Individual Variation and the Acceptance of Average Bioequivalence

Regulatory criteria established for the acceptance of average bioequivalence do not fully satisfy the requirements arising for the interchangeability of drug products. The divergence is illustrated by noting that the regulatory criteria are compatible with large inter-individual variation of within-subject differences or ratios of the relevant kinetic parameters. Regulatory criteria of three jurisdictions are considered: the United States, Canada, and the Province of Ontario. For example, in a crossover trial conducted with 24 subjects, in as many as 60% of the individuals, the difference between the relevant kinetic parameters for the two formations could, on average, be outside the range of 70-130% of the reference product, and still satisfy the criterion of the Food and Drug Administration (FDA) for the acceptance of average bioequivalence. It is suggested that individual bioequivalence can be effectively evaluated in threeand four-way crossover trials.