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.     

A Graphical Tool for Interpreting Regression Coefficients of Trinomial Logit Models

Multinomial logit (also termed multi-logit) models permit the analysis of the statistical relation between a categorical response variable and a set of explicative variables (called covariates or regressors). Although multinomial logit is widely used in both the social and economic sciences, the interpretation of regression coefficients may be tricky, as the effect of covariates on the probability distribution of the response variable is nonconstant and difficult to quantify. The ternary plots illustrated in this article aim at facilitating the interpretation of regression coefficients and permit the effect of covariates (either singularly or jointly considered) on the probability distribution of the dependent variable to be quantified. Ternary plots can be drawn both for ordered and for unordered categorical dependent variables, when the number of possible outcomes equals three (trinomial response variable); these plots allow not only to represent the covariate effects over the whole parameter space of the dependent variable but also to compare the covariate effects of any given individual profile. The method is illustrated and discussed through analysis of a dataset concerning the transition of master’s graduates of the University of Trento (Italy) from university to employment.     

The Eurasian Economic Union: Development Prospects and Possible Obstacles

This article analyzes the development prospects and problems for the Eurasian Economic Union (EAEU). It examines issues of integration within the EAEU, as well as interactions with other countries, both CIS (Commonwealth of Independent States) and non-CIS. The main problem of integration within the EAEU is the dominance of redistributive motives over productive ones. This article assesses the extent of Russian oil and gas transfers to EAEU partners and the impact of tax maneuvers on their size. It shows that the creation of mechanisms for redistributing profits within the EAEU will allow a positive economic effect to materialize from free trade agreements with non-CIS countries. The article assesses the risks for the EAEU related to Russia’s introduction of a unilateral ban on food imports from countries on the sanctions list and to the possible establishment of tariffs on trade with Ukraine.     

Risk Modeling of Interdependent Complex Systems of Systems: Theory and Practice

The emergence of the complexity characterizing our systems of systems (SoS) requires a reevaluation of the way we model, assess, manage, communicate, and analyze the risk thereto. Current models for risk analysis of emergent complex SoS are insufficient because too often they rely on the same risk functions and models used for single systems. These models commonly fail to incorporate the complexity derived from the networks of interdependencies and interconnectedness (I–I) characterizing SoS. There is a need to reevaluate currently practiced risk analysis to respond to this reality by examining, and thus comprehending, what makes emergent SoS complex. The key to evaluating the risk to SoS lies in understanding the genesis of characterizing I–I of systems manifested through shared states and other essential entities within and among the systems that constitute SoS. The term “essential entities” includes shared decisions, resources, functions, policies, decisionmakers, stakeholders, organizational setups, and others. This undertaking can be accomplished by building on state‐space theory, which is fundamental to systems engineering and process control. This article presents a theoretical and analytical framework for modeling the risk to SoS with two case studies performed with the MITRE Corporation and demonstrates the pivotal contributions made by shared states and other essential entities to modeling and analysis of the risk to complex SoS. A third case study highlights the multifarious representations of SoS, which require harmonizing the risk analysis process currently applied to single systems when applied to complex SoS.     

朱熹和孟子解读舜之“怨慕”的不同逻辑

对于舜之“怨慕”,朱熹作出了不同于孟子的解读。这是基于心学、理学内在逻辑的不同。孟子作为私学之儒,和孔子一样,是主张士君子的阳刚人格的,并且从性向善的人性论出发,协调义与利、公与私的关系,而以君臣父子关系都属对待关系;依此,将舜之“怨慕”解读为舜对父母的既怨又慕。朱熹则作为官学之儒,以所谓“气质之性”协调理学先驱荀子的性向恶论,以二歧化思维把天地之性、天理绝对化,以公去私,视君臣父子关系则为下对上的绝对服从关系;依此解读,舜之“怨”只能是自怨。     

