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.     

制度风险的法律维度: 突破非物质文化遗产保护的瓶颈

以风险理论审视非物质文化遗产的现行法律制度,根据风险产生根源不同,非物质文化遗产保护的制度风险会表现为制度运转失灵风险、制度功能偏差风险和公平性缺失风险。化解制度风险,形成制度风险的维度,不可基于同一个标准,而是需要在大的框架之下论及制度风险的法律管控,需要有针对性地创构"建立私权,善用公权"的多元法律控制体系,并在体系内引入技术规制,创设"非物质文化遗产权",推动民间习惯法与法律制度、公法与私法的互动式发展。     

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。     

On the estimation of non linear functions in stochastic volatility models

Abstract

This paper focuses on the inference of suitable generally non linear functions in stochastic volatility models. In this context, in order to estimate the variance of the proposed estimators, a moving block bootstrap (MBB) approach is suggested and discussed. Under mild assumptions, we show that the MBB procedure is weakly consistent. Moreover, a methodology to choose the optimal length block in the MBB is proposed. Some examples and simulations on the model are also made to show the performance of the proposed procedure.     

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。     

为合法经营活动而侵犯公民个人信息的刑法规制

最高人民法院、最高人民检察院《关于办理侵犯公民个人信息刑事案件适用法律若干问题的解释》第六条对为合法经营活动而侵犯公民个人信息行为进行独立规制,是新型犯罪罪状表述抽象化与罪状解释具体化、信息时代信息价值多元化与危害行为多样化、现代社会犯罪治理精细化与刑法评价精准化的内在要求.为合法经营活动而侵犯公民个人信息行为相关规范要素中的“为合法经营活动”应理解为主观超过要素,“获利五万元”应作严格解释,“曾因侵犯公民个人信息”应作广义解释,“其他情节严重”应包括信息数量标准.     

区块链技术下智能合约之于合同的新诠释

应用于交易领域的智能合约融入区块链技术,以代码形式表现,可实现合同履行的自动化和不可逆,超越了传统意义上的合同模式.自助行为说、代理说将智能合约视为对合同过程的外部增强,是侧面功能的法律阐释,并未完全捕捉到实质.智能合约并不一定跨越整个合同过程,也可仅是合同过程某个方面或某个阶段.法律意义上的智能合约不是合同新类型,而是合同关系形式的新发展,即当事人缔结和履行合同的新形式,合同性质未发生实质变化.智能合约满足特定要件构成特殊的书面形式,具有"书面形式+自动履行"功能的特质.民事主体通过智能合约形式订立合同应遵守《民法典》等现行法律的具体规则,以保证合同依法成立与生效.智能合约不等同于具有法律效力的合同,认定其效力应结合智能合约应用中的具体问题展开具体分析.从立法上确认智能合约,在符合国家现有法律、政策基础上编写和应用,实现形式的合法化、内容的规范化是该技术谋求长远发展的保障.技术起步的现阶段,纸质合同、一般电子合同与智能合约在不同方面发挥协作作用,会在未来一段时间内成为民事交往、商业交易的主要状态.     

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。