS is the year of first REMS approval within a given REMS class

IQR interquartile range, REMS risk evaluation and mitigation strategies, ETASU elements to assure safe use

^aA single change date may involve a revision, a minor modification, and/or multiple major modifications

^bColumn counts and percentages may not sum to that of major modifications, as the characteristic of some infrequent modifying elements are not listed

^cp values are from the Cochran–Armitage trend test, the Jonckheere-Terpstra Test, or the log-rank comparison of curves. The log-rank test compares entire survival curves; it does not explicitly compare median time to event

REMS classes approved earlier were more likely to have had a major REMS element changed by end of the observation period. Half of all dates with a modification affecting REMS materials (95 of 167) were associated with at least one goal or design modification. Nearly all medication guide changes, inclusive of removing the requirement, occurred in the 5 years following FDAAA, consistent with the FDA’s decision in 2012 to release many REMS that consisted solely of a medication guide [20].

Figure 2 presents time to first modification by year of index REMS approval. The median time to first modification was 15.4 (IQR 6.9–25.8) months and did not vary statistically by year of index REMS approval (online resource eFig. S2). In sensitivity analyses, characteristics of the first modification were qualitatively similar to the overall findings (online resource eTable S3), suggesting that there was not a pattern in the type of modification occurring first. Time to first modification did not statistically vary on the basis of whether the original REMS class approval occurred concurrently with market approval, subsequently during postmarketing, or when converting a deemed REMS with existing risk management market experience (online resource eFig. S3). Within the subset of REMS classes whose index REMS approval was concurrent with drug approval (N =43), time to first REMS modification did not vary statistically over time (online resource eFig. S4).

Fig. 2.

Time to first modification among REMS classes with ETASUs. N = 67 REMS classes. Three classes in the 2018–2022 stratum did not have a modification and were censored at 31 December 2022. REMS were grouped into “REMS classes” by common drug class/moiety of the active ingredient of the medication. The year of index REMS is the year of first REMS approval within a given REMS class. See Table 2 for median time to first modification. REMS risk evaluation and mitigation strategies, ETASU elements to assure safe use

Case Examples of REMS Program Evolution Over Time

Figures 3, 4, 5 illustrates continuous process improvement and the natural history of modifications for three REMS use cases: release of REMS restrictions when no longer deemed necessary (Fig. 3); maintenance of REMS restrictions and on-going modification to reduce burden for a product with pre-existing risk management requirements that transitioned to a shared REMS system involving multiple generic products (Fig. 4); and complex REMS oversight and modification associated with multiple interdependent opioid-related analgesic products whose regulation was affected by the US opioid epidemic (Fig. 5). They show a range of modifications (online resource eAppendix2) that occur over the life course of postmarketing surveillance, clinical development, and the real-world medical context.

Fig. 3.

Illustrative example of the natural history of REMS modifications over time. Use case: postmarket REMS approval of a new risk management program concurrent with approval of a new indication, and subsequent release, for a single branded product. REMS class = Truvada^® (emtricabine tenofovir). August 2004 market approval for the treatment of human immunodeficiency virus (HIV)-1 infection in adults and pediatric patients weighing at least 17 kg, in combination with other antiretroviral agents. July 2012 index REMS approval concurrent with a new indication in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. REMS risk evaluation and mitigation strategies, ETASU elements to assure safe use

Fig. 4.

Illustrative example of the natural history of REMS modifications over time. Use case: postmarket REMS approval of an existing risk management program, and subsequent single-shared system, for multiple generic products. REMS class = iPledge (isotretinoin). June 1982 Accutane^® (isotretinoin) market approval for the treatment of nodular acne. In 1988, in an attempt to reduce exposure to isotretinoin during pregnancy, the Accutane Pregnancy Prevention Program was established by Hoffman La Roche, Accutane's manufacturer. In April 2002, the FDA-mandated risk management requirements, the System to Manage Accutane-Related Teratogencity (SMART) was initiated. In November 2002, the first generic isotretinoin product was approved. Index REMS approval concurrent with prophylaxis indication. In February 2004, advisory committee review of SMART program recommended iPLEDGE enhancements (restricted distribution) to strengthen risk management. In March 2006, a risk mitigation action plan (RiskMAP), known as iPLEDGE, was enacted. iPLEDGE was a single restricted distribution program involving the new drug application (NDA) holder (Hoffmann-LaRoche) and generic manufacturers. March 2008 each individual isotrentinoin product became a deemed REMS. In June 2009, the innovator product, Accutane^®, was withdrawn from the market. In October 2010, index REMS approval of the Single Shared System, iPLEDGE. REMS risk evaluation and mitigation strategies, SMART System to Manage Accutane-Related Teratogenicity, RiskMAP risk mapping, assessment and planning

