Unanchored Population-Adjusted Indirect Comparison Methods for Time-to-Event Outcomes Using Inverse Odds Weighting, Regression Adjustment, and Doubly Robust Methods With Either Individual Patient or Aggregate Data

Objectives: Several methods for unanchored population-adjusted indirect comparisons (PAICs) are available. Exploring alternative adjustment methods, depending on the available individual patient data (IPD) and the aggregate data (AD) in the external study, may help minimize bias in unanchored indirect comparisons. However, methods for time-to-event outcomes are not well understood. This study provides an overview and comparison of methods using a case study to increase familiarity. A recent method is applied to marginalize conditional hazard ratios, which allows for the comparisons of methods, and a doubly robust method is proposed. Methods: The following PAIC methods were compared through a case study in third-line small cell lung cancer, comparing nivolumab with standard of care based on a single-arm phase II trial (CheckMate 032) and real-world study (Flatiron) in terms of overall survival: IPD-IPD analyses using inverse odds weighting, regression adjustment, and a doubly robust method; IPD-AD analyses using matching-adjusted indirect comparison, simulated treatment comparison, and a doubly robust method. Results: Nivolumab extended survival versus standard of care with hazard ratios ranging from 0.63 (95% CI 0.44-0.90) in naive comparisons (identical estimates for IPD-IPD and IPD-AD analyses) to 0.69 (95% CI 0.44-0.98) in the IPD-IPD analyses using regression adjustment. Regression-based and doubly robust estimates yielded slightly wider confidence intervals versus the propensity score-based analyses. Conclusions: The proposed doubly robust approach for time-to-event outcomes may help to minimize bias due to model misspecification. However, all methods for unanchored PAIC rely on the strong assumption that all prognostic covariates have been included.