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。     

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.     

Enoch Powell,empires, immigrants and education

2018 marks the 50th anniversary of Enoch Powell’s infamous ‘Rivers of Blood’ speech, an intervention that is still viewed as one of the most incendiary statements of the perceived decay and violence likely to follow legislation intended to assure minoritised British citizens of equal rights regardless of their ethnic origin. In this essay, Sally Tomlinson (one of Britain’s foremost multicultural theorists) reflects on Powell’s legacy and the contemporary scene where in the US, UK and across Europe, White resentment and fear is increasingly shaping ‘mainstream’ debates about nationhood, migration and education.     

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。     

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。     

Journey towards independent living: a grounded theory investigation of leaving the care of Girls & Boys Town,South Africa

The journey out of care and towards independent living is a challenge for many care-leavers. There has been little research into the social processes involved in this care-leaving journey. This paper presents the results of a grounded theory investigation into the care-leaving journeys of nine young men who had, several years previously, been in the care of Girls & Boys Town in South Africa. Working from a resilience perspective, with an ecological emphasis, four central social processes emerged that together explain the care-leaving experiences of the participants. These processes are striving for authentic belonging; networking people for goal attainment; contextualised responsiveness and building hopeful and tenacious self-confidence. These four processes are located within contextual boundaries and at the social environmental interface. The paper presents these processes in detail, drawing on selected narratives of the participants and integrated with additional theory. It is hoped that this paper may contribute to theory building concerning care-leaving processes and enhance youth care practices for youth in care and leaving care.     

对区域高等教育战略规划的若干思考--基于《加利福尼亚州高等教育总体规划（1960-1975）》的分析

《加利福尼亚州高等教育总体规划（1960—1975）》是区域高等教育战略规划领域的成功范例，规划内容通过州宪法性效力、州法律法规性效力以及行业约定性效力三种形式发挥作用。准确把握关键问题、秉持院校自治理念、深入开展调研等做法值得借鉴。我国区域高等教育机遇与挑战并存，教育规划应当坚持治理理念、以人为本理念和系统论理念，对区域高校定位作出合理预期与安排，引导区域高等教育健康和谐发展。