Coping with missing data in phase III pivotal registration trials: Tolvaptan in subjects with kidney disease,a case study

Missing data cause challenging issues, particularly in phase III registration trials, as highlighted by the European Medicines Agency (EMA) and the US National Research Council. We explore, as a case study, how the issues from missing data were tackled in a double‐blind phase III trial in subjects with autosomal dominant polycystic kidney disease. A total of 1445 subjects were randomized in a 2:1 ratio to receive active treatment (tolvaptan), or placebo. The primary outcome, the rate of change in total kidney volume, favored tolvaptan (P < .0001). The key secondary efficacy endpoints of clinical progression of disease and rate of decline in kidney function also favored tolvaptan. However, as highlighted by Food and Drug Administration and EMA, the interpretation of results was hampered by a high number of unevenly distributed dropouts, particularly early dropouts. In this paper, we outline the analyses undertaken to address the issue of missing data thoroughly. “Tipping point analyses” were performed to explore how extreme and detrimental outcomes among subjects with missing data must be to overturn the positive treatment effect attained in those subjects who had complete data. Nonparametric rank‐based analyses were also performed accounting for missing data. In conclusion, straightforward and transparent analyses directly taking into account missing data convincingly support the robustness of the preplanned analyses on the primary and secondary endpoints. Tolvaptan was confirmed to be effective in slowing total kidney volume growth, which is considered an efficacy endpoint by EMA, and in lessening the decline in renal function in patients with autosomal dominant polycystic kidney disease.     

How to avoid concerns with the interpretation of two primary endpoints if significant superiority in one is sufficient for formal proof of efficacy

Formal proof of efficacy of a drug requires that in a prospective experiment, superiority over placebo, or either superiority or at least non-inferiority to an established standard, is demonstrated. Traditionally one primary endpoint is specified, but various diseases exist where treatment success needs to be based on the assessment of two primary endpoints. With co-primary endpoints, both need to be “significant” as a prerequisite to claim study success. Here, no adjustment of the study-wise type-1-error is needed, but sample size is often increased to maintain the pre-defined power. Studies that use an at-least-one concept have been proposed where study success is claimed if superiority for at least one of the endpoints is demonstrated. This is sometimes also called the dual primary endpoint concept, and an appropriate adjustment of the study-wise type-1-error is required. This concept is not covered in the European Guideline on multiplicity because study success can be claimed if one endpoint shows significant superiority, despite a possible deterioration in the other. In line with Röhmel's strategy, we discuss an alternative approach including non-inferiority hypotheses testing that avoids obvious contradictions to proper decision-making. This approach leads back to the co-primary endpoint assessment, and has the advantage that minimum requirements for endpoints can be modeled flexibly for several practical needs. Our simulations show that, if planning assumptions are correct, the proposed additional requirements improve interpretation with only a limited impact on power, that is, on sample size.     

The iterative proportional fitting algorithm for adjusted agreement in a non‐inferiority diagnostic clinical trial

In this paper, we describe a method of comparing agreement between two diagnostic contingency tables after adjustment to more clinically relevant marginal distributions using the iterative proportional fitting algorithm. When the categories of a contingency table represent mild, moderate, and severe outcomes, the majority of patients often are in the mild category. Because it is often of more interest to evaluate agreement when patients are uniformly distributed among categories, we present the primary results of two clinical trials with adjustment to this structure. We also describe the relationship between the sponsor's pre‐specified agreement measure for the observed contingency table and kappa for the adjusted table; and by either criterion, we then show that the agreement of the new diagnostic tool with the standard diagnostic tool is comparably non‐inferior to the agreement of the standard diagnostic tool with itself. Copyright © 2014 John Wiley & Sons, Ltd.     

Coloring the War on Drugs: Arrest Disparities in Black,Brown, and White

Using the National Longitudinal Survey of Youth 1997 (NLSY97) data, this study examines racial disparities in arrests for drug offending. Of the total 8984 NLSY97 participants, the study sample was restricted to the 4868 respondents who had ever reported using drugs (black = 1191, Hispanic = 980, white = 2697). The study questions are as follows: (1) Are there racial disparities in arrests for drug use, after controlling for incidence of drug use as well as other socio-demographic variables? (2) Are there racial disparities in arrests for drug dealing, after controlling for incidence of drug dealing as well as other socio-demographic variables? Compared with whites, blacks were more likely to be arrested for drug offending, even after controlling for incidence and other socio-demographic variables. Several socio-demographic variables, particularly gender, were also associated with arrests for drug offending. Bans on racial profiling and other legislative and policy changes are considered as potential strategies to ameliorate drug enforcement disparities.     

