PubMed · 14684632
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Colin Currie. 2003-12-20. Clinical arithmetic.. https://doi.org/10.1136/bmj.327.7429.1418
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In active controlled trials without a placebo arm, there are usually two study objectives: to test a superiority hypothesis that the experimental treatment is more effective than the active control therapy, and to test a non-inferiority hypothesis that the experimental treatment is therapeutically no worse than the active control within a defined margin. For a two-stage adaptive design, it is not necessary to give a fixed sample size calculation at the planning stage of the study when treatment effect information is often insufficient. Instead, decision and estimation of the design specifications can be made more reliably after the first stage when interim results are available. We propose the use of conditional power approach to determine the sample size and critical values for testing the superiority and non-inferiority hypotheses for the second stage based on the observed result of the first stage. The proposed adaptive procedure preserves the overall type I error rate for both superiority and non-inferiority, and has the flexibility of early termination of the study (for futility or efficacy) or extending the study by appropriate sample size.
There is a sizeable literature on methods for detecting gene-environment interaction in the framework of case-control studies, particularly with reference to the assumption of independence of genotype and exposure. In the context of a clinical trial, wherein gene-drug interactions with regard to outcomes are examined, these methods may be readily applied, as gene and drug are independent by randomization. In an active-controlled trial (experimental treatment vs standard) that has collected genotype information, gene-drug interactions can be estimated. In addition, the effect of the experimental treatment vs placebo can be imputed by using data from a historical placebo-controlled trial (standard vs placebo) if either (a) genotype information is available from the historical trial or (b) assumptions are made about the prevalence of genotype and the odds ratios of genotype and disease in the historical trial using information from other studies. Motivation for these procedures is provided by the Genetics of Hypertension Associated Treatment, a large pharmacogenetics, ancillary study of a hypertension clinical trial, and examples from published hypertension trials will be used to illustrate the methods.
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