Discussion

To our knowledge, this is the first longitudinal analysis of modifications to REMS programs with ETASU since FDAAA was enacted. The findings show that REMS with ETASU represent a dynamic cohort of changing and evolving regulated public health interventions operating within the US healthcare system. On one hand, the absolute number of new REMS approvals per year was relatively small when grouped by drug class (median 4/year). However, program modifications were frequent and increased over time, outpacing new REMS class approvals 17:1 in the last 5 years of observation.

A goal of the current analysis was to inform policy implications for improving REMS design. No clear patterns were observed to suggest a specific type of early modification was more common than another and thereby could be prevented through better design. Rather, modifications were due to many reasons, such as adding new indications, updates to labeling that impacted REMS materials, and minor updates to the REMS websites. Nearly all of the REMS classes experienced at least one major modification, and the longer the postmarketing experience, the more likely modifications occurred. The opioid-related REMS classes had the most modifications, but that was to be expected given that these REMS affect a large patient population across a diverse set of providers, the number of individual REMS programs and manufacturers within the REMS class grouping is also large, and the context of risk mitigation for this national public health epidemic has been complex.

Concerns have been raised about the quality of REMS assessments performed by industry as a means for evaluating clinical implications of these programs [21, 22]. On the basis of our longitudinal analysis, the frequency and types of REMS modifications observed appear consistent with postmarketing changes occurring throughout a drug’s product lifecycle. Modifications occurred that confirmed new prescribing information resulting from supplemental applications submitted to the FDA in support of new indications and uses and new product formulations and dose forms [23]. Modifications resulted from active pharmacovigilance and continuous process improvement to modernize risk minimization practices with evolving healthcare delivery practices [15, 24]. Lastly, modifications resulted from loss of market exclusivity and conversion to generic product availability. More than 90% of prescriptions filled annually in the USA are for generic or biosimilar versions of medicines [25], so shared and parallel REMS systems are to be expected as a means to improve efficiency and reduce burden.

Modifications are also a byproduct of changing medical needs and innovation in healthcare delivery and technology and the opportunity to reduce burden and improve efficiencies. For example, REMS adapt to public health emergencies, such as the coronavirus disease 2019 (COVID-19) pandemic [26], and changing preferences, such as the use of telehealth [27]. Adoption of electronic health record systems and electronic prescribing has also affected how care is documented and patients are monitored [28, 29]. Moreover, continuous quality improvement is the hallmark of a learning health system [30] through “the collection and analysis of data … and the application of the new knowledge to influence practice” [31]. In separate analysis of individual REMS programs that had been operating for 7 years or more, major modifications continued to occur independently of meeting health outcome goals [32]. This suggests that even long-operating REMS programs continue to evolve within the changing healthcare environment in which they operate.

If modifications are natural and to be expected over a product’s life course, then the policy-relevant implications focus on transparency and efficiency in supporting a REMS that continues to evolve. Implementation science is being used to advance the regulatory science of pharmaceutical risk management [33, 34] and standardize evaluation [35, 36]. The FDA’s guidance to the industry describes a REMS Logic Model framework to link program design with assessment and provide an intuitive “systematic, structured approach to the design, implementation, and evaluation of a REMS” [14, 37]. The model was based on key tenets of clinical quality improvement and the research on application of common implementation science frameworks to REMS assessment [37, 38]. The REMS Logic Model takes into account the importance of contextual information as well as the scientific assumptions during the design and implementation of a program and can facilitates re-assessment of risk management restrictions as context changes [38].

