凝血因子Ⅷ与Ⅸ按需治疗血友病临床试验疗效指标的探讨  

Discussion about efficacy endpoints of clinical trials of coagulation factor Ⅷ and Ⅸ for hemophilia on demand

作　　者：饶亚岚 季双敏 熊文翔 于爱平 杨焕 高晨燕 RAO Ya-lan;JI Shuang-min;XIONG Wen-xiang;YU Ai-ping;YANG Huan;GAO Chen-yan(Center for Drug Evaluation,National Medical Products Administration,Beijing 100022,China)

机构地区：[1]国家药品监督管理局药品审评中心,北京100022

出　　处：《中国新药杂志》2020年第12期1338-1342,共5页Chinese Journal of New Drugs

摘　　要：凝血因子Ⅷ(FⅧ)或Ⅸ(FⅨ)替代疗法是治疗和预防血友病A或血友病B出血的主要手段。目前国内血源FⅧ或FⅨ制剂治疗血友病的临床试验基本为按需治疗,主要疗效指标一般为活性回收率和止血疗效评价。本文结合临床审评,对按需治疗血友病临床试验的疗效指标及相关问题进行探讨。活性回收率与药动学(pharmacokinetic,PK)参数增量回收率密切相关,其影响因素包括受试者个体差异、用药剂量、因子类型等。活性回收率<66%提示可能存在因子抑制物。重型血友病患者的特点是肌肉和关节反复出血,评估输注凝血因子改善患者关节与肌肉急性出血的四级止血疗效评价是国际公认的血友病疗效指标,但具有一定的主观性。止血疗效与FⅧ/FⅨ的用药剂量密切相关。因此,凝血因子临床有效性需结合多个疗效指标进行评价。Coagulation factorⅧ(FⅧ)orⅨ(FⅨ)replacement therapy is the main means to treat and prevent bleeding of hemophilia A or hemophilia B.At present,the civil clinical trials for hemophilia treated with plasma derived FⅧor FⅨare basically on demand treatment,and the primary efficacy endpoints are in vivo recovery and hemostatic evaluation.Integrated with clinical review,the paper discusses the efficacy endpoints and related issues of clinical trials of hemophilia on demand.The in vivo recovery is closely related to the incremental recovery of pharmacokinetic(PK)parameters,the influencing factors of which include individual differences,dosage,factor types,etc.The in vivo recovery<66%suggested that there might exist factor inhibitors.Severe hemophilia patients are characterized by repeated bleeding of muscles and joints.The four-grade hemostasis evaluation of infusion of clotting factors to improve acute bleeding of joints and muscles is an internationally recognized efficacy endpoint for hemophilia,but it is subjective in certain degree.The effect of hemostasis is closely related to the dosage of FⅧ/FⅨ.Therefore,the clinical efficacy of clotting factors needs to be evaluated in combination with multiple efficacy endpoints.

关 键 词：血友病 凝血因子 临床试验 按需治疗 疗效指标 

分 类 号：R969.4[医药卫生—药理学]