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Abstract:
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Purpose: The 3-at-risk method is a modification of the 3+3 design that seeks to reduce the duration of Phase I studies subject to the traditional risk constraints. Methods: We designed the 3-at-risk method to adapt to asynchronous patient arrival and evaluation, screen failures and patient inevaluabilty, constrained by the maximum level of individual patient risk permitted during a traditional 3+3 design. Simulations explore the impact of inevaluability, screen failure, patient arrival patterns and the underlying dose-toxicity relationship. Results: With clinically relevant parameters, simulations comparing the 3-at-risk method to the 3+3 method demonstrate approximately a 1-month reduction in the average duration of a Phase I clinical trial for every year the study is accruing. Simulations suggested a small (0-2 patient) increase in the median total number of patients required to complete a trial with the 3-at-risk design, representing the trade-off required to obtain the reduction in study duration. Conclusion: The 3-at-risk design reduces the expected Phase I study duration when compared to the traditional 3+3 design while limited to traditional risk.
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