SHOULD IMPROVEMENT IN RHEUMATOID-ARTHRITIS CLINICAL-TRIALS BE DEFINEDAS 50 PERCENT OR 70 PERCENT IMPROVEMENT IN CORE SET MEASURES, RATHER THAN 20 PERCENT

Objective. To determine whether improvement of more than 20% in core s et parameters should be required before patients are characterized as improved in rheumatoid arthritis (RA) clinical trials. Methods. Data f rom 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 Rheumatol ogy (ACR) definition (a 20% threshold for core set parameters [ACR 20] ), a 50% threshold (ACR 50), a 70% threshold (ACR 70), and an ordinal definition in which a patient could be classified in any of 3 categori es (unimproved, ACR 20, or ACR 50), To evaluate the discriminant valid ity of these 4 definitions of improvement, we characterized each patie nt in each trial as improved or not, based on each definition, and com puted a chi-square value differentiating the active treatment group fr om the control group, with the corresponding P value. Results. With an increase in the threshold for improvement, the percentage of placebo- treated patients who were classified as experiencing response dropped dramatically in all trials, as did the percentage of patients receivin g active therapy (second-line drug, combination therapy, tumor necrosi s factor p75-Fc fusion protein) who were classified as experiencing re sponse. Generally, the drop in active treatment response rates was gre ater than the drop in placebo response rates, leaving the difference b etween the 2 groups less at the higher thresholds, Therefore, chi-squa re values fell as the threshold for response was raised. The ordinal d efinition of improvement yielded chi-square values similar to those ob tained using ACR 20 alone. Conclusion. Adopting a definition of effica cy in RA trials that requires 50% or 70% improvement in core set param eters would likely compromise statistical power and make it more diffi cult to distinguish between 2 treatments with different efficacy. ACR 20 should continue to be the primary measure of efficacy in RA trials, with higher thresholds for improvement being determined and reported as secondary efficacy measures.