Generalized phase I-II designs to increase long term therapeutic success rate

Designs for early phase dose finding clinical trials typically are either phase I based on toxicity, or phase I-II based on toxicity and efficacy. These designs rely on the implicit assumption that the dose of an experimental agent chosen using these short-term outcomes will maximize the agent's long-term therapeutic success rate. In many clinical settings, this assumption is not true. A dose selected in an early phase oncology trial may give suboptimal progression-free survival or overall survival time, often due to a high rate of relapse following response. To address this problem, a new family of Bayesian generalized phase I-II designs is proposed. First, a conventional phase I-II design based on short-term outcomes is used to identify a set of candidate doses, rather than selecting one dose. Additional patients then are randomized among the candidates, patients are followed for a predefined longer time period, and a final dose is selected to maximize the long-term therapeutic success rate, defined in terms of duration of response. Dose-specific sample sizes in the randomization are determined adaptively to obtain a desired level of selection reliability. The design was motivated by a phase I-II trial to find an optimal dose of natural killer cells as targeted immunotherapy for recurrent or treatment-resistant B-cell hematologic malignancies. A simulation study shows that, under a range of scenarios in the context of this trial, the proposed design has much better performance than two conventional phase I-II designs.     

The potential for bias in reporting of industry-sponsored clinical trials

Concerns about potentially misleading reporting of pharmaceutical industry research have surfaced many times. The potential for duality (and thereby conflict) of interest is only too clear when you consider the sums of money required for the discovery, development and commercialization of new medicines. As the ability of major, mid-size and small pharmaceutical companies to innovate has waned, as evidenced by the seemingly relentless decline in the numbers of new medicines approved by Food and Drug Administration and European Medicines Agency year-on-year, not only has the cost per new approved medicine risen: so too has the public and media concern about the extent to which the pharmaceutical industry is open and honest about the efficacy, safety and quality of the drugs we manufacture and sell. In 2005 an Editorial in Journal of the American Medical Association made clear that, so great was their concern about misleading reporting of industry-sponsored studies, henceforth no article would be published that was not also guaranteed by independent statistical analysis. We examine the precursors to this Editorial, as well as its immediate and lasting effects for statisticians, for the manner in which statistical analysis is carried out, and for the industry more generally.     

Can a treatment be licenced on the basis of post‐treatment predictive biomarkers?

In recent years, there has been a great deal of literature published concerning the identification of predictive biomarkers and indeed, an increasing number of therapies have been licenced on this basis. However, this progress has been made almost exclusively on the basis of biomarkers measured prior to exposure to treatment. There are quite different challenges when the responding population can only be identified on the basis of outcomes observed following exposure to treatment, especially if it represents only a small proportion of patients. The purpose of this paper is to explore whether or when a treatment could be licenced on the basis of post‐treatment predictive biomarkers (PTPB), the focus is on oncology but the concepts should apply to all therapeutic areas. We review the potential pitfalls in hypothesising the presence of a PTPB. We also present challenges in trial design required to confirm and licence on the basis of a PTPB: what's the control population?, could there be a detriment to non‐responders by exposure to the new treatment?, can responders be identified rapidly?, could prior exposure to the new treatment adversely affect performance of the control in responders? Nevertheless, if the patients to be treated could be rapidly identified after prior exposure to treatment, and without harm to non‐responders, in appropriately designed and analysed trials, may be more targeted therapies could be made available to patients. Copyright © 2014 John Wiley & Sons, Ltd.     

言论自由与公正审判的关系研究——以司法对言论的应对为视角

言论自由作为一把双刃剑它在促进司法公正,防止司法腐败的同时也能构成对公正审判的威胁,原因就在于言论自由与公正审判二者背后的价值基础的不同。出于遏制不当的言论对司法公正造成的不良影响的需要,须对公民的言论进行正确的价值引导,同时司法机关自身也要通过相关的制度建设来保证立场的独立与公正,消除民众对司法行为的合理怀疑而引致的猜测性的言论,实现公民言论自由与公正审判的双重目的。     

司法公正与基本权利

《公民权利和政治权利国际公约》第14条所确立的获得公正审判权是一项已经得到世界上绝大多数民主国家认可的基本权利。获得公正审判权不仅适用于刑事诉讼,也适用于民事诉讼、行政诉讼以及其他关涉公民人身、财产权利的实质意义上的各种"争讼"。我们不仅应将公正审判原则作为一项总括性的权利予以重视和论述,还应看到平等受审原则和公开审判原则的独立价值。     

论庭审语言的特征

庭审语言是对案件事实的陈述,具有固定的程序性特征,讲究有根有据,是将事实、证据、法律进行语言加工后形成的一个有机系统。庭审中,法官语言具有威严性;律师语言的总特征是辩论性、针对性;当事人的语言或委屈、或愤怒,富有攻击性。国外庭审语言比较灵动、活泼,国内庭审的语言主要体现为庄重美,两者之间存在较大差异,这主要是由不同的庭审模式造成的。     

行政诉讼异地审判制度的价值内涵分析

行政诉讼异地审判的出现虽说只是我国司法实践中的一个小小的变动举措,但它却包含着司法为民、司法独立和程序正义等几方面的诉讼价值观,异地审判以中国式的方式诠释了诉讼法律价值在中国的地方性特色和特殊内容。     

胡适诗歌与“尝试”精神

胡适是中国现代文化史上的一位巨人,他在文学、思想、学术等方面都做出了突出的贡献。在诗歌方面,以胡适为代表的早期白话新诗运动是中国诗歌转型的开端,回顾中国现代新诗的历史,胡适是不能被忽略的。他以大胆的"尝试"精神,引领着中国新诗的发展方向。     

论我国加入《公民权利和政治权利国际公约》的批准与保留——以刑事诉讼法为例

目前我国《刑事诉讼法》与《公民权利和政治权利国际公约》的要求具有一定的差距,如指控范围窄于《公约》要求;平等、公开、公正原则不能全面体现;无罪推定原则没有真正确立;刑事审判中对被告人权利最低限度的保障达不到以及一事不再理原则没有真正确立等。同时,根据各国加入《公约》时对公正审判程序的保留情况,分析对我国的启示。在此基础上,探讨我国加入《公约》前对公正审判程序的构建。     

不真正连带责任的诉讼形态——权利实现与程序救济

由于立法不明确,法院对不真正连带责任诉讼形态的选择表现出不确定性.理论上也存在不同认识,在现实法律环境下,应当结合不真正连带责任的性质、效力、诉讼形态的划分标准等因素进行综合考虑,首先应当遵守现有的法律规定;在法律未作明确规定时,债权人具有选择权,可以向任一债务人起诉,也可以选择向全部不真正连带责任人一并起诉,如果债权人同时向不真正连带责任人分别起诉,则应当适用合并审理的有关规定.