中药、天然药物长期毒性研究技术指导原则

指导原则编号:【Z】GPT3-1中药、天然药物长期毒性研究技术指导原则二OO五年三月目录一、概述···················································································································································1二、基本原则········································································································································2（一）实验管理································································································································2（二）具体问题具体分析···········································································································2（三）整体性······································································································································2（四）试验设计·································································································································2三、基本内容·········································································································································3（一）受试物······································································································································3（二）试验动物·································································································································3（三）给药途径································································································································3（四）给药频率································································································································4（五）给药期限································································································································4（六）给药剂量································································································································5（七）观察指标································································································································6（八）观察指标的时间和次数································································································8（九）结果及分析···························································································································8（十）综合评价································································································································9（十一）其他考虑·························································································································10四、不同情况的中药、天然药物长期毒性试验的要求···········································10五、参考文献······································································································································12六、附录················································································································································13（一）长期毒性试验的给药期限·························································································13（二）长期毒性试验中一般需检测的指标····································································13（三）毒性药材······························································································································16七、著者···············································································································································16中药、天然药物长期毒性研究技术指导原则一、概述长期毒性试验是重复给药的毒性试验的总称，描述动物重复接受受试物后的毒性特征，它是非临床安全性评价的重要内容。中华人民共和国卫生部于1994年颁发的《中药新药研究指南》和国家药品监督管理局1999年颁发的《中药新药药理毒理研究的技术要求》，对于统一、规范中药长期毒性试验，推动我国中药的研究和开发起到了积极的作用。但随着新药研究手段的不断改进，对中药、天然药物认识的进一步深入，这些要求越来越表现出它的局限性。长期毒性试验的主要目的应包括以下五个方面：①预测受试物可能引起的临床不良反应，包括不良反应的性质、程度、剂量-反应和时间-反应关系、可逆性等；②推测受试物重复给药的临床毒性靶器官或靶组织；③预测临床试验的起始剂量和重复用药的安全剂量范围；④提示临床试验中需重点监测的指标；⑤为临床试验中的解毒或解救措施提供参考信息。中药在我国已有几千年的应用历史，有丰富的临床应用经验，相对化学药而言多数中药具有毒性较低的特点。但是，中药的低毒和无毒是相对的。当前，各种新技术、新工艺不断应用于中药新药的开发，而且从中药、天然药物中提取的有效成分、有效部位及其制剂日益增多，已不完全等同于传统意义上的中药，因此对其非临床安全性评价应给予足够的重视。长期毒性试验周期长，耗资高，工作量大，若因试验设计不合理，或所进行的试验未充分揭示中药的毒性特征，则会造成人力、物力、财力的浪费，1也会影响新药的研究速度。充分认识长期毒性试验的重要性，合理、科学地进行长期毒性试验设计，对试验结果进行科学的分析，是新药非临床安全性评价的基本要求。本指导原则是根据中药、天然药物的特点，结合国际上药物安全性评价的要求和我国药物安全性评价研究现状而制订的。本指导原则适用于中药、天然药物的长期毒性试验研究。二、基本原则（一）实验管理根据《中华人民共和国药品管理法》，长期毒性试验必须执行“药物非临床研究质量管理规范”。（二）具体问题具体分析中药、天然药物的情况复杂，本文所提及的内容不可能涵盖中药、天然药物长期毒性试验的全部实际情况，在进行中药、天然药物长期毒性研究时，应遵循“具体问题具体分析”的原则。（三）整体性药物的开发是一个连续的、渐进的系统工程，长期毒性试验是药物开发的一个有机组成部分。长期毒性试验不能与药效学、药代动力学和其他毒理学研究割裂，试验设计应充分考虑其他药理毒理研究的试验设计和研究结果。长期毒性试验的结果应该力求与其他药理毒理研究结果互为印证、说明和补充。（四）试验设计试验设计应符合随机、对照、重复的原则。2三、基本内容（一）受试物长期毒性试验的受试物应能充分代表临床试验受试物和上市药品，因此受试物应采用制备工艺稳定、符合临床试用质量标准规定的样品，一般用中试样品，并注明受试物的名称、来源、批号、含量（或规格）、保存条件及配制方法等。如不采用中试样品，应有充分的理由。如果由于给药容量或给药方法限制，可采用原料药进行试验。试验中所用溶媒和/或辅料应标明批号、规格及生产厂家。（二）试验动物长期毒性试验一般需采用两种动物进行，一种为啮齿类，常用大鼠；另一种为非啮齿类，常用Beagle犬或猴。所用动物应符合国家有关药物非临床安全性研究的要求。长期毒性试验一般选择健康、体重均一的动物，雌性应未孕。必要时，也可选用疾病模型动物进行试验。原则上，动物应雌雄各半。当临床拟用于单性别时，可采用相应性别的动物。应根据研究期限的长短和受试物的使用人群范围确定动物的年龄。一般情况下，大鼠为6~9周龄；Beagle犬为6~12月龄。每组动物的数量应能够满足试验结果的分析和评价的需要。一般大鼠可为雌、雄各10~30只，犬或者猴可为雌、雄各3~6只。（三）给药途径原则上应与临床拟用药途径相同。如选择其他的给药途径，应说明理由。3（四）给药频率原则上应每天给药，且每天给药时间相同。试验周期长（3个月或以上）者，也可采取每周给药6天。特殊类型的受试物由于其毒性特点和临床给药方案等原因，应根据具体药物的特点设计给药频率。（五）给