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.     

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.     

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。     

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.     

China’s Choice of Analytical Models for Its Anti-Monopoly Law

Modern analytical models for anti-monopoly laws are a core element of the application of those laws. Since the Anti-Monopoly Law of the People’s Republic of China was promulgated in 2008, law enforcement and judicial authorities have applied different analytical models, leading to divergent legal and regulatory outcomes as similar cases receive different verdicts. To select a suitable analytical model for China’s Anti-Monopoly Law, we need to consider the possible contribution of both economic analysis and legal formalism and to learn from the mature systems and experience of foreign countries. It is also necessary to take into account such binding constraints as the current composition of China’s anti-monopoly legal system, the ability of implementing agencies and the supply of economic analysis, in order to ensure complementarity between the analytical model chosen and the complexity of economic analysis and between the professionalism of implementing agencies and the cost of compliance for participants in economic activities. In terms of institutional design, the models should provide a considered explanation of the legislative aims of the law’s provisions. It is necessary, therefore, to establish a processing model of behavioral classification that is based on China’s national conditions, applies analytical models using normative comprehensive analysis, makes use of the distribution rule of burden of proof, improves supporting systems related to analytical models and enhances the ability of public authorities to implement the law.     

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。     

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。     

社会转型与观念变迁--以“道德缺失”为中心的考察

尽管“道德缺失”是转型期中国一个不容忽视的社会问题，但当代的“道德缺失”现象并非严重到了危机阶段，中国古代也不是“道德天堂”。今天的道德困境可以归因于社会环境的巨大变化。这种问题的解决，需依靠有效的维护机制作为保障。落实到根本，还是要大力发展经济，建设市民社会。     

先秦的“法治”思想和实践考量

先秦法家在与儒家“礼治”的争论中提出“法治”思想,并与战国时期富国强兵的国家策略结合,变法图存的“法治”实践此起彼伏。其中最为成功的是秦国的商鞅变法,秦国由此迅速崛起并最终吞并六国,建立起统一的封建国家。秦帝国的建立是“法治”思想和实践的里程碑,大秦将集权专制和“法治”相互糅合,将法家重刑思想发展到极端,走向了崇尚暴力和滥刑滥杀的野蛮恐怖境地,导致天下怨叛,秦王朝二世而亡,君权至上最终将法治引向了集权专制的死胡同。     

传统农业乡镇城镇化的实践逻辑--以山东省平阴县孝直镇为例

随着城镇化进程不断加快，城镇功能和城市文明向农村地区的扩散已成为一种必然。对于传统农业地区，城镇化的关键在于立足自身资源禀赋，对城镇化的路径和推进机制做出切合实际的选择。在这方面，山东省平阴县孝直镇借助新型农村社区建设和农业现代化推进新型城镇化的模式为研究分析此类问题提供了一个可资借鉴的案例。