Implementation and Use of Risk Evaluation and Mitigation Strategies Programs in Practice: A Scoping Review of the Literature

Abstract

Background Risk Evaluation and Mitigation Strategy (REMS) programs intend to improve medication safety but can add significant administrative burdens to providers and health systems. Various stakeholders have made efforts to use technology to improve REMS programs.

Objectives The objective of this scoping review is to describe studies evaluating workflows, automation, or electronic data exchange related to REMS programs.

Methods A literature search of PubMed, Embase, and Web of Science was performed for articles published between January 2007 and July 2021. Studies were identified using the relevant Medical Subject Headings terms and related keywords. Articles must have described a workflow change and measured the impact of the workflow change.

Results Of 299 citations initially identified, 7 were included in the final review after removing duplicates and articles not meeting predefined inclusion criteria. Included studies consisted of three manuscripts and four conference abstracts. Electronic health record interventions, such as customized order sets and clinical decision support alerts, were the most common strategy reported. Other strategies included developing a portal to verify REMS enrollment, requiring prescribers to contact the dispensing pharmacy, provider education, and restrictions based on the provider specialty. One study evaluated automated data exchange for REMS program processes in a mock environment. Although only three studies reported baseline metrics for comparison, all studies noted an improvement or benefit to the implemented workflow process changes.

Conclusion There is limited evidence describing REMS workflows, automation, and electronic data exchange. Various strategies to address REMS program requirements were reported, but no studies described the use of data exchange standards in a real-world setting despite efforts by the Food and Drug Administration and other stakeholders. Additional efforts are needed to automate REMS programs.

Keywords

risk evaluation and mitigation - health information interoperability - workflow - REMS - patient safety

Background and Significance

When safety risks for medications must be mitigated, the Food and Drug Administration (FDA) can require a Risk Evaluation and Mitigation Strategy (REMS) program.[1] REMS programs are designed to promote patient safety by documenting and sharing information that can be used to inform practice. Information collected through REMS programs can provide quality observational data about the safety of medications in real-world settings.[1] [2] [3] [4] REMS programs include communication and risk management plans for certain drugs to ensure that the benefits of prescription drugs outweigh their risk in real-world settings. This program may be in place for a certain period or on an ongoing basis.[1] [5]

The major components of a REMS program include a medication guide, communication plan, and elements to assure safe use (ETASU).[6] The medication guide and communication plan are intended to inform patients and health care providers on potential risks associated with the medication, respectively. ETASU is used for medications that would otherwise be unavailable due to the serious safety risks and are unique to each REMS program. Elements may include training and certification for health care providers, certification of pharmacies or other entities that dispense the medication, limits on the setting where the medication can be dispensed, required documentation of safe conditions prior to dispensing the medication, ongoing monitoring requirements for patients receiving the medication, or a registry for patients receiving the medication.[7] [8]

The FDA approved a total 297 REMS programs overall. As of January 2022, the number of active REMS programs was 62, of which 13 required medication guide and 58 required ETASU elements. ETASU requirements varied by program with 41 programs requiring dispenser certification, 39 requiring prescriber certification, 38 requiring prescriber training, and 29 requiring patient enrollment. Illustrating the complexity of staying current with the REMS requirements, over the past 7 years, the number of newly approved REMS programs ranged from 4 to 12 per year, the number of revised programs ranged from 3 to 17 revisions per year, and the number of modifications in these revised programs ranged from 32 to 63 per year.[9]

REMS programs have significant administrative requirements for tracking and monitoring. The time and complexity required to meet requirements have increased since program inception in 2007 as there have been more involved ETASU.[10] [11] Participation of multiple stakeholders is required for an effective implementation of REMS programs, including but not limited to pharmaceutical manufacturers, prescribing providers, pharmacists, support staff, and patients. Providers who prescribe medications with REMS requirements carry a large burden. In addition to their already demanding patient care workload, prescribers may need to obtain certification, understand REMS requirements, enroll patients, ensure monitoring orders are placed, and safe use conditions are met. Similarly, meeting REMS program requirements increases pharmacist workload. A pharmacist may need to obtain certification for their pharmacy, ensure that providers and patients are enrolled, obtain dispense authorizations prior to filling a medication, provide required patient education, and monitor compliance with REMS requirements within their pharmacy or health system. Both providers and pharmacists may document REMS-related activities in their existing health information technology (IT) systems (e.g., electronic health record [EHR], pharmacy dispensing platform/software, patient portal) in addition to systems specifically designed for this purpose.[12] Double documentation involves both workflow inefficiencies and the possibility of inaccurate documentation. In addition, stakeholders have reported confusion about how best to meet the requirements and the parties responsible for fulfilling and documenting requirements.[13] Thus, there is a range of ways to accomplish REMS requirements.

