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.     

Inference and optimal design of multiple constant-stress testing for generalized half-normal distribution under type-II progressive censoring

The generalized half-normal (GHN) distribution and progressive type-II censoring are considered in this article for studying some statistical inferences of constant-stress accelerated life testing. The EM algorithm is considered to calculate the maximum likelihood estimates. Fisher information matrix is formed depending on the missing information law and it is utilized for structuring the asymptomatic confidence intervals. Further, interval estimation is discussed through bootstrap intervals. The Tierney and Kadane method, importance sampling procedure and Metropolis-Hastings algorithm are utilized to compute Bayesian estimates. Furthermore, predictive estimates for censored data and the related prediction intervals are obtained. We consider three optimality criteria to find out the optimal stress level. A real data set is used to illustrate the importance of GHN distribution as an alternative lifetime model for well-known distributions. Finally, a simulation study is provided with discussion.     

Hierarchical Bayesian Modeling of Post-Earthquake Ignition Probabilities Considering Inter-Earthquake Heterogeneity

Post-earthquake fires are high-consequence events with extensive damage potential. They are also low-frequency events, so their nature remains underinvestigated. One difficulty in modeling post-earthquake ignition probabilities is reducing the model uncertainty attributed to the scarce source data. The data scarcity problem has been resolved by pooling the data indiscriminately collected from multiple earthquakes. However, this approach neglects the inter-earthquake heterogeneity in the regional and seasonal characteristics, which is indispensable for risk assessment of future post-earthquake fires. Thus, the present study analyzes the post-earthquake ignition probabilities of five major earthquakes in Japan from 1995 to 2016 (1995 Kobe, 2003 Tokachi-oki, 2004 Niigata–Chuetsu, 2011 Tohoku, and 2016 Kumamoto earthquakes) by a hierarchical Bayesian approach. As the ignition causes of earthquakes share a certain commonality, common prior distributions were assigned to the parameters, and samples were drawn from the target posterior distribution of the parameters by a Markov chain Monte Carlo simulation. The results of the hierarchical model were comparatively analyzed with those of pooled and independent models. Although the pooled and hierarchical models were both robust in comparison with the independent model, the pooled model underestimated the ignition probabilities of earthquakes with few data samples. Among the tested models, the hierarchical model was least affected by the source-to-source variability in the data. The heterogeneity of post-earthquake ignitions with different regional and seasonal characteristics has long been desired in the modeling of post-earthquake ignition probabilities but has not been properly considered in the existing approaches. The presented hierarchical Bayesian approach provides a systematic and rational framework to effectively cope with this problem, which consequently enhances the statistical reliability and stability of estimating post-earthquake ignition probabilities.     

Multiparameter evidence synthesis in epidemiology and medical decision-making: current approaches

Summary.  Alongside the development of meta-analysis as a tool for summarizing research literature, there is renewed interest in broader forms of quantitative synthesis that are aimed at combining evidence from different study designs or evidence on multiple parameters. These have been proposed under various headings: the confidence profile method, cross-design synthesis, hierarchical models and generalized evidence synthesis. Models that are used in health technology assessment are also referred to as representing a synthesis of evidence in a mathematical structure. Here we review alternative approaches to statistical evidence synthesis, and their implications for epidemiology and medical decision-making. The methods include hierarchical models, models informed by evidence on different functions of several parameters and models incorporating both of these features. The need to check for consistency of evidence when using these powerful methods is emphasized. We develop a rationale for evidence synthesis that is based on Bayesian decision modelling and expected value of information theory, which stresses not only the need for a lack of bias in estimates of treatment effects but also a lack of bias in assessments of uncertainty. The increasing reliance of governmental bodies like the UK National Institute for Clinical Excellence on complex evidence synthesis in decision modelling is discussed.     

谈多媒体环境下的英语教学策略

依据教育学、心理学有关理论,从教学环节入手,探讨了英语教学在多媒体环境下的教学策略选择原则及相应英语教学策略,提出英语教学的整体筹划策略、信息输入策略、全息评价策略和重现巩固策略。     

Moderate Deviations for Bayes Posteriors

Let ( X_k ) k be a sequence of i.i.d. random variables taking values in a set , and consider the problem of estimating the law of X₁ in a Bayesian framework. We prove, under mild conditions on the prior, that the sequence of posterior distributions satisfies a moderate deviation principle.     

关于元评估

本文阐述了元评估工作的重要意义 ,并对元评估活动所依据的原则 (客观性、整体性　全面性、综合性 )、应遵循的程序和采用的方法 (元研究方法、系统方法、评价方法、模型方法 )作了系统论述。元评估活动将对提高各级领导决策的科学性和自觉性 ,推动社会各个领域乃至整个社会与自然界协调而持续的发展作出宝贵的贡献     

Bayesian modelling of catch in a north-west Atlantic fishery

Summary. We model daily catches of fishing boats in the Grand Bank fishing grounds. We use data on catches per species for a number of vessels collected by the European Union in the context of the Northwest Atlantic Fisheries Organization. Many variables can be thought to influence the amount caught: a number of ship characteristics (such as the size of the ship, the fishing technique used and the mesh size of the nets) are obvious candidates, but one can also consider the season or the actual location of the catch. Our database leads to 28 possible regressors (arising from six continuous variables and four categorical variables, whose 22 levels are treated separately), resulting in a set of 177 million possible linear regression models for the log-catch. Zero observations are modelled separately through a probit model. Inference is based on Bayesian model averaging, using a Markov chain Monte Carlo approach. Particular attention is paid to the prediction of catches for single and aggregated ships.     

英美法系和大陆法系刑事陪审制度功能之比较

陪审制度的功能是陪审制度得以存在和延续的理由 ,笔者首先剖析了陪审制度的沿革及其发展趋势 ;进而阐述陪审制度在两大法系中共有的功能 ;最后分别阐述英美法系和大陆法系刑事陪审制度功能     

刑事诉讼主体的法理分析--以刑事法律关系为基础

犯罪行为引起的刑事法律关系是考察刑事诉讼主体问题的真正法理基础。国家与被告人作为刑事法律关系的主体是刑事诉讼的当事人 ,被害人及其近亲属不是刑事法律关系的主体 ,故不是刑事诉讼当事人 ,只是发动、支持公法性诉讼的公民追诉人。审判权与公诉权的分立 ,本质上是国家将自身作为自己的对象 ,并在自己(裁判者 )与作为对象的自身 (当事人 )之间建立绝对区分 ,体现了作为公共权力的国家的自我反思节制。其他刑事诉讼主体均不是刑事法律关系的主体 ,按照意志关系或者是国家的代表、被告人和被害人的代理人或帮助人 ,或者是不从属于任何一方的诉讼主体。