Exact calculation of power and sample size in bioequivalence studies using two one‐sided tests

The number of subjects in a pharmacokinetic two‐period two‐treatment crossover bioequivalence study is typically small, most often less than 60. The most common approach to testing for bioequivalence is the two one‐sided tests procedure. No explicit mathematical formula for the power function in the context of the two one‐sided tests procedure exists in the statistical literature, although the exact power based on Owen's special case of bivariate noncentral t‐distribution has been tabulated and graphed. Several approximations have previously been published for the probability of rejection in the two one‐sided tests procedure for crossover bioequivalence studies. These approximations and associated sample size formulas are reviewed in this article and compared for various parameter combinations with exact power formulas derived here, which are computed analytically as univariate integrals and which have been validated by Monte Carlo simulations. The exact formulas for power and sample size are shown to improve markedly in realistic parameter settings over the previous approximations. Copyright © 2014 John Wiley & Sons, Ltd.     

Phase I trial design for drug combinations with Bayesian model averaging

Various statistical models have been proposed for two‐dimensional dose finding in drug‐combination trials. However, it is often a dilemma to decide which model to use when conducting a particular drug‐combination trial. We make a comprehensive comparison of four dose‐finding methods, and for fairness, we apply the same dose‐finding algorithm under the four model structures. Through extensive simulation studies, we compare the operating characteristics of these methods in various practical scenarios. The results show that different models may lead to different design properties and that no single model performs uniformly better in all scenarios. As a result, we propose using Bayesian model averaging to overcome the arbitrariness of the model specification and enhance the robustness of the design. We assign a discrete probability mass to each model as the prior model probability and then estimate the toxicity probabilities of combined doses in the Bayesian model averaging framework. During the trial, we adaptively allocated each new cohort of patients to the most appropriate dose combination by comparing the posterior estimates of the toxicity probabilities with the prespecified toxicity target. The simulation results demonstrate that the Bayesian model averaging approach is robust under various scenarios. Copyright © 2015 John Wiley & Sons, Ltd.     

Notes on estimation of the intraclass correlation under the AB/BA crossover trial

Under the AB/BA crossover trial, we focus our attention on estimation of the intraclass correlation in normal data. We develop both point and interval estimators in closed form for the intraclass correlation. We employ Monte Carlo simulation to study the performance of these estimators in a variety of situations. We note that the estimators developed here for the intraclass correlation remain valid even when there are possibly unexpected carry-over effects.     

对中国国库集中支付制度改革的思考

随着中国财政体制改革的不断深入,国库集中支付制度在全国范围内开始逐步推广实施,这项制度的推行对于中国的经济发展具有极其深远的意义。本文主要研究了进行国库集中支付制度改革的意义和所存在的问题,在此基础上提出了进一步完善国库集中支付制度的思路。     

审判经验的迷局与研判——从“案多人少”切入

2008年以来,江苏法院开展了大规模的总结审判经验专项活动。这是在案件数量剧增的态势下法院为化解案多人少的矛盾之为,但得到的经验相当一部分并非是有效提升办案效率的＂精品＂。从短期看,审判经验总结会适得其反,加大案多人少压力;但从长期来看,对于缓解案多人少压力会有所帮助。因此,审判经验有总结的价值,但在传承和发展审判经验时,对于个人经验和集体经验应当区别对待。     

Maternal union instability and childhood mortality risk in the Global South, 2010–14

Efforts to improve child survival in lower-income countries typically focus on fundamental factors such as economic resources and infrastructure provision, even though research from post-industrial countries confirms that family instability has important health consequences. We tested the association between maternal union instability and children’s mortality risk in Africa, Latin America and the Caribbean, and Asia using children’s actual experience of mortality (discrete-time probit hazard models) as well as their experience of untreated morbidity (probit regression). Children of divorced/separated mothers experience compromised survival chances, but children of mothers who have never been in a union generally do not. Among children of partnered women, those whose mothers have experienced prior union transitions have a higher mortality risk. Targeting children of mothers who have experienced union instability—regardless of current union status—may augment ongoing efforts to reduce childhood mortality, especially in Africa and Latin America where union transitions are common.     

Bayesian sample size determination for phase IIA clinical trials using historical data and semi‐parametric prior's elicitation

The Simon's two‐stage design is the most commonly applied among multi‐stage designs in phase IIA clinical trials. It combines the sample sizes at the two stages in order to minimize either the expected or the maximum sample size. When the uncertainty about pre‐trial beliefs on the expected or desired response rate is high, a Bayesian alternative should be considered since it allows to deal with the entire distribution of the parameter of interest in a more natural way. In this setting, a crucial issue is how to construct a distribution from the available summaries to use as a clinical prior in a Bayesian design. In this work, we explore the Bayesian counterparts of the Simon's two‐stage design based on the predictive version of the single threshold design. This design requires specifying two prior distributions: the analysis prior, which is used to compute the posterior probabilities, and the design prior, which is employed to obtain the prior predictive distribution. While the usual approach is to build beta priors for carrying out a conjugate analysis, we derived both the analysis and the design distributions through linear combinations of B‐splines. The motivating example is the planning of the phase IIA two‐stage trial on anti‐HER2 DNA vaccine in breast cancer, where initial beliefs formed from elicited experts' opinions and historical data showed a high level of uncertainty. In a sample size determination problem, the impact of different priors is evaluated.     

Inference in Targeted Group‐Sequential Covariate‐Adjusted Randomized Clinical Trials

This article is devoted to the construction and asymptotic study of adaptive, group‐sequential, covariate‐adjusted randomized clinical trials analysed through the prism of the semiparametric methodology of targeted maximum likelihood estimation. We show how to build, as the data accrue group‐sequentially, a sampling design that targets a user‐supplied optimal covariate‐adjusted design. We also show how to carry out sound statistical inference based on such an adaptive sampling scheme (therefore extending some results known in the independent and identically distributed setting only so far), and how group‐sequential testing applies on top of it. The procedure is robust (i.e. consistent even if the working model is mis‐specified). A simulation study confirms the theoretical results and validates the conjecture that the procedure may also be efficient.     

Order statistics from non-identical right-truncated Lomax random variables with applications

In this paper, we derive some recurrence relations for the single and the product moments of order statistics from n independent and non-identically distributed Lomax and right-truncated Lomax random variables. These recurrence relations are simple in nature and could be used systematically in order to compute all the single and product moments of all order statistics in a simple recursive manner. The results for order statistics from the multiple-outlier model (with a slippage of p observations) are deduced as special cases. We then apply these results by examining the robustness of censored BLUE's to the presence of multiple outliers. Received: November 30, 1998; revised version: March 8, 2000     

Adaptive designs for single‐arm phase II trials in oncology

Clinical phase II trials in oncology are conducted to determine whether the activity of a new anticancer treatment is promising enough to merit further investigation. Two‐stage designs are commonly used for this situation to allow for early termination. Designs proposed in the literature so far have the common drawback that the sample sizes for the two stages have to be specified in the protocol and have to be adhered to strictly during the course of the trial. As a consequence, designs that allow a higher extent of flexibility are desirable. In this article, we propose a new adaptive method that allows an arbitrary modification of the sample size of the second stage using the results of the interim analysis or external information while controlling the type I error rate. If the sample size is not changed during the trial, the proposed design shows very similar characteristics to the optimal two‐stage design proposed by Chang et al. (Biometrics 1987; 43:865–874). However, the new design allows the use of mid‐course information for the planning of the second stage, thus meeting practical requirements when performing clinical phase II trials in oncology. Copyright © 2012 John Wiley & Sons, Ltd.