生物制品首次临床试验起始剂量拟定的一般考虑

Considerations on the dose determination for first-in-human clinical trials with novel biopharmaceuticals

全新药物从临床前向临床推进的过程中,首次临床试验起始剂量的拟定是一个关键风险控制节点。生物制品与小分子药物存在不同的药理作用特点和毒性风险,在首次临床试验起始剂量的拟定上具有与小分子药物不同的考虑侧重点。重点阐述支持首次临床试验起始剂量拟定所需要的临床前研究信息;根据国内外的指导原则,介绍了基于毒性终点、药理终点、以及PK/PD模型进行起始剂量拟定的方法;通过回顾性分析,发现尽管毒性反应剂量法依然是传统保守的方法,但是对于具有免疫激发作用的生物制品更倾向于采用最低预期生物效应剂量法。研究者应基于药物的特点,采用多种方法拟定首次临床试验起始剂量,选取最合适安全的剂量,并加强与监管机构沟通与交流。

In the development process from the preclinical stage to the subsequent clinical phase, one critical risk controlling step is the determination of the first-in-human （FIH） dose. There is difference in the mechanisms of action and toxic risks between biopharmaceuticals and small molecule drugs, therefore different considerations will be involved in the determination of the FIH dose for biopharmaceuticals. This paper presents the overall review of the preclinical studies supporting the determination of FIH dose and the approaches based on the NOAEL, MABLE, and PK/PD model. The experience-based views that the MABLE-based FIH dose for immune activating products would be reasonably safe, although the NOAEL approach remains conservative and widely used for a majority of biopharmaceuticals are also presented. It is suggested that sponsors should determine the appropriate and safe FIH dose by diverse approaches according to the characteristics of product. Early communication between sponsors and regulators is always beneficial.