  Population-adjusted indirect comparisons estimate treatment effects when
access to individual patient data is limited and there are cross-trial
differences in effect modifiers. Popular methods include matching-adjusted
indirect comparison (MAIC) and simulated treatment comparison (STC). There is
limited formal evaluation of these methods and whether they can be used to
accurately compare treatments. Thus, we undertake a comprehensive simulation
study to compare standard unadjusted indirect comparisons, MAIC and STC across
162 scenarios. This simulation study assumes that the trials are investigating
survival outcomes and measure continuous covariates, with the log hazard ratio
as the measure of effect. MAIC yields unbiased treatment effect estimates under
no failures of assumptions. The typical usage of STC produces bias because it
targets a conditional treatment effect where the target estimand should be a
marginal treatment effect. The incompatibility of estimates in the indirect
comparison leads to bias as the measure of effect is non-collapsible. Standard
indirect comparisons are systematically biased, particularly under stronger
covariate imbalance and interaction effects. Standard errors and coverage rates
are often valid in MAIC but the robust sandwich variance estimator
underestimates variability where effective sample sizes are small. Interval
estimates for the standard indirect comparison are too narrow and STC suffers
from bias-induced undercoverage. MAIC provides the most accurate estimates and,
with lower degrees of covariate overlap, its bias reduction outweighs the loss
in effective sample size and precision under no failures of assumptions. An
important future objective is the development of an alternative formulation to
STC that targets a marginal treatment effect.
