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Abstract:
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In dose-finding trials, due to staggered enrollment, it might be desirable to make dose assignment decisions in real-time in the presence of pending toxicity outcomes, for example, when patient accrual is fast or the dose-limiting toxicity is late-onset. Patients’ time-to-event information may be utilized to facilitate such decisions. We propose a unified statistical framework for time-to-event modeling in dose-finding trials, which leads to two classes of time-to-event designs: TITE designs and POD designs. TITE designs are based on inference on toxicity probabilities, while POD designs are based on inference on dose-finding decisions. These two classes of designs contain existing designs as special cases and also give rise to new designs. We discuss theoretical properties of these designs, including large-sample convergence properties, coherence principles, and the underlying decision rules. To facilitate the use of time-to-event designs in practice, we introduce efficient computational algorithms and review common practical considerations, such as safety rules and suspension rules. Finally, the operating characteristics of several designs are compared via computer simulations.
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