OBJECTIVES : In the absence of head-to-head trials, results from indirect treatment comparisons (ITCs) are used by regulatory agencies, payers, and physicians to assess benefit:risk of different therapies to support decision making. The critical need for valid approaches is described and illustrated using an example from infantile-onset spinal muscular atrophy (SMA), a rare degenerative neuromuscular disease where characteristics at treatment initiation are recognized confounders of treatment response.

METHODS : Criteria needed for valid ITCs and methodologic/statistical considerations are discussed. Unanchored matching adjusted indirect comparisons (MAIC) were conducted among patients with infantile-onset SMA from the ENDEAR/SHINE study for nusinersen and the STR1VE study for onasemnogene abeparvovec-xioi.

RESULTS : Valid ITCs require a set of conditions to be met, including comparable study designs (e.g., follow-up time, visit schedules) and the ability to adjust for differences in baseline characteristics. ENDEAR/SHINE and STR1VE participants differed on multiple prognostic factors and inclusion/exclusion criteria differed across trials. ENDEAR/SHINE participants were more severely affected at baseline; on average, they were older at treatment initiation and had lower baseline motor functioning. A sub-population of ENDEAR/SHINE patients that fulfilled STR1VE’s inclusion/exclusion criteria were identified. MAIC was then used to create weights for the individual level data from ENDEAR/SHINE to induce balance with the aggregate baseline characteristics reported for STR1VE. After weighting, event-free, overall and permanent ventilation survival curves for STR1VE and ENDEAR/SHINE were not significantly different (p=0.45, p=0.83, and p=0.41, respectively). In contrast, naive comparisons without baseline adjustment incorrectly concluded that participants in the STR1VE study experienced fewer events for these outcomes than those in ENDEAR/SHINE.

CONCLUSIONS : ITCs are an important but limited tool for assessing relative treatment effects and their application must be carefully considered to produce valid results. Baseline adjustment via MAIC or other methods should be thoughtfully applied when appropriate; unadjusted or inappropriate ITCs may yield misleading conclusions.