Some efforts have been made to address the administrative burden and alleviate the confusion associated with REMS programs. The FDA convened a group of stakeholders to obtain feedback on REMS programs, and standardizing REMS information in pharmacy systems was identified as a high-priority initiative.[4] [13] In addition, the National Council for Prescription Drug Programs (NCPDP) created a REMS REFEREnce Manual, which outlines technical standards for allowing prescribing systems to communicate with REMS administrators.[14] The Office of the National Coordinator for Health IT (ONC-IT) has also developed guidance, yet adoption remains low.[15] A substantial need exists for standardization and automation of the multi-stakeholder REMS process to reduce the burden on prescribers and improve medication safety and access for patients.[4] [8] [13] Thus, we sought to characterize the barriers to REMS program implementation and use, best practices, and reported program outcomes through addressing the following questions:

• What are common features of REMS workflows in practice?

• What are the reported workflow processes and health informatics strategies used by organizations to meet REMS programs requirements?

• What are barriers and facilitators to implementation and use of REMS programs?

Methods

Scoping Literature Review

We conducted a scoping literature review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Literature searches were performed in PubMed, Embase, and Web of Science. Searches were restricted to articles published in English only from January 2007 to July 2021. We looked at articles describing workflows, automation, or electronic data exchange as it relates to REMS programs. The search was performed on July 30, 2021. The search terms are available in [Supplementary Appendix A] (available in the online version). The review was registered in PROSPERO (identifier: CRD42021271944).

Eligibility Criteria

Two blinded study authors reviewed articles based on the article's title and abstracts. A third author was available to resolve any study selection disputes. We included journal articles that described workflows, automation, or electronic data exchange related to REMS programs. We excluded articles that did not include a workflow change and articles that did not measure outcomes from the workflow change. We included peer-reviewed articles and conference abstracts. The studies included randomized control trials, cohort studies, pre- andpostobservation studies, and cross-sectional studies.

Extraction and Data Analysis

Two blinded authors independently conducted the quality assessment and data extraction for all included articles. A third author was available should consensus not be achieved by the two authors. The authors used the Covidence ( http://www.covidence.org ) screening and data extraction tool. The following data were extracted: study identification, methods, population, intervention, outcome variables, and p-values.

Results

Studies Included and Excluded

Initial search results included 299 citations. After removing duplicates and articles not relevant to our aims, seven studies were included in the final review. [Fig. 1] depicts the flow of citation identification and study selection. Of the seven studies,[16] [17] [18] [19] [20] [21] [22] three were full-text articles,[18] [21] [22] and four were conference abstracts.[16] [17] [19] [20] [Tables 1] and [2] depict study design and purpose and implemented workflow process changes and outcomes, respectively. While most identified studies focused on evaluating REMS program compliance after a change in workflow processes,[16] [18] [19] [20] [21] one study assessed time efficiency in the adoption of a pharmacy REMS portal and another tested the feasibility of a real-time pharmacy claims database to improve the efficiency of claims adjudication.[15] [17] The majority of studies were reports of quality improvement projects conducted within medical centers.

Fig. 1 The flow of study identification and selection.

