Target estimands for population-adjusted indirect comparisons

Disagreement remains on what the target estimand should be for population-adjusted indirect treatment comparisons. This debate is of central importance for policy-makers and applied practitioners in health technology assessment. Misunderstandings are based on properties inherent to estimators, not estimands, and on generalizing conclusions based on linear regression to non-linear models. Estimators of marginal estimands need not be unadjusted and may be covariate-adjusted. The population-level interpretation of conditional estimates follows from collapsibility and does not necessarily hold for the underlying conditional estimands. For non-collapsible effect measures, neither conditional estimates nor estimands have a population-level interpretation. Estimators of marginal effects tend to be more precise and efficient than estimators of conditional effects where the measure of effect is non-collapsible. In any case, such comparisons are inconsequential for estimators targeting distinct estimands. Statistical efficiency should not drive the choice of the estimand. On the other hand, the estimand, selected on the basis of relevance to decision-making, should drive the choice of the most efficient estimator. Health technology assessment agencies make reimbursement decisions at the population level. Therefore, marginal estimands are required. Current pairwise population adjustment methods such as matching-adjusted indirect comparison are restricted to target marginal estimands that are specific to the comparator study sample. These may not be relevant for decision-making. Multilevel network meta-regression (ML-NMR) can potentially target marginal estimands in any population of interest. Such population could be characterized by decision-makers using increasingly available ``real-world'' data sources. Therefore, ML-NMR presents new directions and abundant opportunities for evidence synthesis.