Abstract
BackgroundSurvival endpoint is frequently used in early phase clinical trials as the primary endpoint to assess the activity of a new treatment. Existing two-stage optimal designs with survival endpoint either over estimate the sample size or compute power outside the alternative hypothesis space.MethodsWe propose a new single-arm two-stage optimal design with survival endpoint by using the one-sample log rank test based on exact variance estimates. This proposed design with survival endpoint is analogous to Simon’s two-stage design with binary endpoint, having restricted follow-up.ResultsWe compare the proposed design with the existing two-stage designs, including the two-stage design with survival endpoint based on the nonparametric Nelson-Aalen estimate, and Simon’s two-stage designs with or without interim accrual. The new design always performs better than these competitors with regards to the expected total study length, and requires a smaller expected sample size than Simon’s design with interim accrual.ConclusionsThe proposed two-stage minimax and optimal designs with survival endpoint are recommended for use in practice to shorten the study length of clinical trials.
Highlights
Survival endpoint is frequently used in early phase clinical trials as the primary endpoint to assess the activity of a new treatment
Among multiple-stage designs, a two-stage design is widely used in phase II clinical trials whose sample size is relatively smaller than that in the following phase III trial to confirm the effectiveness of the new treatment(s)
In Section Methods, we present the type I error rate and power calculation for a two-stage design with survival endpoint by using the one-sample log-rank test, and provide a detailed search method for two-stage minimax and optimal designs
Summary
Survival endpoint is frequently used in early phase clinical trials as the primary endpoint to assess the activity of a new treatment. Methods: We propose a new single-arm two-stage optimal design with survival endpoint by using the one-sample log rank test based on exact variance estimates. This proposed design with survival endpoint is analogous to Simon’s two-stage design with binary endpoint, having restricted follow-up. A multiple-stage design is often preferable in early phase clinical trials to investigate the activity of a new treatment. Such design is able to protect patients better as compared to the traditional one-stage design by allowing a trial to be stopped earlier when the new treatment is ineffective.
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