Inference in group sequential designs with causal mechanisms: implications for power and mediation analysis

Mediation analysis needs additional consideration in group sequential designs. As with fixed trial designs, the sample size calculation of group sequential designs should account for the total variability underlying a causal mechanism when the treatment effect is hypothesized to be mediated by an intermediate variable, or risk the overall power to detect an intention-to-treat (total) effect being lower than the nominal value. We suggest reporting several estimators and acknowledging that they may be biased for some mediation pathways. More research is needed to develop methods for the analysis of indirect effect under group sequential designs.