Comparator Event Rates, Baseline Activity, and Operational Selection Pressure in Relapsing Multiple Sclerosis Trials: A Meta-Epidemiological Analysis.

backgroundReference-arm annualized relapse rates (ARRs) in relapsing multiple sclerosis trials have declined. We examined whether baseline disease activity and the treatment environment during recruitment changed alongside this trend.

methodsWe analyzed 15 treated-reference arms from nine Phase 3 programs. ARR was related to recruitment era, prior-year relapse activity, MRI markers, and an Operational Selection Pressure Index (OSPI) combining recruitment geography with time since ocrelizumab approval. Associations were descriptive; disability outcomes were audited separately.

resultsReference-arm ARR declined from 0.370 in TEMSO and 0.320 in TOWER to 0.109-0.140 in BTK inhibitor-era programs (ρ = -0.906; 95% CI, -0.985 to -0.279; n = 15). Prior-year relapse activity correlated with ARR (ρ = 0.739; 95% CI, 0.158 to 0.928; n = 13) and declined over time (ρ = -0.725; 95% CI, -0.965 to -0.157; n = 13). MRI findings were inconsistent. OSPI clustered at 0-7.3 in six programs and 65.2-80.5 in BTK inhibitor-era programs and correlated inversely with ARR (ρ = -0.892; 95% CI, -1.000 to -0.569; n = 9). The association persisted across sensitivities but was negligible after adjustment for recruitment midpoint (partial ρ = -0.020). Disability trends depended on reporting metric and effective follow-up.

conclusionsLower baseline relapse activity accompanied declining event yield. OSPI made a treatment-ecosystem transition measurable but could not be separated from calendar era or establish mechanism. Trials require conservative event assumptions, harmonized reporting, and validation using screening and country- or period-specific outcomes.