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 review statistical frameworks for time-to-event modeling in dose-finding trials and summarize existing designs into two classes: TITE deigns 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 individual designs as special cases and also give rise to new designs. We discuss and study the 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 evaluated and compared through computer simulations.

翻译：在剂量调查试验中,由于交错摄入,在毒性结果尚未确定的情况下,也许应该实时作出剂量分配决定,例如,当病人的累积迅速或剂量限制毒性晚于时间时。病人的时间对活动的信息可以用来促进这种决定。我们审查剂量调查试验的时间对活动模型的统计框架,并将现有的设计归纳为两类:TITE的脱钩和POD设计。TETE的设计以毒性概率推断为基础,而POD的设计则以剂量调查决定的推断为基础。这两类设计包括作为特殊情况的现有个别设计,并产生新的设计。我们讨论和研究这些设计的理论性质,包括大量聚合特性、一致性原则以及基本的决定规则。为了便利在实践中使用时间对活动的设计,我们采用了高效的计算算法,并审查了共同的实际考虑,例如安全规则和暂停规则。最后,通过计算机模拟对若干设计的运作特点进行了评估和比较。