A robust method for the assessment of average bioequivalence in the presence of outliers and skewness.

PURPOSE

In this paper, we propose a robust Bayesian method for the assessment of average bioequivalence based on data from conventional crossover studies. We evaluate and motivate empirically the need for robust methods in bioequivalence studies by comparing the results of robust and conventional statistical methods in a large data pool of bioequivalence studies.

METHODS

Robustness of the statistical methodology is achieved by replacing the normal distributions for residuals in the linear mixed model with skew-t distributions. In this way, the statistical model can accommodate skew and heavy-tailed data, particularly outliers, yielding robust statistical inference without the need for excluding outliers from the analysis. We performed a simulation study to investigate and compare the performance of the robust and conventional models.

RESULTS

Our study shows that in some trials, the distribution of residuals is skew and heavy-tailed. In the presence of outliers, the 90% confidence intervals for the ratio of geometric means tend to be narrower for the robust methods than for the conventional method. Our simulation study shows that the robust method has suitable frequentist properties and yields more precise confidence intervals and higher statistical power than the conventional maximum likelihood method when outliers are present in the data.

CONCLUSIONS

As a sensitivity analysis, we recommend the fit of robust models for handling outliers that are occasionally encountered in crossover design bioequivalence data.