Table 1 Details and main purpose of included studies

Author (year)	Title	Study design	Setting	Main purpose
Adams et al[16] (2010)[a]	A Real Time Opioid Class REMS: Technical Feasibility	Cross-sectional	Mock pharmacy/claims database	To test the feasibility of using real-time pharmacy claims to verify patient, prescriber, and pharmacy enrollment in a training database
Tsapepas and Morales-Castro[17] (2015)[a]	Innovations through Information Technology a Process for Mycophenolate Risk Evaluation Mitigation Fulfillment	Cross-sectional	Hospital	To evaluate the impact of REMS compliance via multidisciplinary approach
Chan-Liston et al[18] (2019)	REMS Pharmacy Tasks: The Adoption of an Innovative Electronic Support System	Quasi-experimental, pretest-posttest	REMS-certified pharmacies dispensing lenalidomide, pomalidomide or thalidomide	To evaluate the pharmacy adoption rates of an online REMS Pharmacy Portal designed as an alternative for REMS-certified pharmacies to perform mandatory pharmacy dispense confirmations and to assess whether Pharmacy Portal uptake was affected by the pharmacy daily dispense volume
Do et al[19] (2019)[a]	Improving Adherence to Pregnancy Screening in Patients on Teratogenic Medications Using an Electronic Medical Record Alert System: A Quality Improvement Initiative	Quasi-experimental, pretest-posttest	Pediatric Rheumatology clinic at a single tertiary care center	To improve physician adherence in pregnancy screening for female patients on mycophenolate
Mahmoudjafari et al[20] (2019)[a]	Development of Processes to Ensure Timely Administration of Tocilizumab in the Setting of Cytokine Release Syndrome after Administration of Tisagenlecleucel or Axicabtagene Ciloleucel	Cross-sectional	Large academic medical center	To evaluate the implementation of standard policies and treatment algorithm to treat the acute toxicities seen with tisagenlecleucel and axicabtagene ciloleucel
Prokes and Root[21] (2019)	A Retrospective Analysis of Adherence to Risk Evaluation and Mitigation Strategies Requirements for Pulmonary Arterial Hypertension Drugs	Quasi-experimental, pretest-posttest	Large academic medical center	To assess Risk Evaluation and Mitigation Strategies (REMS) program compliance for pulmonary arterial hypertension (PAH) drugs following the initiation of more rigid protocols and informatics change
Kostrzewa[22] (2021)	Optimization of REMS Program Compliance in a Large Academic Health System	Cross-sectional	Large academic medical center	To evaluate the impact of EHR optimization on REMS program compliance

Abbreviations: EHR, electronic health record; REMS, Risk Evaluation and Mitigation Strategy.

^a Study available only as conference/congress abstract. Full-text article not available.

