Ⅱ期临床剂量反应试验中基于不确定参数模型的剂量估计研究

摘要

Objective We introduces a method MCP-Mod ( Multiple Comparisons and Modeling) ,which can estimate the dose of dose-response studies. Based on the application conditions and analysis method of MCP-Mod,we explore the power to detect a dose-response relationship and the accuracy of model selection and target dose estimation using simulation data. Meth-ods Firstly,the research introduces the fundamental theory and application condition of the MCP-Mod method. Then,simulate data is set to evaluate the power to detect a dose-response relationship and the accuracy of model selection and target dose esti-mation. Results In the simulation,in the aspect of the power to detect a dose-response relationship:6 groups of constant model have an approximately power 0f 0. 05 to detect the dose response relationship,which was similar toα=0. 05. For other parameter models,the larger the sample size,the higher power to detect a dose response relationship. In the aspect of accuracy of model selection:the larger the sample size,the higher degree to identify various models. In the candidate models,exponential model and quadratic model have a high degree of identification,but linear model and logarithmic function have a low degree of identifica-tion. In terms of the accuracy of the dose estimation:M^ED1 underestimates the target dose,M^ED3 overestimates the target dose, and M^ED2 is close to the target dose,so we think M^ED2 has betterconsistency. Conclusion MCP-Mod method not only have a high power to detect a dose response relationship,but also have a high precision to select right model and estimate target dose,so MCP-Mod method is useful for phase II clinical studies,when one is interested in testing the presence of dose-response and in selecting the adequate dose( s) for the confirmatory phase of development.%目的 本研究旨在介绍一种临床剂量反应试验中进行剂量估计的方法MCP-Mod(multiple comparisons and modeling),在此基础上,通过模拟研究探讨MCP-Mod法的表现.方法 本研究首先介绍了MCP-Mod法的应用条件以及基本原理,然后通过模拟研究产生模拟数据,评价MCP-Mod法在确定药物有效的检验效能、模型选择的正确率以及剂量估计的精确度三方面的表现.结果 模拟研究中,在确定药物有效的检验效能方面:6组样本量下常数函数模型检验剂量反应关系成立的效能近似于检验水准;而其他参数模型随着样本量增大则该方法检验剂量反应关系的效能越高.在模型选择正确率方面:各种参数模型的识别度随着样本量增大而增大;在6种候选模型数据中指数模型和二次项模型的识别度较高,而线性函数和对数线性函数的识别度较低.在剂量估计的精确度方面:M^ED1估计量低估了目标剂量,而M^ED3估计量则高估了目标剂量,M^ED2与目标剂量更接近,因此我们认为M^ED2估计量的一致性更好.结论 MCP-Mod法不仅对是否能建立剂量反应关系有较高的检验效能,而且模型选择的正确率以及剂量估计的精确度也比较高,因此该方法对于解决II期临床试验中检验剂量反应关系是否成立并且选择一个合适的剂量用于后续验证性研究的问题是非常有效的.