Comparison of treatment effects between ACR response criteria and target-based outcomes for contemporary rheumatoid arthritis drug approval trials: A meta-epidemiological study.

OBJECTIVE

Regulatory priorities diverge between agencies - the FDA maintained ACR20 response as primary endpoint in rheumatoid arthritis (RA) trials, whereas the EMA emphasized target-based outcomes. We aim to systematically compare treatment effect estimates between American College of Rheumatology (ACR) response criteria (ACR20/50/70) and target-based outcomes in placebo-controlled trials of approved RA therapies.

METHODS

A meta-epidemiological study was performed on randomized placebo-controlled trials investigating approved biological and targeted DMARDs (bioDMARDs and tsDMARDs) in patients with RA. Trials reporting at least one ACR response criterion and one target-based outcome were included. Odds ratios (ORs) for each outcome were computed, followed by calculation of a risk of odds ratio (ROR) to quantify differences in treatment effects between ACR and target-based outcomes. The primary outcome was the treatment effect differences between ACR20 and target-based efficacy estimates, and the second outcome was to explore which alternative ACR response criteria were concordant with target-based outcomes.

RESULTS

A total of 53 RCTs (392 study arms) involving 30,778 RA patients were analyzed. Trials using ACR20 demonstrated significantly greater treatment effect estimates compared to those using remission outcomes (ROR = 0.65, 95% CI 0.52-0.81) and LDA outcomes (ROR = 0.78, 95% CI 0.69-0.89). Higher ACR thresholds (ACR50 and ACR70) showed better consistency with target-based outcomes, with ACR70 aligning with remission (ROR = 0.88, 95% CI 0.76-1.01) and ACR50 aligning with LDA (ROR = 0.95, 95% CI 0.81-1.11). Subgroup analyses indicated that the discordance between ACR20 and target-based outcomes persisted across different intervention drugs, comparison types, and previous treatments.

CONCLUSION

ACR20 overestimates treatment effects relative to target-based outcomes, while ACR50/70 demonstrate better concordance. Harmonizing endpoints by integrating more stringent ACR response or co-primary endpoints (ACR response criteria + target-based outcomes) could bridge regulatory discrepancies and enhance clinical relevance in RA drug development.