Table 2 Implemented workflow process changes and outcomes of included studies

Author (year)	Workflow change implemented	Groups	Outcomes	Conclusions
Adams et al[16] (2010)[a]	Utilization of a real-time pharmacy claims to verify patient, prescriber, and pharmacy enrollment in REMS program at the time of adjudication: mock prescriber (2.2 M records), pharmacy (700K), and patient (20 M) records were created; mock pharmacy claims (10,000) were created; five test conditions simulating enrollment or nonenrollment were created	N/A	• Mock pharmacy claims (10,000) employing the test records and 5 test conditions resulted in 100% accuracy in rejecting invalid claims and accepting valid claim • Maximum processing time < 0.5 seconds	A system using pharmacy claims can process large volumes quickly and accurately. The volume of claims processed (60/second) is ∼3-fold higher than would be required to accommodate an ‘‘all opioid’' REMS (20/second) and ∼20-fold higher to accommodate an ER opioid/methadone REMS (3/second). Assuming a REMS covering 30 million prescriptions, the added pharmacy burden would be 4,000 hours versus 1.5 million hours for a web/IVR system
Tsapepas and Morales-Castro[17] (2015)[a]	Development of a mycophenolate medication use guide to outline REMS requirements to include: (1) Prescriber enrollment (2) Pregnancy testing (3, 4) Patient education and patient/prescriber acknowledgment form (5) Mycophenolate pregnancy registry Guide served as framework to customize CPOE system with order-entry forms with CDS to guide prescribers through REMS components for females	N/A	• Since implementation, 119 FCBP have listed for transplantation and 88% have completed REMS program requirements • Monthly compliance rates range from 60 to 100%	Since implementation, REMS program compliance has increased, including education, patient-prescriber acknowledgment form, and pregnancy testing
Chan-Liston et al[18] (2019)	A self-service pharmacy portal (PP) was developed (December 2013) to allow REMS-certified pharmacies to obtain confirmation numbers instead of calling a Customer Care Representative (CCR) or using the Interactive Voice Response System (IVR) system	CCR or IVR vs. PP	• Change over time (quarterly) in percentage of pharmacy dispense confirmations obtained via the PP (2014-Q2 - 67%, 2016-Q2: 98%, 2018-Q1: 98.5%) • PP adoption rates were not affected by the dispensing volume of the pharmacy	REMS-certified pharmacies rapidly adopted PP use to verify patient and provider enrollment and obtain dispense authorization numbers
Do et al[19] (2019)[a]	BPA alert to prompt ordering of a urine hCG test for female patients age 10 and older prescribed mycophenolate	Before BPA vs. after BPA	• Urine hCG at encounter where mycophenolate was prescribed: 11% (8/71 encounters) vs. 79% (114/144 encounters), p < 0.00001 • No urine hCG within 7 days of prescribing mycophenolate: 72% (51/71) vs. 3% (5/144), p < 0.0001	Implementation of BPA significantly increased urine hCG pregnancy screening at encounters where mycophenolate was prescribed
Mahmoudjafari et al[20] (2019)[a]	Annual pharmacy competency outside of the REMS requirements for all inpatient pharmacy staff to ensure awareness for prompt administration of tocilizumab  PRN entry of tocilizumab released concurrently with cell infusion order readily available on the patient's Medication Administration Record for immediate dispensing  “Prepare and give now” entry for tocilizumab within our toxicity treatment order set in preparation of potential future admission   Attending required to call the inpatient pharmacy for verbal order to dispense dose	N/A	• Seven patients received at least one dose of tocilizumab (range 1 to 4 doses). Median time from dispense to administration: 53.5 minutes	Education efforts and EHR modifications resulted in ability to dispense and administer tocilizumab within 2-hour time frame dictated by REMS requirements
Prokes and Root[21] (2019)	For all four of the medications (macitentan, bosentan, ambrisentan, and riociguat): 1. Therapy restricted to adult pulmonary and cardiology, and pediatric cardiology, neonatology, and critical care attendings and fellows enrolled in the respective REMS program 2. All female patients must also be enrolled in the REMS program prior to initiation (male patients only for bosentan) 3. Complete baseline LFTs (for bosentan) 4. Pregnancy tests for FCBP 5. Ordering processes altered to include order panels with the medication and necessary laboratory tests 6. Providers must answer required questions before the order can be processed 7. Pharmacists must verify patient and prescriber enrollment in the respective REMS programs, negative pregnancy tests for FCBP, and LFTs (for bosentan) via CDS alert which fires upon pharmacist verification to perform this step and this is documented in a pharmacy intervention within the EHR before dispensing the medication	Pre-informatics (n = 50) vs. post-informatics (n = 44)	• Primary endpoint: REMS protocol adherence (pregnancy tests performed within 30 days of medication initiation for FCBP, LFTs ordered within 30 days of bosentan initiation, and initiation of therapy order documented by an approved attending enrolled in the REMS program) improved during the post-informatics period (71 vs. 95%; p = 0.07) • Secondary endpoints: Pregnancy tests performed within 30 days of medication order (36.4 vs. 100%; p = 0.01) LFTs within 30 days of drug initiation (91.7 vs. 100%) • Documentation of initiation of therapy ordered by a REMS-certified prescriber remained unchanged (87.5 vs. 86%)	Initiation of more rigid ordering protocols for the endothelin receptor antagonist (ERAs) (macitentan, bosentan, or ambrisentan) and riociguat improved pharmacist and physician compliance with REMS requirements
Kostrzewa[22] (2021)	Six inpatient medications on health system formulary required action for REMS program: alvimopan, ambrisentan, bosentan, clozapine, macitentan, riociguat. EHR optimization included: (1) Banner on EHR patient main page alerting provider patient is on a REMS medication and prompts pharmacist to complete a note (2) Note template to walk pharmacist through all required information for each unique REMS program	N/A	• Results reported over 1-year period after EHR optimization go-live (August 2018 to July 2019) • Of 777 inpatient admissions for 545 unique patients during which an inpatient REMS medication was administered, 318 admissions had at least one note (56 admissions had > 1) resulting in 40.93% compliance	EHR optimization can significantly influence REMS program compliance

Abbreviations: BPA, best practice advisory; CCR, customer care representative; CDS, clinical decision support; CPOE, computerized provider order entry; EHR, electronic health record; ER, emergency room; FCBP, female of childbearing potential; hCG, human chorionic gonadotropin; IVR, interactive voice response; LFT, liver function tests; PP, pharmacy portal; PRN, pro re nata (as needed); REMS, Risk Evaluation and Mitigation Strategy.

^a Study available only as conference/congress abstract. Full-text article not available.

