论文标题
致命剂量调查试验的回顾性分析
Retrospective analysis of a fatal dose-finding trial
论文作者
论文摘要
对肿瘤学中第1阶段临床试验的常见描述“主要涉及安全”是由于它们几乎普遍地采用了固有不安全的剂量降低实践而掩盖了它们。与剂量滴定相反，在同类剂量上的升级将患者视为可交换的患者，这是面对药代动力学和药物学（PKPD）广泛认识的个体间异质性的无可辩明性假设。以前，我以预防性的一致性原则提出了这一论点，该原则将张的众所周知的连贯性概念（2005）与现代以患者为中心和精确剂量的势力接触。但是，在这里，我通过分析双特异性T细胞AFM11的试验来探讨这些问题，其中发生了致命的毒性。为此，我为单一序数毒性开发了贝叶斯剂量反应模型。通过构建该模型的先验，以与设计和进行的AFM11试验保持一致，我证明了该设计的不兼容性，并有任何合理的安全期望。实际上，该模型很容易对有毒反应概率的前瞻性估计，这表明该试验中的死亡可能很有可能。
The commonplace description of phase 1 clinical trials in oncology as "primarily concerned with safety" is belied by their near universal adoption of dose-escalation practices which are inherently unsafe. In contrast with dose titration, cohort-wise dose escalation regards patients as exchangeable, an indefensible assumption in the face of widely appreciated inter-individual heterogeneity in pharmacokinetics and pharmacodynamics (PKPD). I have previously advanced this argument in terms of a precautionary coherence principle that brings the well-known coherence notion of Cheung (2005) into contact with modern imperatives of patient-centeredness and precision dosing. Here, however, I explore these matters in some mechanistic detail by analyzing a trial of the bispecific T cell engager AFM11, in which a fatal toxicity occurred. To this end, I develop a Bayesian dose-response model for a single ordinal toxicity. By constructing this model's priors to align with the AFM11 trial as designed and conducted, I demonstrate the incompatibility of that design with any reasonable expectation of safety. Indeed, the model readily yields prospective estimates of toxic response probabilities that suggest the fatality in this trial could have been foreseen as likely.
