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.     

Design selection for strong orthogonal arrays

Strong orthogonal arrays (SOAs) were recently introduced and studied as a class of space‐filling designs for computer experiments. An important problem that has not been addressed in the literature is that of design selection for such arrays. In this article, we conduct a systematic investigation into this problem, and we focus on the most useful SOA(n,m,4,2 + )s and SOA(n,m,4,2)s. This article first addresses the problem of design selection for SOAs of strength 2+ by examining their three‐dimensional projections. Both theoretical and computational results are presented. When SOAs of strength 2+ do not exist, we formulate a general framework for the selection of SOAs of strength 2 by looking at their two‐dimensional projections. The approach is fruitful, as it is applicable when SOAs of strength 2+ do not exist and it gives rise to them when they do. The Canadian Journal of Statistics 47: 302–314; 2019 © 2019 Statistical Society of Canada     

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.     

住宅小区景观的配套设计与绿化

当前，小区的景观配置及绿化已经成为人们选择住宅的重要条件之一。小区景观设计的细节往往是小区景观的配套设计与绿化成功的关键。住宅小区景观的配套设计与绿化是自然与人的完美协调与交融，是人的精神通过加工寄托于景物的一个过程。     

Evaluation of an intervention supporting breastfeeding among late-preterm infants during in-hospital stay

BackgroundLate-preterm infants show lower breastfeeding rates when compared with term infants. Current practice is to keep them in low-risk wards where clinical guidelines to support breastfeeding are well established for term infants but can be insufficient for late-preterm.ObjectiveThe aim of this study was to evaluate an intervention supporting breastfeeding among late-preterm infants in a maternity service in the Basque Country, Spain.MethodsThe intervention was designed to promote parents’ education and involvement, provide a multidisciplinary approach and decision-making, and avoid separation of the mother-infant dyad. A quasi-experimental study was conducted with a control (n = 212) and an intervention group (n = 161). Data was collected from clinical records from November 2012 to January 2015. Feeding rate at discharge, breast-pump use, incidence of morbidities, infant weight loss and hospital stay length were compared between the two groups.ResultsInfants in the control group were 50.7% exclusive breastfeeding, 37.8% breastfeeding, and, 11.5% formula feeding at discharge, whereas in the intervention group, frequencies were 68.4%, 25.9%, and 5.7%, respectively (p = 0.002). Mothers in the intervention group were 2.66 times more likely to use the breast-pump after almost all or all feeds and 2.09 times more likely to exclusively breastfeed at discharge. There were no significant differences in morbidities and infant weight loss between groups. Hospital stay was longer for infants who required phototherapy in the intervention group (p = 0.009).ConclusionThe intervention resulted in a higher breastfeeding rate at discharge. Interventions aimed to provide specific support among late-pretem infants in maternity services are effective.     

Modifications of sequential designs in bioequivalence trials

Bioequivalence (BE) studies are designed to show that two formulations of one drug are equivalent and they play an important role in drug development. When in a design stage, it is possible that there is a high degree of uncertainty on variability of the formulations and the actual performance of the test versus reference formulation. Therefore, an interim look may be desirable to stop the study if there is no chance of claiming BE at the end (futility), or claim BE if evidence is sufficient (efficacy), or adjust the sample size. Sequential design approaches specially for BE studies have been proposed previously in publications. We applied modification to the existing methods focusing on simplified multiplicity adjustment and futility stopping. We name our method modified sequential design for BE studies (MSDBE). Simulation results demonstrate comparable performance between MSDBE and the original published methods while MSDBE offers more transparency and better applicability. The R package MSDBE is available at https://sites.google.com/site/modsdbe/ . Copyright © 2015 John Wiley & Sons, Ltd.     

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.     

三维实体设计与工程制图课程的改革

三维实体设计是工程设计的必然趋势,设计方法的变革导致企业对人才的新需求,也给传统的工程制图课程体系带来了巨大的冲击。改革与现代生产和人才需求不相适应的教学内容,建立以三维设计为主线,以培养创新思维和创新能力为目标的工程制图新体系,是工程制图课程改革的方向。     

基于WEB的远程教学管理软件分析与设计

本论文主要讨论了基于WEB远程教学管理软件的分析与设计。首先对远程教育与传统教育进行了比较研究,确定远程教育是现代教育发展的方向;其次对开发基于WEB远程教学管理软件进行了环境分析和需求分析;最后讨论了远程教学管理软件的实现,包括软件模块结构设计和网站的总体框架。     

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.