为确保及时获得安全、优质、有效且负担得起的仿制药，仿制药使用者付费修正案（GDUFA）于 2012 年 7 月 9 日签署成为法律，目前授权有效期至 2027 年 9 月 30 日（GDUFA III）(1)。GDUFA 的主要目标是解决与复杂和非复杂仿制药相关的挑战，并确保监管审评的及时性和一致性。
根据 GDUFA 监管科学研究计划，美国 FDA 公开鼓励使用定量方法和建模（quantitative methods and modeling，QMM）方法以及模型集成证据（model-integrated evidence，MIE）来支持仿制药产品的开发和审批(2,3,4,5,6)。MIE 方法利用虚拟生物等效性（virtual bioequivalence，VBE）试验结果指导关键体内研究的设计，并通过支持考虑体外测试并减少其它推荐的常规体内研究（包括但不限于 PK、PD 或可比性临床终点研究(3)）的替代 BE 方法来获得药品批准。对于复杂仿制药和口服剂型，QMM 方法的应用可以并且正在用于支持替代 BE 方法和监管审评(2,3,7,8,9,10,11,12,13,14)。这些定量方法包括机械建模，例如基于生理的药代动力学（PBPK）建模和计算流体动力学 (CFD) 建模，定量临床药理学工具集，例如群体药代动力学（PPK）方法，以及先进的数据分析方法。
除资助 QMM 方法的内部和外部研究及其在支持药品开发和批准的 MIE 中的整合外，FDA 还努力改善制药行业和 FDA 之间的互动框架。在这些互动的范围内，FDA 引入了模型主文件（MMF）的概念，以促进模型共享和模型接受，并最终推进仿制药开发以及简化监管提交和评估(15,16)。
MIE 对于非复杂和复杂仿制药的促进作用是通过考虑药品质量属性来表征和预测体内性能，为减少人体测试的研究设计提供信息，以及支持解决与某些药品相关的挑战的替代 BE 方法。
2022 年 10 月 27 日至 28 日，FDA 和复杂仿制药研究中心 (CRCG) 在制药行业的重要反馈下合作举办了为期两天的研讨会，讨论将 QMM 方法整合到 MIE 内以支持仿制药产品开发的最佳实践。研讨会的标题是“利用建模方法支持仿制产品开发”(15)。
研讨会展示了 Tsakalozou 等人提出的所有仿制药 MIE 方法的监管可接受性的提高。更具体地说，针对 Wu 等人总结的口服剂型。以及 Walenga 等人(17-19)讨论的局部作用药物产品。这些研讨会报告讨论了监管框架以及计算机工具和方法的开发如何促进复杂仿制药的开发。先进数据分析工具的应用（例如多变量分析、人工智能/机器学习 (AI/ML)）以及 Gong 等人(20) 总结的如何使用这些工具支持复杂仿制药的开发并提高监管审评期间科学评价的效率和一致性。FDA、学术界和制药行业的代表深入讨论了 MMF 的潜在类型和 MMF 案例研究，强调了 Fang 等人(21)总结的模型可重用性、简化监管申报以及增强监管审评与 MMF 框架一致性的优势。
此次研讨会极大地加强了行业、学术界和 FDA 之间的沟通和协调。尽管研讨会与会者指出了在监管决策中实施 QMM 所面临的挑战，但为开发最佳实践奠定了基础，以验证其是否达到预期目的，并将其应用于支持非复杂和复杂仿制药的替代 BE 评估。研讨会的成果将用于促进 QMM 方法的应用，并制定将此类方法纳入仿制药开发计划和监管申报的最佳实践。
作为仿制药开发和监管申请中不断发展的方法，建模和模拟方法有可能克服当前开发复杂仿制药或具有复杂问题的仿制药所面临的挑战，并最大限度地减少人体试验的负担。随着 MIE 方法和 MMF 框架的使用，监管申报中建模和模拟的可接受性预计会提高。来自监管机构、仿制药行业、顾问、学术界和其它建模和模拟领域的专家致力于不断改进 MIE 实践和法规。
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撰稿人 | 识林-椒
责任编辑 | 邵丽竹
审核人 | 何发
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