• ICH E10;
  • power;
  • preservation of effect;
  • regulatory approval;
  • sample size

International Conference on Harmonization E10 concerns non-inferiority trials and the assessment of comparative efficacy, both of which often involve indirect comparisons. In the non-inferiority setting, there are clinical trial results directly comparing an experimental treatment with an active control, and clinical trial results directly comparing the active control with placebo, and there is an interest in the indirect comparison of the experimental treatment with placebo. In the comparative efficacy setting, there may be separate clinical trial results comparing each of two treatments with placebo, and there is interest in an indirect comparison of the treatments. First, we show that the sample size required for a trial intended to demonstrate superiority through an indirect comparison is always greater than the sample size required for a direct comparison. In addition, by introducing the concept of preservation of effect, we show that the hypothesis addressed in the two settings is identical. Our main result concerns the logical inconsistency between a reasonable criterion for preference of an experimental treatment to a standard treatment and existing regulatory guidance for approval of the experimental treatment on the basis of an indirect comparison. Specifically, the preferred treatment will not always meet the criterion for regulatory approval. This is due to the fact that the experimental treatment bears the burden of overcoming the uncertainty in the effect of the standard treatment. We consider an alternative approval criterion that avoids this logical inconsistency. Copyright © 2011 John Wiley & Sons, Ltd.