Abstract
Standard network meta-analysis and indirect comparisons combine aggregate data from multiple studies on treatments of interest, assuming that any factors that interact with treatment effects (effect modifiers) are balanced across populations. Population adjustment methods such as multilevel network meta-regression (ML-NMR), matching-adjusted indirect comparison (MAIC), and simulated treatment comparison (STC) relax this assumption using individual patient data from one or more studies, and are becoming increasingly prevalent in health technology appraisals and the applied literature. Motivated by an applied example and two recent reviews of applications, we undertook an extensive simulation study to assess the performance of these methods in a range of scenarios under various failures of assumptions. We investigated the impact of varying sample size, missing effect modifiers, strength of effect modification and validity of the shared effect modifier assumption, validity of extrapolation and varying between-study overlap, and different covariate distributions and correlations. ML-NMR and STC performed similarly, eliminating bias when the requisite assumptions were met. Serious concerns are raised for MAIC, which performed poorly in nearly all simulation scenarios and may even increase bias compared with standard indirect comparisons. All methods incur bias when an effect modifier is missing, highlighting the necessity of careful selection of potential effect modifiers prior to analysis. When all effect modifiers are included, ML-NMR and STC are robust techniques for population adjustment. ML-NMR offers additional advantages over MAIC and STC, including extending to larger treatment networks and producing estimates in any target population, making this an attractive choice in a variety of scenarios.