Sample Size Reestimation in Clinical Trials

This paper describes an approach to performing interim sample size reestimation based on the observed treatment difference in clinical trials. The approach combines the advantages of the group sequential and sample size reestimation methods and provides an efficient design for clinical trials. It provides flexibility but still maintains the integrity of the trial. To control the overall type I error level, a method is proposed to adjust the group sequential stopping boundaries adjusted for sample size reestimation and negative stops. The adjusted stopping boundaries are flexible to different rules of sample size reestimation and reuse the alpha values saved by negative stops. The adjustment is based on the exact type I error change and, therefore, the penalty for the type I error inflation due to such an interim reestimation is kept to a minimum. The efficiency of sample size reestimation without positive stops is compared with the group sequential method using unconditional power and expected sample size. All results are based on sufficient mathematical justifications.