The post-FDAAA era examined in this study is analogous to the years following the landmark Kefauver–Harris Amendments of 1962, which granted the FDA power to require proof of efficacy—in the form of “adequate and well-controlled investigations”—as a condition for drug approval [39]. It took decades to establish regulations for clinical trials and modern pre-approval drug development methods [40]. The current study examined the evolution of REMS classes in the 15 years following FDAAA. During this period, the FDA was similarly establishing scientific standards, this time focused on post-approval drug development. Successful risk management and ongoing modification involves many participants, including drug manufacturers who are responsible for implementation of the REMS and accountable for the health outcomes, physicians who prescribe and monitor, pharmacists who dispense, and patients who use the medication. Looking forward, REMS will continue to evolve as the FDA employs innovative technologies and approaches to advance patient safety, ensure continuity of care, and support efficiencies through standardization and integration of these programs into healthcare delivery [41] and through advances in post-approval monitoring and evaluation of real-world effectiveness [42].

Study limitations include reliance on public information alone to code modification type and the public health intent of REMS goals. However, the FDA has made efforts to promote transparency by making the REMS approval letters public, and the authors validated major and minor modification classification using the FDA’s guidance examples. Given the goal to understand the natural history of REMS from an epidemiologic perspective, REMS were grouped together in related classes for this analysis; therefore, reported modification rates (aggregated by REMS classes) are not equivalent to raw modification rates when disaggregated by individual REMS and reported by regulators. Lastly, data are limited by observation period, and follow-up is right censored, with older REMS classes having longer observation periods.

Conclusions

Findings indicate that FDA-mandated REMS with ETASU represent a dynamic cohort of changing and evolving risk management programs operating at national scale within the US healthcare system. Modifications were common over the life course of the products and demonstrated responsiveness to new scientific evidence and changing clinical context. Continued monitoring of REMS requirements and modifications is warranted, including research examining impacts on access and burden and health outcomes when requirements are released.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

Research reported in this publication was supported in part by the US Food and Drug Administration through an Intergovernmental Personal Act (IPA) Contract with the University of Colorado Denver and by National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) Colorado Clinical and Translational Science Award (CTSA) Grant Number UL1 TR002535 and Loyola CTSA Grant Number 2UL1TR002389. The content is solely the responsibility of the authors and does not necessarily represent the official views of the FDA or National Institutes of Health.

Declarations

Conflicts of interest

E.C. is self-employed and was paid for her statistical consulting services. C.L. and G.T. are currently self-employed, but at the time the research was conducted, they were employed by the US Food and Drug Administration. E.M. has served as a paid consultant on issues of drug safety to Eli Lilly, i2o, Reata Pharmaceuticals, and Syneos Health and to the Class Plaintiffs of the Xyrem (Sodium Oxybate) Antitrust Litigation, including United Healthcare Services, Inc., Humana Inc., Molina Healthcare, Inc., and Health Care Service Corporation, Inc., and receives compensation for these services. The terms of this arrangement have been reviewed and approved by Loyola University Chicago in accordance with its policy on objectivity in research. C.L. is currently self-employed, but at the time the research was conducted, she was employed by the US Food and Drug Administration. C.L. has served as a paid consultant for UBC and GSK. G.A.T. is employed by Perspective Pharmacovigilance, Inc.,but at the time the research was conducted, she was employed by the US Food and Drug Administration. Elaine Morrato is an editorial board member of Drug Safety. Elaine Morrato was not involved in the selection of peer reviewers for the manuscript nor in any of the subsequent editorial decisions.

Ethics approval

The study was approved by the Colorado Multiple Institutional Review Board (protocol #18-1871).

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and material (data transparency)

REMS reports, REMS data files and Historic REMS information, and data description are publicly available for download directly from the FDA REMS website: https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsData.page.

Goals, summary, REMS material, assessment plan, and update history are available for active REMS: https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm.

The REMS dashboard offers an interactive web-based tool to visual REMS information:

https://fis.fda.gov/sense/app/ca606d81-3f9b-4480-9e47-8a8649da6470/sheet/dfa2f0ce-4940-40ff-8d90-d01c19ca9c4d/state/analysis. An XLSX data file with class characteristics and modification categorization are available upon request from the authors.

Code availability (software application or custom code)

The coding dictionary is provided in the supplemental resources. Statistical code is available upon request from the authors.

Authors’ contribution

All authors meet all four criteria for authorship: (1) substantial contributions to conception or design of the work, or the acquisition, analysis, or interpretation of data for the work; (2) drafting of the work or reviewing it critically for important intellectual content; (3) final approval of the version to be published; and (4) agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.