Response‐adaptive designs for binary responses: How to offer patient benefit while being robust to time trends?

Response‐adaptive randomisation (RAR) can considerably improve the chances of a successful treatment outcome for patients in a clinical trial by skewing the allocation probability towards better performing treatments as data accumulates. There is considerable interest in using RAR designs in drug development for rare diseases, where traditional designs are not either feasible or ethically questionable. In this paper, we discuss and address a major criticism levelled at RAR: namely, type I error inflation due to an unknown time trend over the course of the trial. The most common cause of this phenomenon is changes in the characteristics of recruited patients—referred to as patient drift. This is a realistic concern for clinical trials in rare diseases due to their lengthly accrual rate. We compute the type I error inflation as a function of the time trend magnitude to determine in which contexts the problem is most exacerbated. We then assess the ability of different correction methods to preserve type I error in these contexts and their performance in terms of other operating characteristics, including patient benefit and power. We make recommendations as to which correction methods are most suitable in the rare disease context for several RAR rules, differentiating between the 2‐armed and the multi‐armed case. We further propose a RAR design for multi‐armed clinical trials, which is computationally efficient and robust to several time trends considered.     

Predictive Hierarchic Modeling of Operational Characteristics in Clinical Trials

An analytic methodology for patient enrollment modeling using a Poisson-gamma model is developed by Anisimov & Fedorov (2005–2007). For modeling hierarchic processes associated with enrollment, a new methodology using evolving stochastic processes is proposed. This provides rather general and unified framework to describe various operational processes associated with enrollment. The technique for calculating predictive distributions, mean, and credibility bounds for evolving processes is developed. Some applications to modeling operational characteristics in clinical trials are considered with focus to modeling events associated with incoming and follow-up patients in different settings. For these models, predictive characteristics are derived in a closed form.     

试析蒙古高原二元对立的政治格局

蒙古高原特殊的地理环境 ,使这里成为游牧民族生息繁衍的摇篮。在高原内部 ,由于自然环境与地缘政治的差异 ,又分为漠南与漠北两个相互独立的地理单元。以此为基础 ,在蒙古高原上出现了一次次二元对立的政治格局     

Randomization tests in recursive response-adaptive randomization procedures

In a randomized clinical trial, response-adaptive randomization procedures use the information gathered, including the previous patients' responses, to allocate the next patient. In this setting, we consider randomization-based inference. We provide an algorithm to obtain exact p-values for statistical tests that compare two treatments with dichotomous responses. This algorithm can be applied to a family of response adaptive randomization procedures which share the following property: the distribution of the allocation rule depends only on the imbalance between treatments and on the imbalance between successes for treatments 1 and 2 in the previous step. This family includes some outstanding response adaptive randomization procedures. We study a randomization test to contrast the null hypothesis of equivalence of treatments and we show that this test has a similar performance to that of its parametric counterpart. Besides, we study the effect of a covariate in the inferential process. First, we obtain a parametric test, constructed assuming a logit model which relates responses to treatments and covariate levels, and we give conditions that guarantee its asymptotic normality. Finally, we show that the randomization test, which is free of model specification, performs as well as the parametric test that takes the covariate into account.     

贵州城乡经济一体化现状、问题及对策研究

本文首先分析了城乡经济一体化的基本内涵,同时主要采用城乡居民收入差异系数、城乡居民恩格尔系数差异系数、二元对比系数以及城乡居民收入差异倍数、城乡居民积累差异倍数五个基本指标分析了贵州省1978年-2006年城乡差异的现状。分析得出贵州省存在较显著的城乡二元经济结构,城乡经济一体化任重而道远。     

从制度伦理的视角窥探我国"三农"问题

“三农”问题是困扰我国农村建设的核心问题。“三农”问题根源于我国的二元社会经济结构中背离了正义原则的制度缺陷。科学的制度安排是“三农”问题得以解决的基本前提。从制度伦理的视角对我国的“三农”问题进行科学的审视是一种必然。要彻底解决“三农”问题,废除城乡差别,给农民以国民待遇,必须从制度创新入手。     

城市公共交通出行者交通信息选择行为研究

先进的交通信息服务系统建设是我国城市交通可持续发展的必由之路。文章基于大连市公共交通出行信息需求专项调查,通过多维度频率分布研究,对不同个人属性、信息服务特征等条件下公共交通出行者的交通信息内容需求进行分析,进一步建立公共交通出行者交通信息选择binary logistic模型,对公共交通出行者交通信息选择行为进行研究。研究显示,公共交通出行者交通信息内容需求因个人属性、信息服务特征等因素存在较大差别,交通信息内容对公共交通出行者交通信息选择行为存在不同程度的影响。最后,文章基于实证研究结果,提出面向城市公共交通出行者的交通信息服务系统规范化建设的相关策略。     

Active‐controlled,non‐inferiority trials in oncology: arbitrary limits,infeasible sample sizes and uninformative data analysis. Is there another way?

In oncology, it may not always be possible to evaluate the efficacy of new medicines in placebo-controlled trials. Furthermore, while some newer, biologically targeted anti-cancer treatments may be expected to deliver therapeutic benefit in terms of better tolerability or improved symptom control, they may not always be expected to provide increased efficacy relative to existing therapies. This naturally leads to the use of active-control, non-inferiority trials to evaluate such treatments. In recent evaluations of anti-cancer treatments, the non-inferiority margin has often been defined in terms of demonstrating that at least 50% of the active control effect has been retained by the new drug using methods such as those described by Rothmann et al., Statistics in Medicine 2003; 22:239-264 and Wang and Hung Controlled Clinical Trials 2003; 24:147-155. However, this approach can lead to prohibitively large clinical trials and results in a tendency to dichotomize trial outcome as either 'success' or 'failure' and thus oversimplifies interpretation. With relatively modest modification, these methods can be used to define a stepwise approach to design and analysis. In the first design step, the trial is sized to show indirectly that the new drug would have beaten placebo; in the second analysis step, the probability that the new drug is superior to placebo is assessed and, if sufficiently high in the third and final step, the relative efficacy of the new drug to control is assessed on a continuum of effect retention via an 'effect retention likelihood plot'. This stepwise approach is likely to provide a more complete assessment of relative efficacy so that the value of new treatments can be better judged.     

Estimates of subgroup treatment effects in overall nonsignificant trials: To what extent should we believe in them?

In drug development, it sometimes occurs that a new drug does not demonstrate effectiveness for the full study population but appears to be beneficial in a relevant subgroup. In case the subgroup of interest was not part of a confirmatory testing strategy, the inflation of the overall type I error is substantial and therefore such a subgroup analysis finding can only be seen as exploratory at best. To support such exploratory findings, an appropriate replication of the subgroup finding should be undertaken in a new trial. We should, however, be reasonably confident in the observed treatment effect size to be able to use this estimate in a replication trial in the subpopulation of interest. We were therefore interested in evaluating the bias of the estimate of the subgroup treatment effect, after selection based on significance for the subgroup in an overall “failed” trial. Different scenarios, involving continuous as well as dichotomous outcomes, were investigated via simulation studies. It is shown that the bias associated with subgroup findings in overall nonsignificant clinical trials is on average large and varies substantially across plausible scenarios. This renders the subgroup treatment estimate from the original trial of limited value to design the replication trial. An empirical Bayesian shrinkage method is suggested to minimize this overestimation. The proposed estimator appears to offer either a good or a conservative correction to the observed subgroup treatment effect hence provides a more reliable subgroup treatment effect estimate for adequate planning of future studies.