CLINICAL TRIAL METHODOLOGY IN SCHIZOPHRENIA

我们提出的研究计划涉及发展 临床试验方法，包括新的实验设计和 统计分析方法，用于抗精神病药物的研究 用于治疗精神分裂症的药物：（1）虽然 “灵活剂量”或“医生选择”设计反映了临床 实践并适应患者的个体差异， 受到严厉批评。我们将开展统计生物测定 模型估计相对效力，同时考虑到 安慰剂应答者和难治性患者以及剂量 信息. (2)当检测与标准品的相对效价 对于所有的行为和副作用变量都不一样， 将开发允许识别亚组的方法， 相对效价的变量 常数(3)通常，评级中项目的类别 具有通过任意分配量化隐式等级顺序的量表 将整数值均匀分布到类别中。我们将开发 根据剂量进行标量分配的方法 来自试验本身的响应数据。(4)交叉设计， 有效的，并可分析是否结转效应 目前将开发，以便一个相对较小的样本量 将有足够的能力对比治疗。(5)模型来 分析多变量观察结果， 通过同时分析确定两种治疗的生物等效性 在所有的药物和/或代谢物的血清水平 将制定观察时间点。(6)我们将发展 评估合并优点的统计方法 治疗零假设的性质导致了 在分析组合研究中存在相当大的混乱 疗法这些通常涉及HO形式的假设： 组合不优于A或组合：不优于B。 (7)协商中出现的其他统计问题， 将考虑与临床研究人员合作。

The research program we propose concerns the development of clinical trial methodology, including new experimental designs and methods of statistical analysis, for the study of antipsychotic drugs used in the treatment of schizophrenia: (1) Although "flexible dose" or "doctor's choice" designs mirror clinical practice and accommodate individual patient variations they have been seriously criticized. We will develop statistical bioassay models that estimate relative potency while taking into account placebo responders and refractory.patients as well as the dosage information. (2) When the relative potency of a test to a standard is not the same for all behavioral and side effect variables we will develop methods that permit the identification of subgroups of the variables with respect to which relative potency is constant. (3) Generally, the categories within items in a rating scale have implicit rank order quantified by arbitrarily assigning equispaced integer values to the categories. We will develop methods whereby scalar assignments are made on the basis of dose response data from the trial itself. (4) Crossover designs that are efficient and are analyzable whether or not carryover effects are present will be developed so that a relatively small sample size will have adequate power to contrast therapies. (5) Models to analyze multivariate observations for evaluation of the bioequivalence of two treatments through the simultaneous analysis of serum levels of drug and/or metabolites at all of the observation time points will be developed. (6) We shall develop statistical methodology for assessing the merits of combination therapies. The nature of the null hypothesis has led to considerable confusion in the analysis of studies of combination therapy. These usually involve hypotheses of the form HO: combinations not better than A or combination: not better than B. (7) Other statistical problems that arise in consultation and collaborating with clinical researchers will be considered.