Lower Baseline Relapse Activity Accompanies Declining Comparator Event Rates in MS Trials

Declining comparator-arm relapse rates can complicate event assumptions in relapsing multiple sclerosis trials. This meta-epidemiological analysis examined 15 treated-reference arms from nine phase 3 programs, relating annualized relapse rates (ARRs) to recruitment era, prior-year relapse activity, MRI markers, and an Operational Selection Pressure Index (OSPI). The index combined recruitment geography with time since ocrelizumab approval; disability outcomes were audited separately.

Reference-arm ARR fell from 0.370 in TEMSO and 0.320 in TOWER to 0.109–0.140 in BTK inhibitor-era programs. ARR correlated inversely with recruitment era (ρ = −0.906; 95% CI, −0.985 to −0.279; 15 arms). Prior-year relapse activity correlated with ARR (ρ = 0.739; 13 arms) and declined over time (ρ = −0.725). MRI findings were inconsistent.

OSPI correlated inversely with ARR across nine programs (ρ = −0.892), but the association was negligible after adjustment for recruitment midpoint (partial ρ = −0.020). Disability trends varied with reporting metric and effective follow-up. These descriptive findings support conservative event assumptions and harmonized reporting, but cannot establish a selection mechanism or separate the treatment environment from calendar era. The authors called for validation using screening data and country- or period-specific outcomes. Only the abstract was available for this assessment.