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使用具有信息性缺失的纵向模型对抑郁症试验中的安慰剂反应进行建模。

Modelling placebo response in depression trials using a longitudinal model with informative dropout.

作者信息

Gomeni Roberto, Lavergne Agnes, Merlo-Pich Emilio

机构信息

Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Verona, Italy.

出版信息

Eur J Pharm Sci. 2009 Jan 31;36(1):4-10. doi: 10.1016/j.ejps.2008.10.025. Epub 2008 Nov 8.

Abstract

Dropouts are common events in longitudinal studies in depression. Ignoring missing information may lead to biased and inconsistent assessment of study results. A non-linear model was recently developed to describe the time-course of HAMD-17 clinical score in the placebo arms of antidepressant clinical trials. In this paper we complemented this model by introducing an informative dropout component to jointly estimate HAMD-17 time-course and dropout mechanism. The aims of this work were to: (a) characterise typical placebo response in depression trials in presence of dropouts, (b) explore which dropout mechanism better describe the time-varying probability of a subject to dropout from the trial, and (c) define a framework for the development of clinical trial simulation in depression. A meta-analytic approach was used on placebo data collected in 6 clinical trials including 695 subjects suffering from Major Depressive Disorders. Alternative hypotheses for "missingness" were evaluated using different hazard models. The "Missing Not At Random" performed statistically (p<0.01) better than "Missing At Random", that in turn performed better (p<0.01) than "Missing Completely At Random" model. This finding provided new insights on the validity of the analyses currently used in many longitudinal clinical trials to support the registration of a new medicinal product.

摘要

在抑郁症纵向研究中,失访是常见现象。忽略缺失信息可能导致对研究结果的评估出现偏差且不一致。最近开发了一种非线性模型来描述抗抑郁药物临床试验安慰剂组中汉密尔顿抑郁量表-17(HAMD-17)临床评分的时间进程。在本文中,我们通过引入一个信息性失访成分来补充该模型,以联合估计HAMD-17的时间进程和失访机制。这项工作的目的是:(a)在存在失访的情况下描述抑郁症试验中的典型安慰剂反应,(b)探索哪种失访机制能更好地描述受试者在试验中失访的时变概率,以及(c)定义一个抑郁症临床试验模拟开发的框架。对6项临床试验收集的安慰剂数据采用荟萃分析方法,这些试验包括695名患有重度抑郁症的受试者。使用不同的风险模型评估“缺失”的替代假设。“非随机缺失”在统计学上(p<0.01)比“随机缺失”表现更好,而“随机缺失”又比“完全随机缺失”模型表现更好(p<0.01)。这一发现为目前许多纵向临床试验中用于支持新药注册的分析的有效性提供了新的见解。

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