Exact Confidence Limits for the Probability of Response in Two-stage Designs

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In addition to point estimate for the probability of response in a two-stage design (e.g. Simon's two-stage design for binary endpoints), confidence limits should be computed and reported. The current method of inverting the p-value function to compute 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.


Clinical trials; Confidence interval; Coverage probability; Simon's two-stage design



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