Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database
Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database
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DOI：
10.1016/j.taap.2017.09.006
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发表时间：
2017-11-01
影响因子：
3.8
通讯作者：
Kadambi, Vivek J.
中科院分区：
文献类型：
--
作者：
Monticello, Thomas M.;Jones, Thomas W.;Kadambi, Vivek J.
动物试验在药物开发中的贡献受到了广泛的争论和挑战。创建了一个全行业的非临床到临床转化数据库，以确定动物模型中的安全评估如何转化为首次人体临床风险。该盲态数据库由 182 个分子组成，包含动物毒理学数据以及第一阶段人体研究的临床观察结果。动物和临床数据按器官系统分类并确定相关性。使用2 x 2列联表（真阳性、假阳性、真阴性、假阴性）进行统计分析。敏感性为 48%，阳性预测值 (PPV) 为 43%。非人类灵长类动物在预测不良反应方面表现最强，尤其是胃肠道和神经系统类别。当在啮齿动物和非啮齿动物中发现相同的靶器官时，PPV 增加。特异性为 84%，阴性预测值 (NPV) 为 86%。比格犬在预测不存在临床不良反应方面表现最强。如果在任一测试物种中均未观察到靶器官毒性，则 NPV 增加。虽然非临床研究可以证明 PPV 对于某些物种和器官类别具有巨大价值，但 NPV 是测试物种和目标器官中更强的预测性能指标，表明动物研究中不存在毒性强烈预测临床中的类似结果。这些结果支持当前动物试验的监管范式，支持安全进入临床试验，并为新兴的替代模型提供背景。
The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2 x 2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis. Sensitivity was 48% with a 43% positive predictive value (PPV). The nonhuman primate had the strongest performance in predicting adverse effects, especially for gastrointestinal and nervous system categories. When the same target organ was identified in both the rodent and nonrodent, the PPV increased. Specificity was 84% with an 86% negative predictive value (NPV). The beagle dog had the strongest performance in predicting an absence of clinical adverse effects. If no target organ toxicity was observed in either test species, the NPV increased. While non clinical studies can demonstrate great value in the PPV for certain species and organ categories, the NPV was the stronger predictive performance measure across test species and target organs indicating that an absence of toxicity in animal studies strongly predicts a similar outcome in the clinic. These results support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials and provide context for emerging alternate models.