Exact confidence limits for the probability of response in two-stage designs.

In addition to point estimate for the probability of response in a two-stage design (e.g., Simon's two-stage design for a Phase II clinical trial with binary endpoints), confidence limits should be Cute the confidence interval does not guarantee coverage probability in a two-stage setting. The existing exact approach to calculate one-sided limits is based on the overall number of responses to order the sample space. This approach could be conservative because many sample points have the same limits. We propose a new exact one-sided interval based on p-value for the sample space ordering. Exact intervals are computed by using binomial distributions directly, instead of a normal approximation. Both exact intervals preserve the nominal confidence level. The proposed exact interval based on the p-value generally performs better than the other exact interval with regard to expected length and simple average length of confidence intervals. Therefore, the new interval calculation based on p-value is recommended for use in practice.