Review of methods and criteria for the evaluation of bioequivalence studies.

Guidelines for the performance and analysis of bioequivalence studies are not very specific. The advantages and disadvantages of the following methods and tests are discussed: analysis of variance by summation or by use of general linear models, nonparametric procedures, aposteriori probabilities and tests on the normality of residuals and on the variability of the results. Arguments for or against an analysis of data after logarithmic transformation versus analysis of untransformed data are presented. If the confidence intervals lie within certain limits, preparations may be considered equivalent. The criteria leading to those limits are discussed. It is recommended that concentration-dependent data of bioequivalence studies be evaluated by analysis of variance after logarithmic transformation, applying general linear models. Data that by theoretical reasons cannot be normally or log-normally distributed should be analysed by nonparametric methods. Otherwise these methods can only be recommended if a significant deviation from normality has been noted and only for two-way cross-over designs. For a geometric evaluation (after logarithmic transformation) the regions of acceptance should be symmetrical in the logarithm, e.g. (80%, 125%).