Indirect treatment comparison (ITC) is widely used to estimate the comparative effectiveness of treatments when head-to-head trials are unavailable. For the typical scenario of anchored ITC where one trial compares drug A to drug C (AC trial) and another compares drug B to drug C (BC trial), the comparative effectiveness of drugs A versus B is calculated by subtracting (or dividing) the relative treatment effect of A versus C in the AC trial by that of B versus C in the BC trial, assuming the covariate distributions in both trials are balanced. This operation is valid only if the chosen effect measure is transitive, that is, in a three-arm randomized trial of drugs A, B, and C, the direct treatment effect of A versus B equals the indirect treatment effect of A versus B through their comparisons to C. For survival outcomes, many ITCs use the hazard ratio (HR) as the effect measure. In this article, we demonstrate that HR is generally not transitive and should be used with caution. As more reliable alternatives, we recommend effect measures with better transitivity properties: the restricted mean survival time (RMST) difference, the landmark survival probability difference (or ratio) at a prespecified time point, and the average hazard with survival weights (AH-SW) difference.

Matching-adjusted indirect comparison (MAIC) has been increasingly applied in health technology assessments (HTA). By reweighting subjects from a trial with individual participant data (IPD) to match the summary statistics of covariates in another trial with aggregate data (AgD), MAIC enables a comparison of the interventions for the AgD trial population. However, when there are imbalances in effect modifiers with different magnitudes of modification across treatments, contradictory conclusions may arise if MAIC is performed with the IPD and AgD swapped between trials. This can lead to the “MAIC paradox,” where different entities reach opposing conclusions about which treatment is more effective, despite analyzing the same data. In this paper, we use synthetic data to illustrate this paradox and emphasize the importance of clearly defining the target population in HTA submissions. Additionally, we recommend making de-identified IPD available to HTA agencies, enabling further indirect comparisons that better reflect the overall population represented by both IPD and AgD trials, as well as other relevant target populations for policy decisions. This would help ensure more accurate and consistent assessments of comparative effectiveness.