美国第14届DILI研讨会最新介绍.ppt

* * 综合意见 SEOP是目前DILI诊断中最佳工具 RUCAM表可以更多地在临床和科研中运用，若怀疑，可用SEOP进一步评判 DILIN研究方向： 积累可用的真实的DILI病例 结合基因组学、生物标志、文献报告等结果，综合成基于网络的电子工具辅助DILI诊断 同时也在修订RUCAM表的内容并电子化 因果评判方法对比 DILIN Expert “Consensus” Clinical practice Expert opinion RUCAM Setting Implication 6 mon DILI onset Epidemiology Mechanistic studies Bedside Drug cessation ? Real time ? Regulatory Mechanistic studies # Reviewers 3 1 1 Categories 1 to 5 50% likelihood 1 to 5 F/U duration 6 months ? Days to weeks 1 to 3 mon Competing etiologies excluded ++++ All (including CMV, EBV, HCV, HEV) ++/-- HAV, HBV, HCV, liver imaging ++/-- HAV, HBV, Ischemia, autoimmune Generaliz-ability Limited ++++ variable operator experience +/- Reproducibility Kappa = 0.6 ??? Kappa=0.33 主要内容 DILI的预测、发现和相关进展 美国DILI研讨会的背景 DILI临床诊断的因果评价系统 临床试验人群是否反映真实世界？ 20 March 2014 * 1) refer to serum enzyme (ALT, AST) activities as liver FUNCTION tests;2) grade SEVERITY of injury by serum enzyme elevations (NCI CTCAEs);3) refer to positive/negative sensitivity/specificity values as “PREDICTIVE”; 4) use ROC sensitivity, specificity, areas without considering INCIDENCE;5) use the term “chemical Hy’s Law” (must know probable causality).  应区分细胞损伤和器官功能不全的概念，避免以下 概念的误区 20 March 2014 * The only true liver function tests routinely done are:- serum bilirubin concentration- prothrombin time, or INR- albumin concentration 1) do NOT refer to serum enzyme activities as liver FUNCTION tests 伴活动性肝病基础的DILI判断 RUCAM not designed to assess dili causality when the baseline ALT value is abnormal Some items needed in RUCAM scoring are unavailable in pre-marketing clinical trials - liver injury “signature” of new drug based on past experience - alcoholism and pregnancy excludes enrollment -re-challenge precluded in clinical trials Therefore, prefer Expert Opinion approach 慢性肝病者非抗病毒药临床试验中的ALT值判断 The following values are proposed for clinical trials: Baseline ALT value: Because the definitive ULN is disputed, the baseline co