Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, 1 Ironbridge Road, Uxbridge, UK.
Drug Discov Today. 2018 Apr;23(4):776-787. doi: 10.1016/j.drudis.2018.01.045. Epub 2018 Feb 3.
Clinical proof-of-concept trials crucially inform major resource deployment decisions. This paper discusses several mechanisms for enhancing their rigour and efficiency. The importance of careful consideration when using a surrogate endpoint is illustrated; situational effectiveness of run-in patient enrichment is explored; a versatile tool is introduced to ensure a strong pharmacological underpinning; the benefits of dose-titration are revealed by simulation; and the importance of adequately scheduled observations is shown. The general process of model-based trial design and analysis is described and several examples demonstrate the value in historical data, simulation-guided design, model-based analysis and trial adaptation informed by interim analysis.
临床概念验证试验至关重要地为重大资源部署决策提供信息。本文讨论了几种提高其严谨性和效率的机制。讨论了在使用替代终点时需要仔细考虑的重要性；探讨了患者入组富集的实际效果；引入了一种通用工具来确保强有力的药理学基础；通过模拟揭示了剂量滴定的好处；并展示了充分安排观察的重要性。描述了基于模型的试验设计和分析的一般过程，并且几个示例说明了历史数据、模拟引导设计、基于模型的分析以及基于中期分析的试验调整中的价值。
