Table 1.

Selected Level Benefit-Risk Assessment Frameworks and Methods for Chronic Pain Clinical Trials

NAME	DESCRIPTION	EXAMPE
GROUP LEVEL ASSESSMENTS
EMA PrOACT-URL	The EMA PrOACT-URL is an eight-step qualitative analysis that provides a generic problem structure for identifying favorable and unfavorable effects, as well as the uncertainty of each, that has been adopted by the EMA [39; 40]. The framework is based on the field of decision analysis and was developed through the public-private partnership, IMI PROTECT.	Rheumatoid Arthritis [157]
FDA BRF	The FDA BRF five-step qualitative framework provides a simple and user-friendly snapshot of benefit-risk assessment that is intended to be broadly applicable [48–50; 87]. It should be updated as new information is received and can be used throughout the regulatory process. The five steps and questions asked include: (1) Analysis of the condition/”what is the problem?”; (2) Unmet Medical Need/”what other potential interventions exist?”; (3) Benefit; (4) Risk/”what am I worried about?”; (5) Risk Management/”what can I do to mitigate/monitor those concerns?”	Chronic pain (general) [114]
PhRMA BRAT	PhRMA BRAT is a six-step qualitative analysis developed to facilitate benefit-risk assessment by pharmaceutical companies and regulators. The method results in a summary table using the following: decision context, outcomes, data sources, framework, outcome importance, and display and interpret key metrics [28; 100]. Benefits and risks are not integrated in this framework, but are assessed separately to reduce complexity.	Migraine [100]
MCDA	Multicriteria decision analysis (MCDA) is a quantitative analysis method based on decision theory that combines evaluations of multiple potential benefits and risks (based on pre-specified criteria) into a weighted benefit-risk assessment [33; 111]. The scoring and weighting process allows the effects of different interventions to be placed on a common scale that allows for comparisons across interventions.	Chronic cancer pain [135]
INHB	Incremental Net Health Benefit (INHB) is a quantitative analysis method that is based on health-outcomes modeling that incorporates a life-expectancy measure adjusted for quality of life (i.e., quality-adjusted life year; QALY) [30; 57; 58]. The QALY represents an adjustment to length of life for the quality of life experienced and can be easily adapted to benefit-risk analysis by separating outcomes into expected health improvements with positive QALYs (benefits) and adverse health impacts with negative QALYs (risks). Benefit-risk differentials can then be expressed as either ratios or differences although the latter is preferred because the difference can be interpreted as healthy days (or months or years) of life gained (lost) since the units of measurement are the same. While standalone use of the INHB in pain populations is rare, clinical benefit-risk (net QALY impact) is the denominator in a range of cost-utility studies that have evaluated pain interventions.	Arthritis [103]
INDIVIDUAL LEVEL ASSESSMENTS
DOOR	The DOOR method is a quantitative analysis that provides a probability of a participant in the active group having a more desirable outcome than a participant in the control group. These probabilities are determined by ranking trial participants based on the desirability of their total experience of benefits and risks, and then the resulting rankings are compared between intervention arms [42; 43]. A key benefit of DOOR is that its calculation and interpretation are straightforward relative to other benefit-risk assessment methods.	Not yet examined in a chronic pain population
ETC Measure	The ETC Measure is a quantitative analysis that Integrates responder criteria for pain reduction (>20%, >30%, or >50% reduction in pain intensity from baseline) and adverse events (no AEs, no or mild AEs, and no or mild drug-related AEs) [88]. The approach assigns a score for both efficacy and tolerability for each day the patient is in the study, thus accounting for incidence, severity, and duration of AEs in one metric. The combination of scores across efficacy and tolerability over time forms a continuous ETC score that generally provides greater statistical power than dichotomous outcomes. The ETC score ranges from 0 to 1 with a clinically intuitive interpretation. For example, a score of 0.45 means the patient’s response was ‘good’ with respect to both efficacy and tolerability 45% of the time.	Chronic low back pain [88]
OARSI	OARSI has provided patient-focused, evidence-based, expert consensus guidelines for the management of knee OA that include the recommendation to perform a quantitative analysis using a composite benefit and risk score [105]. The score is voted on across a panel of expert physicians and calculated as the product of the benefit score (on a scale of 1–10) and the transposed risk score (where 1 = highest and 10 = safety) yielding a range of 1 (worst) to 100 (best). The group’s mean risk and benefit scores [along with 95% confidence intervals (CIs)] for each treatment are then plotted separately as bar graphs.	Knee osteoarthritis [105]
OMERACT	The OMERACT is a quantitative method that relies on a contingency table that allows for two or three levels of benefit across two or three levels of harm (Figure 1) [12]. The specific benefit and harm levels are uniquely defined depending on the chronic pain condition(s) and treatment(s). The interpretation of contingency table is consistent across studies, with an ‘unqualified success’ being a patient with a good response without any AEs and an ‘unmitigated failure’ being a patient having no benefit, but experiencing at least one AE.	Rheumatoid Arthritis [12]

Note: Additional benefit-risk approaches that might be considered, and not highlighted in the present table for brevity, include multiple-criteria decision analysis (MCDA), discrete-event simulation, probabilistic simulation, and Bayesian belief networks [109; 110]. AE (Adverse Event); BRF (Benefit-Risk Framework); DOOR (Desirability of Outcome Ranking Evaluation); EMA (European Medicines Agency); ETC (Efficacy-Tolerability Composite); FDA (United States Food and Drug Administration); IMI PROTECT (Innovative Medicines Initiative Pharmacoepidemiological Research on Outcomes of Therapeutics); INHB (Incremental Net Health Benefit); (MCDA (Multi-Criterion Decision Analysis); OMERACT (Outcome Measures in Rheumatology); OARSI (Osteoarthritis Research Society International); PhRMA BRAT (Pharmaceutical Research and Manufacturers of America Benefit-Risk Action Team); PrOACT-URL (Problem formulation, Objectives, Alternatives, Consequences, Trade-offs, Uncertainties, Risk attitude, and Linked decisions).