Adaptation for Regulatory Application: A Content Analysis of FDA Risk Evaluation and Mitigation Strategies Assessment Plans (2014–2018) Using RE-AIM

Abstract

Background: Risk Evaluation and Mitigation Strategies (REMS) are safety programs that U.S. Food and Drug Administration can require to ensure a drug's benefits outweigh its risks and can be considered public health interventions. FDA's 2019 draft Guidance for Industry on REMS Assessments encourages the development of "novel methods for assessing REMS [to] help advance the science of post-market assessment of effectiveness of risk mitigation strategies." Objective: To characterize REMS assessment plans using RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework and identify areas for advancing methods for evaluating REMS programs. RE-AIM was selected for its wide application evaluating the translation of scientific advances into practice for public health impact. Methods: A content analysis of REMS assessment plans (N = 18) and measures(n = 540) was conducted for REMS programs approved by FDA between 1/1/2014-12/31/2018. Eligibility criteria were: a new drug application or biologic license application, included FDA-mandated mitigation strategies called elements to assure safe use (ETASU), and represented a single product REMS program. Assessment plans were collected from publicly available regulatory approval letters from REMS@FDA website. Blinded reviewers categorized each REMS assessment measure to a RE-AIM dimension, adjudicated their application (average IRR 75%), and refined the adapted dimensions' definitions. Dimensions were also mapped to REMS Assessment guidance categories. Results: The median number of assessment measures per REMS assessment plan was 31 (IQR: 21-36). Frequency of measures per RE-AIM criteria per REMS program was: Reach (median = 2; IQR: 2-4); Effectiveness (median = 2.5; IQR:1-4); Adoption (median = 3.5; IQR: 2-5); Implementation (median = 18; IQR: 15-24); Maintenance (median = 0; IQR: 0-1). Adoption (among prescriber, health system agents of implementation) was more commonly assessed than Reach (population-attributable number of patients affected). Assessment of heterogeneity of Adoption and Reach was generally absent. Toyserkani et al. Adaptation of RE-AIM for FDA REMS Assessments Implementation assessment measures were most common among drugs requiring evidence of safe-use conditions before dispensing or administering the drug. Patientlevel Effectiveness and Maintenance assessments were most common among drugs requiring patient monitoring. Discussion: Implementation science frameworks, such as RE-AIM, can be applied to characterize REMS assessment measures and identify opportunities for standardizing and strengthening their evaluation. Methods to measure Maintenance are needed to provide real-world evidence of REMS integration into the healthcare system.

The Use of Real‐World Data to Assess the Impact of Safety‐Related Regulatory Interventions

“…Because many REMS are complex and the risks that they are designed to mitigate differ from one REMS to the next, REMS programs vary in their design, 42 a feature that affects their assessments. Toyserkani and colleagues conducted a content analysis of 18 REMS assessments plans using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE‐AIM) framework 43,44 . Across the five domains of the RE‐AIM framework, they found that most assessments measured Reach (the extent to which the REMS intervention reached the intended stakeholders) and Effectiveness (the extent to which safe‐use conditions were followed and the extent to which the intended safety‐related health outcome or a surrogate thereof was attained).…”

The use of implementation science theories, models, and frameworks in implementation research for medicinal products: a scoping review

“…Studies varied in terms of purpose. Two studies aimed to compare the content of plans for programs to minimize drug-safety risks and the corresponding regulatory guidance pertaining to the implementation and evaluation of such programs [40,41]. Three other studies evaluated the uptake of a drug or drug-related innovation and/or barriers and facilitators to its adoption (i.e., HIV prophylaxis treatment, new patientcentered drug labeling guidelines, statin prescribing and use) [21,42,43].…”

“…[Insert Table 3 here] Studies varied in use across implementation phases and speci c application. Six studies reported using the IS TMF after implementation of the intervention [40,41,43,44,46,47]. Three of the post-implementation studies [43,44,46] used the TMFs to guide the planning of data collection tools and analysis.…”

“…Three of the post-implementation studies [43,44,46] used the TMFs to guide the planning of data collection tools and analysis. Two studies used TMFs to map constructs included in regulatory guidance on evaluating Risk Evaluation and Mitigation Strategy (REMS) programs, and in REMS program assessment plans [40,41]. One study used the TMF to identify barriers and facilitators to implementation of an intervention (e.g., a digital asthma inhaler) [47].…”

Optimization of REMS Program Compliance in a Large Academic Health System

“…The actions required can involve several stakeholders and moving parts. In addition, it can be hard to clearly see the connection to effectiveness and impact of these programs [4][5][6][7][8] , which hampers buy-in and therefore compliance. 9,10 The Food and Drug Administration (FDA) Amendments Act in 2007 gave the FDA authority to require drug manufacturers to provide additional information, or REMS, to ensure the benefits of using a medication would outweigh the risks, as the FDA deemed appropriate.…”