Common Features of REMS Workflows in Practice and Strategies for REMS Program Compliance

The most common features and strategies reported in REMS workflow studies included EHR optimization/customization,[17] [19] [20] [21] [22] customized order sets,[20] [21] clinical decision support (CDS) alerts,[19] [20] [21] logging pharmacy interventions, or completing pharmacy notes to verify REMS compliance with each order.[21] [22] Other strategies include the development of a pharmacy portal to verify REMS enrollment,[18] requiring prescribers to contact dispensing pharmacies to verify order,[20] educating providers and pharmacists,[18] [20] and prescriber restriction based on specialty.[21]

One study focused on the process of pharmacy claims adjudication[16] to determine the feasibility of integrating health care IT platforms to reduce claims processing time. Mock patients, providers, pharmacies, and claims were created. Five different test conditions simulating differing enrollment statuses were created and assigned to claims. Four test conditions simulated one of three stakeholders as “not enrolled (invalid claim),” and one test condition simulated all three stakeholders as “enrolled (valid claim).” This is the only study identified that reported automation of data exchange in REMS program processes, albeit in a mock setting. No study reported integration with third-party vendors, REMS administrators, or pharmaceutical manufacturers to automate data exchange per NCPDP standards to incorporate REMS processes into provider and pharmacy workflow seamlessly.

All studies noted an improvement or benefit to the implemented workflow process changes, though only three studies reported baseline metrics for comparison. None of the studies mentioned time, resources, or costs incurred to develop and execute the reported workflow process changes.

Bias and Heterogeneity

Standard analysis for bias was not conducted due to study design and low sample sizes. Additionally, studies varied significantly in intervention, outcome reporting, duration of evaluation, and follow-up. Therefore, quantitative comparison or meta-analysis of included studies could not be performed.

Barriers and Facilitators

Reported facilitators to implementation included staff training and education through in-person or live interactive training,[18] annual pharmacy staff competency,[20] or staff meetings, and EHR education documentation.[22] Other facilitators included ongoing oversight and maintenance by designated groups or individuals, soliciting feedback from frontline staff,[22] and deploying an iterative Plan-Do-Study-Act quality improvement design.[19] Implementation barriers included lack of consistency among EHRs in how and where female reproductive potential was documented, including the criteria used to define reproductive potential,[21] attempting to tackle a large volume of REMS programs and changes instead of focusing efforts, and overlooking the need to continually reeducate staff.[22]

Discussion

Our study aimed to review the literature describing the implementation of systems and workflows to improve the process of REMS, including the design criteria of such systems, evaluation metrics, reported outcomes, and research gaps. The impetus for this review originated from the apparent gap in peer-reviewed literature that addresses key REMS workflow implementation issues. The seven studies included in the final review employed technology-based workflow interventions and showed numeric improvements in the process outcomes of rates of adherence to REMS requirements, time to dispense complex medications in an acute care patient setting, and successful adoption of an online REMS pharmacy portal.

Two full-length manuscripts and one abstract described improvement in compliance with REMS elements for specific medications after customizing existing CDS and computerized physician order entry functionalities in the commercially available EHR (Epic, Verona, Wisconsin, United States).[21] [22] One abstract reported a similar result from a previously published intervention[23] that streamlined the ordering process using medication logic modules within the EHR (Allscripts, Chicago, Illinois, United States). The functionalities used included system restriction of ordering based on physician specialty, CDS popup alerts or passive banners within the patient chart (known as Best Practice Advisories or BPAs), order sets/panels, required hard-stop questions embedded within the medication order, and links to medication information and medication use guidelines from the electronic Medication Administration Record (MAR).[17] Another abstract reported the ability to use order sets, help text, and the MAR within the EHR to ensure adherence to the REMS requirement of the timely administration of tocilizumab in the setting of cytokine release syndrome after the infusion of chimeric antigen receptor T-cell therapy.[20]

A study from 2010 reported the technical feasibility of using mock pharmacy claim adjudication transactions to fulfill REMS patient, pharmacy, and provider enrollment requirements.[16] An important step to streamlining REMS programs is defining electronic data standards that support information exchange among the various REMS stakeholders.[24] The REMS program requirements for individual medications must be documented in a standard, structured format and stored in a central repository. The FDA requires manufacturers to submit some product information using the Structured Product Labeling (SPL) standard approved by Health Level 7, but traditionally this has not included REMS information. Beginning in 2022, manufacturers will also be required to submit REMS information via the SPL standard.[25] NCPDP added REMS transaction standards to the SCRIPT Standard Implementation Guide to support incorporating REMS within the existing e-prescribing workflow, including REMS initiation and query requests and responses.[14] In addition, the NCPDP Telecommunication Implementation Guide includes standards to facilitate REMS bidirectional communication between dispensing providers (e.g., pharmacies), reimbursement adjudicators, and REMS administrators and between these entities and switches or intermediaries as determined by business needs.[26] Additional transactional standards are necessary for data exchange between EHRs and REMS administrators for medications given in hospitals or clinics where NCPDP standards do not apply. Adopting the NCPDP SCRIPT standards, the ONC-IT Interoperability Standards Advisory identifies the standard calling to “allow prescribers to communicate with a REMS administrator” as a standard for implementation by the industry but rates the adoption level of this standard as none or minimal.[15] Our review did not find any studies describing or evaluating the implementation of the REMS transactions components of the NCPDP SCRIPT or Telecommunications standards in a clinical environment.

