Robustness and corrections for sample size adaptation strategies based on effect size estimation

A study on the robustness of the adaptation of the sample size for a phase III trial on the basis of existing phase II data is presentedwhen phase III is lower than phase II effect size. A criterion of clinical relevance for phase II results is applied in order to launch phase III, where data from phase II cannot be included in statistical analysis. The adaptation consists in adopting the conservative approach to sample size estimation, which takes into account the variability of phase II data. Some conservative sample size estimation strategies, Bayesian and frequentist, are compared with the calibrated optimal conservative strategy (viz. COS) which is the best performer when phase II and phase III effect sizes are equal. The Overall Power (OP) of these strategies and the mean square error (MSE) of their sample size estimators are computed under different scenarios, in the presence of the structural bias due to lower phase III effect size, for evaluating the robustness of the strategies. When the structural bias is quite small (i.e., the ratio of phase III to phase II effect size is greater than 0.8), and when some operating conditions for applying sample size estimation hold, COS can still provide acceptable results for planning phase III trials, even if in bias absence the OP was higher. Main results concern the introduction of a correction, which affects just sample size estimates and not launch probabilities, for balancing the structural bias. In particular, the correction is based on a postulation of the structural bias; hence, it is more intuitive and easier to use than those based on the modification of Type I or/and Type II errors. A comparison of corrected conservative sample size estimation strategies is performed in the presence of a quite small bias. When the postulated correction is right, COS provides good OP and the lowest MSE. Moreover, the OPs of COS are even higher than those observed without bias, thanks to higher launch probability and a similar estimation performance. The structural bias can therefore be exploited for improving sample size estimation performances. When the postulated correction is smaller than necessary, COS is still the best performer, and it also works well. A higher than necessary correction should be avoided. Copyright © Taylor & Francis Group, LLC.