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首页> 外文期刊>Journal of the royal statistical society >An information theoretic phase Ⅰ-Ⅱ design for molecularly targeted agents that does not require an assumption of monotonicity
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An information theoretic phase Ⅰ-Ⅱ design for molecularly targeted agents that does not require an assumption of monotonicity

机译：不需要单调假设的分子靶向药物的信息理论阶段Ⅰ-Ⅱ设计

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摘要

For many years phase Ⅰ and phase Ⅱ clinical trials have been conducted separately, but there has been a recent shift to combine these phases. Although a variety of phase Ⅰ-Ⅱ model-based designs for cytotoxic agents have been proposed in the literature, methods for molecularly targeted agents (TAs) are just starting to develop. The main challenge of the TA setting is the unknown dose-efficacy relationship that can have either an increasing, plateau or umbrella shape. To capture these, approaches with more parameters are needed or, alternatively, more orderings are required to account for the uncertainty in the dose-efficacy relationship. As a result, designs for more complex clinical trials, e.g. trials looking at schedules of a combination treatment involving TAs, have not been extensively studied yet. We propose a novel regimen finding design which is based on a derived efficacy-toxicity trade-off function. Because of its special properties, an accurate regimen selection can be achieved without any parametric or monotonicity assumptions. We illustrate how this design can be applied in the context of a complex combination-schedule clinical trial. We discuss practical and ethical issues such as coherence, delayed and missing efficacy responses, safety and futility constraints.
机译：多年来，Ⅰ期和Ⅱ期临床试验是分开进行的，但是最近出现了将这些阶段合并的转变。尽管文献中提出了多种基于Ⅰ-Ⅱ期模型的细胞毒性药物设计方法，但分子靶向药物（TAs）的方法才刚刚开始发展。 TA设置的主要挑战是未知的剂量效率关系，这种关系可能具有逐渐增加的平稳或伞形形状。为了捕获这些，需要具有更多参数的方法，或者需要更多排序以解决剂量-效果关系中的不确定性。结果，设计了更复杂的临床试验，例如关于涉及TA的联合治疗方案的临床试验尚未得到广泛研究。我们提出了一种新的方案发现设计，该设计基于派生的功效-毒性折衷函数。由于其特殊的特性，无需任何参数或单调性假设即可实现准确的方案选择。我们说明了如何在复杂的组合时间表临床试验中应用这种设计。我们讨论了实践和道德问题，例如一致性，延迟和缺少有效性的响应，安全性和徒劳性约束。

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