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传统的药物临床研究方案设计大多依赖于经验,缺乏统计学等方面的客观评价,我们提出一种方法,分析参数不确定性对药物临床研究的计算机模拟(Clinical trail simulation,CTS)中效能预测质量的影响及其重要性的评估,为方案的制定提供更为科学和客观的依据。论文基于药动-药效(pharmacokinetics-pharmacodynamics,PK-PD)模型,运用CTS技术,分别给出了仿真模型、处理效应模型和给定PK-PD的临床试验效能模型的建立方法及原理,并讨论了模型的不确定性。对仿真结果,采用方差分析的敏感度分析法并结合η2统计,探讨模型参数的不确定性对CTS模拟结果的影响。经实例仿真,得到相应效能预测值的标准差和其第五百分位数。通过分析计算得到的敏感指数,反映了输入参数的重要性与不重要性,简单直观地表示了参数不确定性对预测结果影响的大小。经仿真试验证明:该方法在一定程度上是有用并且有效的,可为临床试验方案的制定提供科学和客观的依据。
Traditional drug clinical research programs mostly rely on objective experience, lack of statistics and other aspects of objective evaluation. We propose a method to analyze parameter uncertainty in clinical trail simulation (Clinical trail simulation, CTS) performance prediction quality The impact and importance of the assessment, the formulation of programs to provide a more scientific and objective basis. Based on the pharmacokinetics-pharmacodynamics (PK-PD) model and the CTS technique, this paper presents the methods and principles for establishing a simulation model, a treatment effect model and a clinical trial efficacy model for a given PK-PD Discuss the model’s uncertainty. The simulation results were analyzed by variance analysis sensitivity analysis combined with η2 statistics to explore the impact of model parameters uncertainty on CTS simulation results. The simulation results show that the standard deviation of the corresponding performance prediction and its fifth percentile. By analyzing and calculating the sensitive index, it reflects the importance and unimportance of the input parameter, and simply and intuitively shows the influence of parameter uncertainty on the prediction result. The simulation test proves that this method is useful and effective to a certain extent and can provide a scientific and objective basis for the formulation of clinical trials.