Journal of biopharmaceutical statistics
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Two stage switching between testing for superiority (SUP) and noninferiority (NI) has been an important statistical issue in the design and analysis of the active-controlled clinical trials. Tsong and Zhang (2005) has shown that the Type I error rates do not change when switching between SUP and NI with the traditional generalized historical control (GHC) approach, however, they may change when switching with the cross-trial comparison (X-trial) approach. Tsong and Zhang (2005) further proposed a simultaneous test for both hypotheses to avoid the problem. ⋯ Since with the X-trial approach, using the simultaneous test, superiority is tested using all four treatment arms (current test and active control arms, active control and placebo arms in historical trials), the Type I error rate and power are expected to be somewhat different from the conventional superiority test (using the current test and active control arms only). Through a simulation study, we demonstrate that the Type I error rate and power between simultaneous test and the conventional superiority test are compatible. We also examine the impact of the assumption of equal variances of the current trial and the historical trial.
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Noninferiority trials without a placebo arm often require an indirect statistical inference for assessing the effect of a test treatment relative to the placebo effect or relative to the effect of the selected active control treatment. The indirect inference involves the direct comparison of the test treatment with the active control from the noninferiority trial and the assessment, via some type of meta-analyses, of the effect of the active control relative to a placebo from historical studies. ⋯ Consideration of the two kinds of Type I error rates is also important for defining a noninferiority margin. For the indirect statistical inference, the practical utility of any method that controls only the across-trial Type I error rate at a fixed small level is limited.
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In an active controlled noninferiority trial without a placebo arm, one of the major considerations is the selection of the noninferiority margin. Although the ICH E10 guideline provides general principles for the selection of appropriate noninferiority margins, there are no established rules or gold standards for the selection of noninferiority margins in active control trials. Hung et al. (2003) proposed a margin selection based on relative risk. ⋯ Statistical tests for mixed noninferiority margin are also derived. An example concerning the efficacy of a test therapy to an active control on a clinical adverse event in the target patient population with cardiovascular disease is presented to illustrate the proposed method. Simulation studies were also conducted to assess the type I error rate and the power.
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This paper provides reflections on the opportunities, scope and challenges of adaptive design as discussed at PhRMA's workshop held in November 2006. We also provide a status report of workstreams within PhRMA's working group on adaptive designs, which were triggered by the November workshop. Rather than providing a comprehensive review of the presentations given, we limit ourselves to a selection of key statements. The authors reflect the position of PhRMA's working group on adaptive designs.
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Comparative Study
Comparison of concordance correlation coefficient estimating approaches with skewed data.
The concordance correlation coefficient (CCC) is an index that assesses the agreement between continuous measures made by different observers. At least four methods are used to estimate the CCC: two (Lin's method, Variance Components) which are defined on the basis that data are normally distributed, and the two others (U-statistics, GEE) which do not assume any particular distribution of the data. Here the four methods are compared with skewed data from a model in which the subject means follow a log-normal distribution while the within-subject variability is assumed to be normally distributed. An example of alcohol consumption is considered and a simulation study is performed.