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.     

丹巴土司制度发展历史考证

丹巴位于“藏彝走廊”的核心区域，其对汉藏民族关系、中央政权与边疆地区的稳定均具有重要影响。自忽必烈时期开始丹巴即开始实行土司制度直至新中国成立，研究丹巴的土司制度发展历史对梳理“藏彝走廊”民族关系及社会发展历史具有重要作用。本文对丹巴土司制度的发展历史进行了考证，并对其境内的四个土司的管辖范围、权力地位进行了梳理，以期对该地区历史发展研究提供一些参考与借鉴。     

Non-parametric estimation of reciprocal coordinate subtangent for right censored dependent scheme

The concept of reciprocal coordinate subtangent (RCST) has been used as a useful tool to study the monotone behavior of a continuous density function and for characterizing probability distributions. In this paper, we propose a non-parametric estimator for RCST based on the censored dependent data. Asymptotic properties of the estimator are established under suitable regularity conditions. A simulation study is carried out to examine the performance of the estimator. The usefulness of the estimator is also examined through a real data.     

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。     

Probabilistic population projections for countries with generalized HIV/AIDS epidemics

In 2015, the United Nations (UN) issued probabilistic population projections for all countries up to 2100, by simulating future levels of total fertility and life expectancy and combining the results using a standard cohort component projection method. For the 40 countries with generalized HIV/AIDS epidemics, the mortality projections used the Spectrum/Estimation and Projection Package (EPP) model, a complex, multistate model designed for short-term projections of policy-relevant quantities for the epidemic. We propose a simpler approach that is more compatible with existing UN projection methods for other countries. Changes in life expectancy are projected probabilistically using a simple time series regression and then converted to age- and sex-specific mortality rates using model life tables designed for countries with HIV/AIDS epidemics. These are then input to the cohort component method, as for other countries. The method performed well in an out-of-sample cross-validation experiment. It gives similar short-run projections to Spectrum/EPP, while being simpler and avoiding multistate modelling.     

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.     

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。     

乡村振兴视域中的农民主体作用、制约因素及路径选择——基于湖南岳阳乡村的调查与思考

农民是农业和农村的主体,也是乡村振兴的内生因素,发挥农民主体作用对实施乡村振兴战略意义重大。当前农民对乡村振兴关注度和支持度较高,农民的主体作用发挥成为乡村振兴的根本动力。但现实中,农民主体作用也受到诸如农业综合效益较低、农民自身思想文化和能力素质不高、管理机制滞后及基础条件薄弱等多方面的因素制约,需要党委、政府综合施策,采取完善乡村治理、健全政策扶持、建立引导机制、补齐短板缺陷、加强培育培训等一系列政策措施,尊重、引导、激励和支持农民自我管理、自我发展,激发农民的主动性、积极性、创造性。