凝血因子Ⅷ产品抑制物发生率及相关临床试验要求

The inhibitor incidence of coagulation factor Ⅷ product and related clinical trial requirements

凝血因子Ⅷ(FⅧ)产品的替代疗法是治疗和预防血友病A患者出血的主要手段,产生抑制物是重要的药物不良反应。本文结合已上市FⅧ产品的临床试验数据及上市后研究的结果,探讨FⅧ产品抑制物发生的特点及相关临床试验要求,为FⅧ产品临床审评及研发提供参考。五项登记和队列研究提供的证据显示,重型血友病A的未经治疗患者(PUPs)接受FⅧ产品治疗50~75暴露日(EDs)的抑制物发生率在26%~45%,国内已进口FⅧ产品在PUPs临床试验的抑制物发生率在此区间范围。FⅧ抑制物虽然在PUPs中较常见,但在暴露日超过150 EDs的先前治疗过的患者(PTPs)中少见。国内已进口的FⅧ产品在重型血友病A的PTPs临床试验的抑制物发生率为0~2.1%。欧洲药品管理局(EMA)在综合分析已有数据后认为,现有证据不能确定不同品牌和类别的FⅧ产品抑制物风险的差异,每种产品的抑制物风险应单独评估。EMA的指导原则要求FⅧ产品上市前及上市后完成至少200例PTPs至少100EDs的临床试验,PUPs纳入上市后疾病登记系统,以监测抑制物风险。美国食品药品监督管理局(FDA)及我国对于FⅧ产品抑制物相关临床试验要求与EMA基本一致。在考察产品抑制物风险时,不仅要关注抑制物发生率,还应具体分析产生抑制物的风险因素,判断检测到的抑制物是否具有临床意义。

The replacement therapy of coagulation factor Ⅷ(FⅧ) is the main method to treat and prevent bleeding of hemophilia A patients. Inhibitor development is the most serious complication. Based on the clinical trial and post marketing data of FⅧ products, this paper discusses the characteristics of FⅧ inhibitors and the related clinical trial requirements to provide a reference for the clinical review and development of FⅧ products. Five registry and cohort studies shows that the incidence of inhibitors in previously untreated patients(PUPs) of severe hemophilia A treated with FⅧ products for 50~75 days of exposure(EDs) ranges from 26% to 45%. The incidence of inhibitors in clinical trials of PUPs with imported FⅧ products is in the same range. Although common in PUPs, inhibitor development is rare in previously treated patients(PTPs) with exposure days greater than 150 EDs. The incidence of inhibitors in clinical trials of PTPs with severe hemophilia A treated with imported FⅧ products is 0-2.1%. After analysis of the existing data, European Drug Administration(EMA) concluded that there was no clear evidence of the difference in the risk of inhibitor development in F Ⅷ products of different class or brand,and the risk of inhibitor development should be evaluated in each product. For monitoring the risk of inhibitor development in FⅧ product,at least 200 cases of PTPs treated with the produce for at least 100 EDs in clinical trials are required before and after marketing authorization by the guidance of EMA,and PUPs should be monitored through a disease registry after marketing authorization. The clinical trial requirements of American Food and Drug Administration( FDA) and China related to inhibitor development of FⅧ product are consistent with that of EMA. When investigating the risk of inhibitor development in FⅧ products,we should not only pay attention to the incidence of inhibitors,but also analyze the risk factors of inhibitor development and clinical significance of inhibitors.