Statistical considerations in a delayed‐start design to demonstrate disease modification effect in neurodegenerative disorders

There has been a paradigm shift in diagnostic conceptualization of Alzheimer's disease (AD) based on the current evidence suggesting that structure and biology changes start to occur before clinical symptoms emerge. Consequently, therapeutic drug development is also shifting to treat early AD patients using biomarkers for enrichment in clinical trials. A similar paradigm shift is occurring for Parkinson disease. In the absence of acceptable biomarkers that could be combined with a clinical endpoint to demonstrate a disease modification (DM) effect in neurodegenerative disorders, a delayed‐start design can be applied to demonstrate a lasting effect on the disease course. The delayed‐start design includes two treatment periods, where in period 1, patients are randomized to receive an active treatment or placebo, and in period 2, placebo patients are switched to the active treatment while patients in the active treatment arm will continue the same treatment. The hypothesis is that patients who start the active treatment later will fail to catch up to the treatment benefit achieved by patients who receive the active treatment in both periods. A usual analytical approach has sought to demonstrate the divergence of slope during period 1 and the parallelism of slopes during period 2 as the DM effect. However, due to heterogeneity in timing and the magnitude of maximal effect among patients, nonlinear response over time could be observed within the two treatment arms in both periods. We propose an approach to evaluate the DM effect with the linearity assumption for treatment differences, but not for each arm separately.     

Kitchen Hygiene in the Spotlight: How Cooking Shows Influence Viewers’ Hygiene Practices

Poor hygiene when handling food is a major cause of foodborne illness. To investigate whether hygiene practices visible in television cooking shows influence viewers’ kitchen hygiene, a study on the adoption of demonstrated hygiene behavior was conducted under controlled, experimental conditions. In a study ostensibly on cooking by following recipes participants (n = 65) were randomly assigned to one of three conditions, in which they watched a cooking video that differed only with regard to the hygiene behavior of the chef. In condition 1, the chef engaged in poor hygiene practices while preparing the dish, in condition 2 the chef's hygiene behavior was exemplary and in condition 3, the chef's hygiene behavior was not visible (control condition). After watching the video, participants were instructed to cook the recipe individually in the fully equipped laboratory kitchen. Cooking sessions were videotaped and experimenters blind to condition coded hygiene lapses committed by participants. The level of kitchen hygiene displayed in the cooking video significantly affected hygiene practices of participants cooking the recipe. Participants who had watched the cooking video with correct hygiene practices committed significantly fewer hygiene lapses than those who had watched the video with poor hygiene practices. From a risk communication perspective, TV cooking shows are well placed to convey knowledge of essential hygiene practices during food preparation to a broad audience. To facilitate behavioral change toward safer food‐handling practices among viewers, visibly performing correct hygiene practices in cooking shows is a promising strategy.     

Längsschnittdaten und Mehrebenenanalyse

In the present article a few basic multilevel models for longitudinal data are introduced and applied to the Household Income and Labor Dynamics in Australia Survey 10 (HILDA) for demonstrational purposes. The covered models are adaptions of the random-intercept-only model, the random-intercept models and the random- intercept random-slope model with and without level-1 and level-2 predictors to longitudinal data. The modeling of contextual effects is covered. One particularity in longitudinal data is the fact that persons (level-2) may be regarded as the context of the time-varying observations on level-1. To incorporate the macro-level of sociology, it is necessary to expand the model to a third level. A model with three levels is introduced and in addition a simple growth curve model and a multivariate multilevel model are presented.     

激励机制四原则

成功有效的激励机制必须把员工个人利益与公司集体利益统一起来。如果奖励的结果对员工有益,那么也必须对公司有益,反之亦然。如果奖励的结果对公司有害,则必然也对员工有害。这在遵纪守法的各个方面表现得尤为突出。     

Performance of some multiple testing procedures to compare three doses of a test drug and placebo

A study design with two or more doses of a test drug and placebo is frequently used in clinical drug development. Multiplicity issues arise when there are multiple comparisons between doses of test drug and placebo, and also when there are comparisons of doses with one another. An appropriate analysis strategy needs to be specified in advance to avoid spurious results through insufficient control of Type I error, as well as to avoid the loss of power due to excessively conservative adjustments for multiplicity. For evaluation of alternative strategies with possibly complex management of multiplicity, we compare the performance of several testing procedures through the simulated data that represent various patterns of treatment differences. The purpose is to identify which methods perform better or more robustly than the others and under what conditions. Copyright © 2005 John Wiley & Sons, Ltd.     

Methods for clarifying criteria for study continuation at interim analysis

In monitoring clinical trials, the question of futility, or whether the data thus far suggest that the results at the final analysis are unlikely to be statistically successful, is regularly of interest over the course of a study. However, the opposite viewpoint of whether the study is sufficiently demonstrating proof of concept (POC) and should continue is a valuable consideration and ultimately should be addressed with high POC power so that a promising study is not prematurely terminated. Conditional power is often used to assess futility, and this article interconnects the ideas of assessing POC for the purpose of study continuation with conditional power, while highlighting the importance of the POC type I error and the POC type II error for study continuation or not at the interim analysis. Methods for analyzing subgroups motivate the interim analyses to maintain high POC power via an adjusted interim POC significance level criterion for study continuation or testing against an inferiority margin. Furthermore, two versions of conditional power based on the assumed effect size or the observed interim effect size are considered. Graphical displays illustrate the relationship of the POC type II error for premature study termination to the POC type I error for study continuation and the associated conditional power criteria.