To reduce the administrative burden of dispensing providers, one study reported rapid adoption of an online REMS portal created by the REMS pharmaceutical sponsor. This portal allows REMS-certified pharmacies to obtain dispense authorization online instead of calling a customer care representative or using the interactive voice response system. This study demonstrates pharmacy's strong preference for more straightforward mechanisms to interact with REMS.[18] Evaluations of automated REMS programs should measure improvements in workflow and time savings over nonautomated REMS programs.

One study reported a lack of standardization across EHRs in the representation of clinical concepts needed to determine if REMS elements are required. Endothelin receptor antagonists and soluble guanylate cyclase inhibitors (e.g., riociguat) are teratogenic medications with REMS programs that require monthly pregnancy tests for females of child-bearing age. The authors found a lack of consistency between EHRs in determining child-bearing age, with one study using 56 years as the upper cutoff and another used 59 years.[21] Others have reported that EHR vendors do not supply CDS tools to fulfill REMS requirements, resulting in the need for each institution to allocate resources to customize their systems.[23] The American Pharmacists Association (APhA) convened a large group of REMS stakeholders in 2010 who discussed that lack of REMS standardization could lead to reduced patient access and limited provider participation. The group recommended that all stakeholders (patients, prescribers, pharmacists, manufacturers, wholesalers, and system vendors) work collaboratively with the FDA to standardize REMS programs.[27]

In 2015, the FDA launched the “Common REMS Platform” initiative to provide a set of open, electronic data standards to be used by technology providers and REMS programs to reduce the burden of REMS compliance. The proposed common REMS platform intends to integrate REMS requirements into health IT systems within the workflow and support interoperability and streamlined communication between stakeholders.[24] A group of experts in 2016 who participated in a cooperative FDA workshop identified opportunities in the identification of data elements, refinement of the REMS process steps, and facilitating interoperable data exchange.[28] None of the studies that matched our inclusion criteria discussed using the FDA REMS Platform as a reference for implementation..

Low adoption of the NCPDP SCRIPT REMS data exchange standards recommended by ONC-IT and slow progress on the development of the Common REMS Platform are due to several factors. An important factor is the large number of stakeholder entities involved in the REMS process, including the FDA, pharmaceutical manufacturers, REMS administrators, prescribing providers, dispensing pharmacies, drug distributors, prescription benefit management companies, and e-prescribing and health IT vendors, each with their systems and processes. A second factor is the complexity of the drug distribution system, as not every medication product follows the traditional prescribing from a provider to a community pharmacy for the patient to pick up and administer. A growing number of medications can only be dispensed from certain specialty pharmacies, and other medications are for in-clinic administration, only bypassing the e-prescribing transactions. REMS data standards should be flexible enough to accommodate the complexity and variability of the drug distribution channels. Other barriers include different information systems used, inconsistent interpretation of requirements, and the lack of a sustainable funding model to pay for the required costs. The APhA REMS stakeholders discussed multiple opinions on which entities should financially contribute to the cost of REMS activities, but they did not reach a consensus.[27]

Our scoping literature review is not without limitations. The small number of studies that met the criteria of our scoping review revealed the scarcity of peer-reviewed literature addressing the comprehensive evaluation of the outcomes of REMS implementations. This scarcity of literature does not imply that provider organizations are not conducting evaluations of REMS programs as such evaluations might be occurring, and even may be shared through various forums, but the organizations may lack the resources, expertise, or the incentive to undertake the peer-review submission process. The included studies in our review demonstrated a lack of consistency in their outcome metrics, comparator groups, and methods to reduce research bias. Using a comparator or baseline groups to study the impact of implementing a REMS improvement and employing techniques such as cluster randomization and interrupted-time series analysis could minimize bias in future studies.[29] An ongoing study designed by the FDA and health system collaborators uses a multimodal approach to evaluating REMS programs.[30] This multiyear study aims to understand patterns of drug use, adherence to safety requirements, and patient outcomes under REMS programs, and the experience of physicians and patients will be incorporated into the outcomes. While this study addresses a gap in the literature, its published protocol does not include outcomes related to the workflow, time burden, data quality, and does not plan to incorporate the experience of pharmacists who are essential stakeholders in the REMS process.

