Should imporvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent?

Abstract

Objective.To determine whether improvement of more than 20% in core set parameters should be required before patients are characterized as improved in rheumatoid arthritis (RA) clinical trials.Methods. Data from 6 RA trials were reanalyzed to evaluate the discriminant validity (ability to differentiate active treatment from control) of 4 proposed definitions of improvement: the current American College of Rheumatology (ACR) definition (a 20% threshold for core set parameters [ACR 20]), a 50% threshold (ACR SO), a 70% threshold (ACR 70), and an ordinal definition in which a patient could be classified in any of 3 categories (unimproved, ACR 20, or ACR 50). To evaluate the discriminant validity of these 4 definitions of improvement, we characterized each patient in each trial as improved or not, based on each definition, and computed a chi-square value differentiating the active treatment group from the control group, with the corresponding P value.

Clinical improvement as reflected in measures of function and health-related quality of life following treatment with leflunomide compared with methotrexate in patients with rheumatoid arthritis: Sensitivity and relative efficiency to detect a treatment effect in a twelve-month, placebo-controlled trial

“…As previously dis- (18). Although cutoff points other than the 20% used for the ACR 20% measure are currently being analyzed across different data sets to determine the most appropriate response levels, this report presents the performance at a 20% threshold for the various measures, since this is the level currently recommended and currently recognized by regulatory authorities.…”

A cost-effectiveness analysis of treatment options for patients with methotrexate-resistant rheumatoid arthritis

“…We chose the ACR 20 response criteria as our outcome measure because they are the most widely adopted among recent arthritis trials. In a recent publication evaluating the utility of different ACR response criteria, the ACR 20 were recommended as the primary measure of efficacy in RA trials (18). However, because the ACR 20 improvement index does not optimally reflect the degree of improvement beyond (ACR) 20%, a CE analysis employing only ACR 20 is likely to bias clinicians against more efficacious therapeutic options that can achieve Ͼ20% improvement.…”

“…ACR response data for all considered treatment options, except triple therapy, were available in each clinical trial (6,7,10) or in a publication evaluating the utility of different ACR criteria (18). The efficacy represents the probability of achieving an ACR response with each drug, subtracting the effect of the control drug (or placebo) among those who would not have improved with the control drug (or placebo) ( Table 1).…”

“…In this analysis, cyclosporine ϩ MTX was dominated unless the efficacy of triple therapy was substantially lower than that of cyclosporine ϩ MTX. Therefore, the range in the graph covers the triple therapy outcome only below its baseline, although the literature suggests that this is unlikely (18,19). This sensitivity analysis indicates that a substantial reduction in cyclosporine cost is necessary, even with triple therapy outcome below its baseline, for cyclosporine ϩ MTX to become a preferred option over triple therapy with CE ratios that are 5-, 10-, or even 20-fold multiples of our reference CE ratios.…”

ACR 20: Clinical or statistical significance?

“…A recent analysis of clinical trials (5) has indicated that in comparisons of drug versus placebo, use of a 20% response to indicate efficacy according to ACR criteria (ACR 20) yields drug/placebo differences that have greater statistical significance than is found with the use of a 50% response (ACR 50) or 70% response (ACR 70). Randomized controlled clinical trials are clearly necessary to evaluate therapies independent of the biases that inevitably arise in uncontrolled situations, and the ACR 20 is a valid index for the agents included in the reviewed studies.…”