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.     

Validation of the Australian Midwifery Standards Assessment Tool (AMSAT): A tool to assess midwifery competence

Background

There is no current validated clinical assessment tool to measure the attainment of midwifery student competence in the midwifery practice setting. The lack of a valid assessment tool has led to a proliferation of tools and inconsistency in assessment of, and feedback on student learning.

Deliberate acquisition of competence in physiological breech birth: A grounded theory study

Problem

Research suggests that the skill and experience of the attendant significantly affect the outcomes of vaginal breech births, yet practitioner experience levels are minimal within many contemporary maternity care systems.

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。     

A modified random-effect procedure for combining risk difference in sets of 2×2 tables from clinical trials

Summary Meta-analyses of sets of clinical trials often combine risk differences from several 2×2 tables according to a random-effects model. The DerSimonian-Laird random-effects procedure, widely used for estimating the populaton mean risk difference, weights the risk difference from each primary study inversely proportional to an estimate of its variance (the sum of the between-study variance and the conditional within-study variance). Because those weights are not independent of the risk differences, however, the procedure sometimes exhibits bias and unnatural behavior. The present paper proposes a modified weighting scheme that uses the unconditional within-study variance to avoid this source of bias. The modified procedure has variance closer to that available from weighting by ideal weights when such weights are known. We studied the modified procedure in extensive simulation experiments using situations whose parameters resemble those of actual studies in medical research. For comparison we also included two unbiased procedures, the unweighted mean and a sample-size-weighted mean; their relative variability depends on the extent of heterogeneity among the primary studies. An example illustrates the application of the procedures to actual data and the differences among the results. This research was supported by Grant HS 05936 from the Agency for Health Care Policy and Research to Harvard University.     

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.