One strength of our review is that, to our knowledge, it is the first comprehensive review of the literature identifying key workflow issues for health system to consider as they implement and evaluate REMS programs. It also demonstrates the need for more research assessing the impact of REMS-related workflow process changes and emphasizes that future research should be of more rigorous methodologies. A collaborative approach for the adoption of the REMS data exchange standards and development of automated REMS programs would need to include all stakeholders and government regulators to ensure that systems requirements and implementation plans are patient-centric, flexible to accommodate the complexity of drug distribution, can meet clinical safety and regulatory needs, and have a sustainable funding model to support the development, maintenance, and operational costs. The adoption of electronic medical records was greatly accelerated by targeted funds for adoption and meaningful use. Perhaps a similar infrastructure funding is needed to stimulate the development and adoption of automated REMS systems with meaningful outcome metrics.

This comprehensive scoping literature review provides an opportunity to review key issues that should be considered when performing a standardized evaluation to measure improvements in patient safety for REMS programs. REMS programs can be a burden to health systems and providers, and effective methods for addressing REMS program requirements remains unclear. Health systems invest heavily in resources and personnel to implement REMS programs and remain compliant with the requirements with little or no assessment of its impact on patient outcomes.

Conclusion

This scoping review found limited high-quality evidence describing REMS workflows, automation, and electronic data exchange. Strategies to address REMS program requirements included interventions such as developing order sets, CDS alerts, a centralized pharmacy portal, and manual interventions or education. The wide variation in reported strategies reflects the complex and disconnected nature of REMS programs. While there have been significant efforts by the FDA, standard development organizations, and other stakeholders, additional efforts are needed to automate REMS programs.

Clinical Relevance Statement

This is the first scoping review summarizing workflows, automation, or electronic data exchange associated with REMS programs. There is a lack of high-quality evidence describing methods to automate and streamline REMS program requirements despite efforts by the FDA's Common REMS Platform and other stakeholders. Additional efforts are needed to automate REMS programs.

Multiple-Choice Questions

1. What interventions to improve REMS workflows have been reported in recent studies?

   • Developing an API between an EHR and a REMS administrator registry.

   • Incorporating data exchange standards into clinical workflows.

   • Implementing a SMART on FHIR application in the EHR.

   • Creating institution-specific clinical decision support in the EHR.

   Correct answer: The correct answer is d. This study found that localized EHR changes are the most common method for incorporating REMS program requirements into clinical workflows. No studies evaluating data exchange in a clinical environment were found.

2. Select the best statement about REMS data standards

   • REMS transaction standards need to be created to facilitate data exchange between e-prescribing systems and REMS administrators.

   • NCPDP provides standards for data exchange between healthcare settings where REMS medications are administered (e.g., hospitals) and REMS administrators.

   • NCPDP REMS standards were recognized by ONC-IT ISA but adoption in practice has been slow.

   • REMS program requirements are available in Structured Product Labeling (SPL) format for all medications with a required REMS program.

   Correct answer: The correct statement is c. NCPDP REMS standards were adopted by the ONC-IT ISA but adoption in practice has been slow. These standards address bidirectional communication between electronic prescribing systems or retail pharmacies and REMS administrators. Data exchange between health care settings where medications are administered (e.g., hospitals) and REMS administrators is outside the scope of NCPDP standards. The FDA will require REMS program information in SPL format beginning in 2022.

Conflict of Interest

S.T., M.A., N.S., and S.H. are employees and shareholders of Pfizer. B.L. was a Pharmacy Informatics Intern whose intern experience was funded by Pfizer Medical Affairs. Y.Q. is an employee of Beth Israel Deaconess Medical Center and received funds from Pfizer Medical Affairs for a Pharmacy Informatics Internship Program.

Protection of Human and Animal Subjects

No human or animal subjects were included in this project.

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Publication History

Received: 12 April 2022

Accepted: 18 October 2022

Article published online:
08 December 2022