Abstract:

Purpose. i) To develop novel approaches for the construction of bio-equivalence ( BE) limits incorporating both the intrasubject variability and the geometric mean ratio (GMR), and ii) to assess the performance of the novel approaches in comparison to several scaled BE procedures and the classic unscaled average BE. Methods. Plots of the BE limits or the extreme GMR values accepted as a function of the coefficient of variation ( CV) were constructed for published and the developed scaled procedures. Two-period crossover BE investigations with 12, 24, or 36 subjects were simulated with assumptions of a CV 10%, 20%, 30%, or 40%. The decline in the percentage of accepted studies was recorded as the true GMR for the two formulations was raised from 1.00 to 1.50. Acceptance of BE was evaluated by published and the developed scaled procedures, and, for comparison, by the unscaled average BE. Results. Two GMR-dependent BE limits are proposed for the evaluation of average BE: i) BELscG1 with Ln(Upper, Lower BE limit) = +/-{[}(5-4GMR)0.496s + Ln(1.25)], and ii) BELscG2 with Ln(Upper, Lower BE limit) = +/-{[}(3-2GMR)(0.496s + Ln(1.25))], where s is the square root of the intrasubject variance. The range of BE limits becomes narrower as GMR values deviate from unity, and increases with variability. The two new approaches exhibit the highest statistical power at low CV values. At high levels of variability, BELscG1 and BELscG2 show high statistical power, as well as the lowest percentages of acceptance among the scaled methods when GMR = 1.25. The latter becomes more obvious when a large number of subjects is incorporated in the studies. Conclusions. The GMR and CV estimates of the BE study can be used in conjunction with the GMR vs. CV plot for the assessment of average BE. The new approaches, BELscG1 and BELscG2, appear to be highly effective at all levels of variation investigated.