Inference and Decision Making for 21st-Century Drug Development and Approval

ABSTRACT

The cost and time of pharmaceutical drug development continue to grow at rates that many say are unsustainable. These trends have enormous impact on what treatments get to patients, when they get them and how they are used. The statistical framework for supporting decisions in regulated clinical development of new medicines has followed a traditional path of frequentist methodology. Trials using hypothesis tests of “no treatment effect” are done routinely, and the p-value < 0.05 is often the determinant of what constitutes a “successful” trial. Many drugs fail in clinical development, adding to the cost of new medicines, and some evidence points blame at the deficiencies of the frequentist paradigm. An unknown number effective medicines may have been abandoned because trials were declared “unsuccessful” due to a p-value exceeding 0.05. Recently, the Bayesian paradigm has shown utility in the clinical drug development process for its probability-based inference. We argue for a Bayesian approach that employs data from other trials as a “prior” for Phase 3 trials so that synthesized evidence across trials can be utilized to compute probability statements that are valuable for understanding the magnitude of treatment effect. Such a Bayesian paradigm provides a promising framework for improving statistical inference and regulatory decision making.     

我国民事审级制度的改革与完善——比较法学视角下的分析

比较分析中国、日本、德国、美国、法国及我国台湾地区的民事审级制度可以看出我国审级制度中存在的弊端。实际上 ,实行有条件的三审终审制更具合理性。为此 ,我国原有的两审终审制必须加以改革 ,那就是实行以两审终审为原则、以三审终审为例外的民事审级制度。     

专业观众展览会参观动机研究——来自东莞的证据

以展览业发达的东莞为研究样地,利用因素分析与聚类研究相结合的综合定量方法,对专业观众的观展动机进行综合评估及分类研究。研究表明,专业观众的非购买动机甚过购买动机,他们观展动机的四个维度因子依次为:搜集信息、建立市场关系、考察奖励、采购行为。本研究还发现专业观众的观展动机分为目标模糊型、信息搜集导向型、目标多维明确型三种类型。     

Asymptotic bias in the linear mixed effects model under non-ignorable missing data mechanisms

Summary.  In longitudinal studies, missingness of data is often an unavoidable problem. Estimators from the linear mixed effects model assume that missing data are missing at random. However, estimators are biased when this assumption is not met. In the paper, theoretical results for the asymptotic bias are established under non-ignorable drop-out, drop-in and other missing data patterns. The asymptotic bias is large when the drop-out subjects have only one or no observation, especially for slope-related parameters of the linear mixed effects model. In the drop-in case, intercept-related parameter estimators show substantial asymptotic bias when subjects enter late in the study. Eight other missing data patterns are considered and these produce asymptotic biases of a variety of magnitudes.     

追求自我解放 寻觅自由人生--劳伦斯笔下的理想女性厄秀拉

劳伦斯笔下的叛逆女性厄秀拉是劳伦斯塑造的最理想的人物.她为人正直,追求真理与不合理的社会进行奋力抗争,虽屡遭失败,仍不放弃追求,最后在大自然和周游世界中获得了自由.厄秀拉的这种追求是作家拯救西方人摆脱精神危机的有价值的尝试.     

从部门本位回归到基本理性——对检察机关职权配置的思考

目前,我国法学界对检察机关职权配置问题存在着激烈的争论。争论的主要问题有三个。其中,检察机关是否有侦查权是个伪问题,其本质是检察机关行使侦查权时由谁来监督;检察官不是“中立及超然”的司法人员,不应当有对强制措施的批准权;检察官不应当以居高临下的“法律监督者”的身份监督审判程序,而是应当通过程序动议权和上诉权监督审判程序。目前主张维持检察机关职权现状的学者,有严重的部门本位主义,检察权改革应当摒弃部门本位主义。     

审判委员会制度的理论架构

对审委会制度的改革,有人主张废除审委会制度为其核心内容;也有人主张目前应在保留的基础上予以改革和完善。废改之争,焦点是研究方法之争。主废和主改各有其弊,应通过立法程序按照“不审不判”的思路重塑审委会制度,明确审委会审判组织的地位,赋予其合议、陪审、咨询、调研四大职能及案件实体决定权和指导权,并建立和完善相应的程序。     

Issues in applying recent CPMP ‘Points to Consider’ and FDA guidance documents with biostatistical implications

The International Conference on Harmonisation guideline ‘Statistical Principles for Clinical Trials’ was adopted by the Committee for Proprietary Medicinal Products (CPMP) in March 1998, and consequently is operational in Europe. Since then more detailed guidance on selected topics has been issued by the CPMP in the form of ‘Points to Consider’ documents. The intent of these was to give guidance particularly to non‐statistical reviewers within regulatory authorities, although of course they also provide a good source of information for pharmaceutical industry statisticians. In addition, the Food and Drug Administration has recently issued a draft guideline on data monitoring committees. In November 2002 a one‐day discussion forum was held in London by Statisticians in the Pharmaceutical Industry (PSI). The aim of the meeting was to discuss how statisticians were responding to some of the issues covered in these new guidelines, and to document consensus views where they existed. The forum was attended by industry, academic and regulatory statisticians. This paper outlines the questions raised, resulting discussions and consensus views reached. It is clear from the guidelines and discussions at the workshop that the statistical analysis strategy must be planned during the design phase of a clinical trial and carefully documented. Once the study is complete the analysis strategy should be thoughtfully executed and the findings reported. Copyright © 2003 John Wiley & Sons, Ltd.     

A simple estimator for a shared frailty regression model

Summary. We propose a simple estimation procedure for a proportional hazards frailty regression model for clustered survival data in which the dependence is generated by a positive stable distribution. Inferences for the frailty parameter can be obtained by using output from Cox regression analyses. The computational burden is substantially less than that of the other approaches to estimation. The large sample behaviour of the estimator is studied and simulations show that the approximations are appropriate for use with realistic sample sizes. The methods are motivated by studies of familial associations in the natural history of diseases. Their practical utility is illustrated with sib pair data from Beaver Dam, Wisconsin.     

A modified false discovery rate multiple-comparisons procedure for discrete data, applied to human immunodeficiency virus genetics

Summary.  To help to design vaccines for acquired immune deficiency syndrome that protect broadly against many genetic variants of the human immunodeficiency virus, the mutation rates at 118 positions in HIV amino-acid sequences of subtype C versus those of subtype B were compared. The false discovery rate (FDR) multiple-comparisons procedure can be used to determine statistical significance. When the test statistics have discrete distributions, the FDR procedure can be made more powerful by a simple modification. The paper develops a modified FDR procedure for discrete data and applies it to the human immunodeficiency virus data. The new procedure detects 15 positions with significantly different mutation rates compared with 11 that are detected by the original FDR method. Simulations delineate conditions under which the modified FDR procedure confers large gains in power over the original technique. In general FDR adjustment methods can be improved for discrete data by incorporating the modification proposed.