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.     

从《了凡四训》到《训儿俗说》——关于袁了凡及其家风家训的思想史考察

袁了凡（袁黄）以其《了凡四训》闻名于世，该书亦被当作训子家书。其实，了凡所作家训并非《了凡四训》，而是《训儿俗说》。作为王龙溪（王畿）的及门弟子，了凡在思想上是阳明后学的一分子，其人生轨迹属于典型的儒家士大夫，其日常修持及著述呈现三教汇通的思想特色。了凡家风淳朴，家学深厚，以儒为宗，兼收并蓄，强调道德主义，注重积德行善，具有出世情怀，对其人格产生深刻影响。     

体验型产品消费行为的羊群效应及机理研究——基于电影行业消费行为的实证解释

互联网环境下消费者购买体验型产品时对网络信息的依赖性很大。因此，研究社交媒体影响下体验型产品的消费者决策选择行为具有现实意义。本文以电影行业的票房偏离及消费跟风现象为切入点，探究体验型产品的羊群效应并对其产生的内在机理进行解释。采集艺恩资讯的票房数据以及豆瓣的电影基本信息及影评等数据作为研究样本，从消费者"羊群行为"视角分析其对电影票房的影响。研究发现：在控制了质量等内生性影响之后，消费者羊群效应依然存在；产品特征信息对羊群效应起到了调节作用，从而形成理性跟随；采用预期差异模型可以解释消费者实现理性跟随的过程。研究结论对于电影行业宏观政策制定及对体验型产品合理进行营销推广提供了理论基础与实证依据。     

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。     

基于信号博弈的卖方欺诈行为分析

本文主要基于信号博弈的卖方欺诈行为进行研究，假设拍卖中可能存在欺诈型和诚实型两种卖家，其中欺诈行为有概率发生在第二价格拍卖中：欺诈型卖方冒充竞拍者递交仅次于最高价的报价从而获得额外收益。两种卖家根据各自效用选择拍卖形式：第一价格或者第二价格。而竞买者将卖者的选择作为信号，更新对卖方类型的判断，然后制定报价策略。这是一个买卖方信号交叉影响的过程。考虑到拍卖过程中买方价值相关性，本文在建立模型中参考了关联价值原理。针对该模型进行分析，得出了不同情况下的买卖方策略，并且研究了买方报价、买方判断、卖方收益三者之间的关系。文中利用贝叶斯公式对双方的策略选择问题进行预测，与单纯的概率分布方法相比，更具实践价值。     

‘Colour-evasiveness’ and racism without race: the disablement of asylum-seeking children at the edge of fortress Europe

This article explores discriminatory discourses articulated by Italian professionals operating in educational, health and social services for refugees in Rome, in relation to the educational and social inclusion of unaccompanied asylum-seeking and refugee children. It locates such narratives within the historical ‘concealment and invisibilisation of race and racism’ that have characterised Italy particularly since the end of the Second World War, while showing how they legitimate contemporary processes of disablement and over-representation of forced migrant children in the category of Special Educational Needs. A theoretical framework influenced by Dis/ability Critical Race Studies, Italian postcolonial studies, and Judith Butler’s notions of subjectivation and performative politics is used to discuss how a ‘colour-evasive’ racial ideology has seeped into various institutions in Italian society, and importantly into education policies and practices.     

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。     

External knowledge search,absorptive capacity and radical innovation in high-technology firms

Open innovation and absorptive capacity are two concepts based on the idea that companies can leverage the knowledge generated externally to improve their innovation performance. The aim of this paper is to analyse the joint effect of open innovation and absorptive capacity on a firm's radical innovation. Open innovation is expressed in terms of external search breadth and depth strategies and absorptive capacity is described by distinguishing between potential and realized absorptive capacity. In order to test our hypotheses, we carried out empirical research in firms operating in high-technology industries. The results indicate that internal routines and processes for absorbing external knowledge help explain radical innovation as they show a significant effect of potential and realized absorptive capacity. Also, there is a moderating effect of absorptive capacity on open innovation. Specifically, potential absorptive capacity exerts a positive effect on the relationship between external search breadth and depth and radical innovation. Realized absorptive capacity moderates the influence of external search breadth. These findings confirm the complementary nature of absorptive capacity and open innovation search strategies on radical innovation.     

Who Should Pay for Interdependent Risk? Policy Implications for Security Interdependence Among Airports

We study interdependent risks in security, and shed light on the economic and policy implications of increasing security interdependence in presence of reactive attackers. We investigate the impact of potential public policy arrangements on the security of a group of interdependent organizations, namely, airports. Focusing on security expenditures and costs to society, as assessed by a social planner, to individual airports and to attackers, we first develop a game-theoretic framework, and derive explicit Nash equilibrium and socially optimal solutions in the airports network. We then conduct numerical experiments mirroring real-world cyber scenarios, to assess how a change in interdependence impact the airports' security expenditures, the overall expected costs to society, and the fairness of security financing. Our study provides insights on the economic and policy implications for the United States, Europe, and Asia.