摘要
目的 分析美国食品药品管理局(FDA)、欧洲药品局(EMA)、澳大利亚药品管理局(TGA)、国家药品监督管理局(NMPA)等国家或组织的药品管理部门颁布的局部作用经口吸入制剂生物等效性试验研究主要指导原则或相关指南。同时,着重研究分析FDA《特定药物的生物等效性指导原则》经口吸入制剂药物生物等效性研究相关规定,为我国仿制药质量和疗效一致性评价工作提供借鉴和帮助。方法 比较上述各国发布的相关经口吸入制剂生物等效性国际指导原则主要异同点。针对我国仿制药质量与疗效一致性评价参比制剂名单中的典型经口吸入制剂药物品种,从剂型、给药方式、体外试验、药动学(PK)、临床药效学(PD)终点比较、试验设计、受试者选择和检测物质选择等多个方面对FDA公布的 《特定药物的生物等效性指导原则》进行详细分析。结果 FDA、EMA等国际监管机构对吸入制剂呼吸用药生物等效性总体要求有一定差异,EMA要求采用逐步方法策略,而FDA采用的是总体证据权重方法,并且FDA明确提出采用群体生物等效性(population bioequivalence,PBE) 方法进行生物统计学比较。虽然各监管机构均推荐开展药动学研究,但FDA目的在于比较待测制剂和参比制剂的全身暴露,EMA目的在于评估比较待测制剂和参比制剂在肺部沉积及全身暴露。FDA仅对异丙托溴铵、酒石酸左沙丁胺醇等特定药物提出开展药效学研究,而EMA建议对支气管扩张剂和吸入性糖皮质激素等药品开展药效学研究,并要求需要监测对下丘脑-垂体-肾上腺轴(HPA)的影响等。TGA在遵循EMA相关规定的基础上,更加侧重于体内临床效果比较。NMPA总体要求与FDA基本一致,但在药效学终点BE研究上借鉴了EMA部分规定。总体而言,FDA的要求比EMA更加严格,其中FDA公布的涉及经口吸入制剂《特定药物的生物等效性指导原则》对具体化学仿制药的生物等效性评价从多个方面进行较为详细的规范,对仿制药的发展有重要的推动作用。结论 分析比较上述各国发布的相关经口吸入制剂生物等效性国际指导原则主要异同点,并重点介绍FDA公布的经口吸入制剂《特定药物的生物等效性指导原则》,有利于理解世界各地不同机构的生物等效性标准,对我国正在进行的仿制药质量和疗效一致性评价具有一定指导和借鉴意义。
Abstract
OBJECTIVE To study the main guidelines or related guidelines for the study of bioequivalence of locally acting orally inhaled drug products (OIDP) issued by the drug regulatory authorities of the United States Food and Drug Administration, the European Medicines Agency, the Australian Drug Administration, the National Medical Products Administration and other countries or organizations. At the same time, it focuses on the analysis of the FDA's "Guidelines for Bioequivalence of Specific Drugs" and the relevant provisions of the bioequivalence study of OIDPs, which provide reference and assistance for the consistent evaluation of the quality and efficacy of our generic drugs. METHODS Comparatively analyze the similarities and differences in the relevant international guidelines on bioequivalence of OIDP issued by the above countries. For the quality and efficacy consistency evaluation of China's generic drug quality and efficacy of reference formulations in the list of typical oral inhalation drug varieties, the FDA published the "Guidelines for Bioequivalence of Specific Drugs" for detailed analysis of the dosage form, mode of administration, in vitro experiments, clinical pharmacokinetics and pharmacodynamics, trial design, subject selection, test substances and other aspects. RESULTS Although there are many commonalities, there are also many differences in the regulatory recommendations for clinical studies such as formulation, in vitro testing, in vivo pharmacokinetics and pharmacodynamics for bioequivalence studies of OIDPs. Among them, the FDA published the "Guiding Principles on Bioequivalence of Specific Drugs" involving oral inhalation preparations, which provides detailed provisions on the bioequivalence evaluation of specific chemical generics from various aspects, and has an important role in promoting the development of generic drugs in China. CONCLUSION Analysis and comparison of the above-mentioned countries issued relevant international guidelines on bioequivalence of OIDPs, and focus on the FDA published "Guidelines on Bioequivalence of Specific Drugs", is conducive to understanding the bioequivalence standards of different institutions around the world, and has certain guidance and reference significance to the ongoing evaluation of the quality and efficacy of generic drugs in China.
关键词
经口吸入制剂 /
生物等效性试验 /
国际指导原则
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Key words
orally inhaled drug product /
bioequivalence /
international guidelines
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朱凤昌, 王爱国, 刘丽宏, 曹秀萍, 江翊国, 杨春宁, 张华吉, 韩凤, 丁丽霞.
局部作用经口吸入制剂呼吸用药生物等效性国际指导原则对比分析[J]. 中国药学杂志, 2020, 55(24): 2078-2084 https://doi.org/10.11669/cpj.2020.24.014
ZHU Feng-chang, WANG Ai-guo, LIU Li-hong, CAO Xiu-ping, JIANG Yi-guo, YANG Chun-ning, ZHANG Hua-ji, HAN Feng, DING Li-xia.
International Guidelines Study for Bioequivalence of Respiratory Drugs for Locally Acting Orally Inhaled Drug Products[J]. Chinese Pharmaceutical Journal, 2020, 55(24): 2078-2084 https://doi.org/10.11669/cpj.2020.24.014
中图分类号：
R951
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参考文献
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