Benefit-risk assessment and reporting in clinical trials of chronic pain treatments: IMMPACT recommendations

Abstract

Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results.

Figure 1

Figure 1 is reproduced from a previous publication [12] and copyright permissions were approved by Figure 1 is reproduced from a previous publication and copyright permissions were approved by Wiley. The figure illustrates the OMERACT 3×3 Combined Table of Benefits and Risks assessment method [12]. The results represented in the figure are from two randomized controlled trials including the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial (Top Panel) and the Rheumatoid Arthritis Comparison of Active Therapies (RACAT) trial (Bottom Panel). In the panels on the left, results of treatment groups are pooled and categorized according to the combined occurrence of benefit and harm, each in 3 categories. Results are expressed as a percentage of the total group, corrected for rounding. White lines delineate the cutoffs for the 2×2 categorization in the right-hand panels. The panels on the right show the results (percent per treatment group) with the combined occurrence of benefit and harm, each in 2 categories: for benefit, the European League Against Rheumatism (EULAR) good response (yes/no); for harm, the occurrence of any serious adverse event (SAE; yes/no). The length of the diagonal bar in each cell is proportional to the percentage of patients in that cell. The orange/blue (bottom left to top right) diagonal shows the balance between worst and best outcomes. The light grey/purple (top left to bottom right) diagonal shows the balance between 2 types of tradeoff: no benefit + no harm, and benefit + harm. nsAE (non-SAE); MTX (methotrexate); ETN (etanercept); triple (MTX, sulfasalazine, hydroxychloroquine).