Blinded continuous monitoring in clinical trials with recurrent event endpoints

In studies with recurrent event endpoints, misspecified assumptions of event rates or dispersion can lead to underpowered trials or overexposure of patients. Specification of overdispersion is often a particular problem as it is usually not reported in clinical trial publications. Changing event rates over the years have been described for some diseases, adding to the uncertainty in planning. To mitigate the risks of inadequate sample sizes, internal pilot study designs have been proposed with a preference for blinded sample size reestimation procedures, as they generally do not affect the type I error rate and maintain trial integrity. Blinded sample size reestimation procedures are available for trials with recurrent events as endpoints. However, the variance in the reestimated sample size can be considerable in particular with early sample size reviews. Motivated by a randomized controlled trial in paediatric multiple sclerosis, a rare neurological condition in children, we apply the concept of blinded continuous monitoring of information, which is known to reduce the variance in the resulting sample size. Assuming negative binomial distributions for the counts of recurrent relapses, we derive information criteria and propose blinded continuous monitoring procedures. The operating characteristics of these are assessed in Monte Carlo trial simulations demonstrating favourable properties with regard to type I error rate, power, and stopping time, ie, sample size.     

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.     

An Interview with Joyce Edward: Exemplary Clinician, Advocate, and Scholar

Over the years, noteworthy social workers have been interviewed for the Clinical Social Work Journal. This article features an interview with Joyce Edward who is recognized for her many extraordinary contributions to clinical social work. Joyce has co-written or co-edited three exceptional books for the social work clinician, she has been an esteemed teacher and a vocal activist for quality mental health care. In this interview Joyce reflects on family influences, her work as a social caseworker, the psychoanalytic luminaries with whom she trained, her concerns about the clinical education of today's social work students, and finally, her perspective on managed mental health care.     

我国民事审级制度的改革与完善——比较法学视角下的分析

比较分析中国、日本、德国、美国、法国及我国台湾地区的民事审级制度可以看出我国审级制度中存在的弊端。实际上 ,实行有条件的三审终审制更具合理性。为此 ,我国原有的两审终审制必须加以改革 ,那就是实行以两审终审为原则、以三审终审为例外的民事审级制度。     

Improving the contributions of technology assessment to the health care system of the U.S.A.

Summary Based on 14 case studies of highly effective therapies and the reasons they succeeded less frequently than they could, we propose a variety of steps to improve the health care system of the U.S.A. Whatever proposal emerges from current national debates until innovations are shown to be safe and effective, they should not be supported; when slightly better technologies are much more expensive than other good ones we need to consider appropriate choices carefully; simplified billing and bookkeping would reduce our costs; when a technology is rapidly introduced cautionnary measures may be needed; tracking immunization and repairing their omissions requires a new system; educational programs such as seen effective in hypertension should be applied in other areas such as vaccination; in organ transplantation the nation should consider “presumed consent”; our payment system sometimes creates perverse incentives and therefore needs review; and the preferences of the public in allocation of health resources need to be discovered once the public is informed about the issues. Research supported by Andrew W. Mellon Foundation.     

Asymptotic bias in the linear mixed effects model under non-ignorable missing data mechanisms

Summary.  In longitudinal studies, missingness of data is often an unavoidable problem. Estimators from the linear mixed effects model assume that missing data are missing at random. However, estimators are biased when this assumption is not met. In the paper, theoretical results for the asymptotic bias are established under non-ignorable drop-out, drop-in and other missing data patterns. The asymptotic bias is large when the drop-out subjects have only one or no observation, especially for slope-related parameters of the linear mixed effects model. In the drop-in case, intercept-related parameter estimators show substantial asymptotic bias when subjects enter late in the study. Eight other missing data patterns are considered and these produce asymptotic biases of a variety of magnitudes.     

提高高等医学院校临床教学质量的若干思考

提高医学院校的临床教学质量应做好四个方面的工作:提高认识、增强教学意识,调动临床教学工作的积极性;加强临床教师队伍的建设,注重提高临床教学效果;加强临床教学管理规范化制度化建设;深化临床教学改革。     

论吸毒的心理演变及其矫治对策

吸毒人员一般都要经历一个从好奇、追求刺激、寻求解脱等尝试吸毒 ,到养成吸毒习惯 ,再到依赖毒品的心理演变过程。根据吸毒的心理演变规律 ,运用心理矫治技术 ,采取恰当的矫治措施 ,可以彻底消除吸毒人员对毒品的心理依赖 ,完全戒掉毒瘾。为此 ,在简要分析了吸毒的严重危害性和心理演变过程的基础上 ,着重探讨了对心瘾的矫治对策     

Will Swedish and Dutch drug policy converge? The role of theory

Sweden and The Netherlands are often referred to as the archetypes of prohibition and harm reduction, respectively. Both nations have, however, recently adopted political measures that fit well in the other country's model. But they have also taken steps that reflect traditional thinking. Are we witnessing the initial stages of convergence or are recent developments better interpreted as adjustments? This article addresses these questions by comparing Swedish and Dutch theoretical understandings of ‘the drug problem’. Goals and practices are illuminated in the context of underlying theory, raising the question: Can substantial convergence be achieved without significant prior changes in theoretical perceptions? It is found that the theoretical understandings of the two paradigms do not mix easily, complicating attempts at convergence. Moreover, both countries have invested a great deal of political prestige in their respective models, further exacerbating the problem. A conceivable way to circumvent these difficulties is suggested.