Combining evidence from clinical trials in conditional or accelerated approval

Conditional (European Medicines Agency) or accelerated (U.S. Food and Drug Administration) approval of drugs allows earlier access to promising new treatments that address unmet medical needs. Certain post-marketing requirements must typically be met in order to obtain full approval, such as conducting a new post-market clinical trial. We study the applicability of the recently developed harmonic mean ${\chi }^2$-test to this conditional or accelerated approval framework. The proposed approach can be used both to support the design of the post-market trial and the analysis of the combined evidence provided by both trials. Other methods considered are the two-trials rule, Fisher's criterion and Stouffer's method. In contrast to some of the traditional methods, the harmonic mean ${\chi }^2$-test always requires a post-market clinical trial. If the $p$-value from the pre-market clinical trial is $\ll 0.025$, a smaller sample size for the post-market clinical trial is needed than with the two-trials rule. For illustration, we apply the harmonic mean ${\chi }^2$-test to a drug which received conditional (and later full) market licensing by the EMA. A simulation study is conducted to study the operating characteristics of the harmonic mean ${\chi }^2$-test and two-trials rule in more detail. We finally investigate the applicability of these two methods to compute the power at interim of an ongoing post-market trial. These results are expected to aid in the design and assessment of the required post-market studies in terms of the level of evidence required for full approval.     

行政级别、城市规模与土地产出效率

2019年1月1日起施行的《行政区划管理条例》强调通过优化行政区划设置，强化政府的行政化管理。行政级别作为国家政治权力在地理空间上的体现，对城市的资源配置、社会治理、政策规划实施起到重要作用。城市可以凭借行政级别的优势在中国的行政区经济发展模式下获取正反馈效应，因此从行政级别的角度理解城市发展也就抓住了中国特色的行政区经济模式的关键。研究首先对我国行政级别的制度背景、演化发展历程及发展趋势展开系统性梳理分析。在此基础上，基于空间政治经济学的视角运用新经济地理理论、规模经济理论、区域经济协同发展理论对行政级别、城市规模与土地产出效率之间的影响关系展开研究。分别从权力职能、财政能力、资源配置三个维度分析城市行政级别对土地产出效率的推动作用，由规模集聚、过度积累两个维度分析城市规模对土地产出效率的倒U型结构作用，再从行政区与经济区发展协同的角度分析城市行政级别与城市规模对土地产出效率的协同作用。在实证研究部分，研究通过对我国特色政治制度下行政级别设定的分析，将城市行政级别、城市规模、土地产出效率纳入统一的面板数据模型中进行定量分析，在对数据进行单位根和格兰杰因果检验的基础上，利用2000-2016年中国地级及以上城市样本进行面板数据固定效应模型分析，并通过内生性检验对模型内变量之间的干扰问题进行控制。为进一步探寻城市规模对土地产出效率倒U型作用下存在的最优区间值，研究利用门槛效应模型以全社会资本存量作为门槛变量通过500次自抽样门槛效应检验对城市规模存在的结构变化点进行探寻。通过理论与实证分析，研究发现：第一，行政级别对土地产出效率的提升具有显著影响；第二，城市规模对土地产出效率呈现倒U型作用，城市在387万人时处于最优城市规模；第三，行政级别、城市规模对土地产出效率的协同作用较小，现阶段城市行政级别与城市规模之间存在不协调的现象。最后，研究在着眼长远发展展开行政区划设置，强化行政区划设置在城市空间治理中的作用、通过行政区划制度协调行政区经济发展，促进区域空间结构体系的良性健康发展、促进行政区划设置与土地产出效率的协同作用，提升城市土地资源配置与城市发展的匹配程度三方面提出相应政策建议。     

Sample size re-estimation in Phase 2 dose-finding: Conditional power versus Bayesian predictive power

Unblinded sample size re-estimation (SSR) is often planned in a clinical trial when there is large uncertainty about the true treatment effect. For Proof-of Concept (PoC) in a Phase II dose finding study, contrast test can be adopted to leverage information from all treatment groups. In this article, we propose two-stage SSR designs using frequentist conditional power (CP) and Bayesian predictive power (PP) for both single and multiple contrast tests. The Bayesian SSR can be implemented under a wide range of prior settings to incorporate different prior knowledge. Taking the adaptivity into account, all type I errors of final analysis in this paper are rigorously protected. Simulation studies are carried out to demonstrate the advantages of unblinded SSR in multi-arm trials.     

The effect of knowledge collaboration on business model reconfiguration

This study examines whether and to what extent the presence and intensity of knowledge collaboration across different partners affects business model reconfiguration (BMR). We build on the business model (BM) literature and operationalize BMR by introducing the presence and intensity of collaboration and firm size effects as main explanatory factors in affecting the propensity of incremental and radical BMR. We analyze a large sample of UK firms during 2002–2014 to capture the effect of knowledge collaboration and firm size on BMR. Positively incremental forms of BMR will be influenced by the presence and intensity of knowledge collaboration, while radical forms of BMR are affected by the intensity of collaboration with customers and the collaboration with suppliers by large firms. Furthermore, firms of different sizes do not equally benefit from knowledge collaboration with suppliers for both incremental and radical BMR, while they do equally benefit from collaboration with other partner types.     

超声多信号融合表征颗粒两相流实验研究

从颗粒两相流超声波动理论出发,提出多信号融合概念,采用单次和多次反射法同时测量颗粒两相流中高频宽带超声波声阻抗、声速和声衰减谱,获取了颗粒两相流系统中密度、浓度、粒径信息.基于该理论研制了可用于同时测量高浓度颗粒两相流密度、浓度、粒径的装置.高浓度水煤浆颗粒两相流测量结果显示,测量密度、浓度与平均粒径与标准对比较为吻合.