影子银行、地方政府债务及金融发展动态关系研究——基于省级面板VAR模型

基于2004—2017年中国省级面板数据,运用面板向量自回归(PVAR)模型,使用系统GMM估计、脉冲响应函数、方差分解以及格兰杰因果关系检验等方法分析了影子银行、地方政府债务及金融发展之间的动态关系.结果表明:影子银行、地方政府债务与金融发展水平三者之间存在动态耦合关系.在地方政府融资能力受到约束的情况下,影子银行为地方政府提供了多元的融资方式,在增加政府融资能力的同时提升了政府债务水平;而地方政府债务需求显著推动了影子银行规模的快速发展.同时,影子银行过度扩张危害了金融市场的健康发展,降低金融发展水平,继而使地方政府的融资渠道受到约束.但金融发展并不能有效约束影子银行规模,原因在于,政府融资需求是影子银行的主要动力,若不能控制地方政府的借贷行为则无法从源头解决问题.监管机构在去杠杆的过程中,应该综合考虑影子银行与地方政府债务、金融发展之间的动态关系,如此才能够实现预期的政策效果.     

A Bayesian Analysis of Abundance,Trend, and Population Viability for Harbor Seals in Iliamna Lake,Alaska

Harbor seals in Iliamna Lake, Alaska, are a small, isolated population, and one of only two freshwater populations of harbor seals in the world, yet little is known about their abundance or risk for extinction. Bayesian hierarchical models were used to estimate abundance and trend of this population. Observational models were developed from aerial survey and harvest data, and they included effects for time of year and time of day on survey counts. Underlying models of abundance and trend were based on a Leslie matrix model that used prior information on vital rates from the literature. We developed three scenarios for variability in the priors and used them as part of a sensitivity analysis. The models were fitted using Markov chain Monte Carlo methods. The population production rate implied by the vital rate estimates was about 5% per year, very similar to the average annual harvest rate. After a period of growth in the 1980s, the population appears to be relatively stable at around 400 individuals. A population viability analysis assessing the risk of quasi‐extinction, defined as any reduction to 50 animals or below in the next 100 years, ranged from 1% to 3%, depending on the prior scenario. Although this is moderately low risk, it does not include genetic or catastrophic environmental events, which may have occurred to the population in the past, so our results should be applied cautiously.     

需求率受推广努力水平影响的新能源汽车租赁系统协调契约

考虑由新能源汽车租赁企业和政府组成的二级系统，在需求率为随机且与推广努力水平相关的市场环境下，建立了新能源汽车租赁企业和政府之间的博弈模型，探讨了分散决策、集中决策、收益共享与成本共担契约下的最优车队配置和推广努力水平，并对三种情形下的最优决策进行了比较和分析。研究结果表明：在分散决策情况下无法实现系统协调，通过引入成本共担与收益共享组合契约，当契约参数满足一定条件时，该组合契约模型不仅可以实现系统协调而且可以使系统成员达到帕累托改进。最后通过算例分析，验证了模型了可靠性和有效性。     

伸展构造背景下倾角资料的构造解释

系统总结了在伸展构造背景下，导致反映构造特征的地层倾角模式复杂化的多种因素。沉积相的不同、岩性变化、井眼状况和测井作业时间等多种因素都可能使地层倾角资料复杂化。进一步指出在拉张盆地中，进行倾角资料的构造解释，必须了解其构造样式的多样性和复杂性，解释存在的多解性。重点解剖了铲式断层在横剖面情况下，对于不同构造位置下的倾角模式。详细分析了一个倾角模式对应多种构造样式的倾角构造解释实例。倾角资料的构造解释应是综合解释，既要综合井筒的相关地质资料，又要综合测井与地质知识，还必须考虑综合地震资料。     

Tests for time series of counts based on the probability-generating function

We propose testing procedures for the hypothesis that a given set of discrete observations may be formulated as a particular time series of counts with a specific conditional law. The new test statistics incorporate the empirical probability-generating function computed from the observations. Special emphasis is given to the popular models of integer autoregression and Poisson autoregression. The asymptotic properties of the proposed test statistics are studied under the null hypothesis as well as under alternatives. A Monte Carlo power study on bootstrap versions of the new methods is included as well as real-data examples.