Some statistical considerations on the FDA draft guidance for individual bioequivalence

In December of 1997, the FDA proposed a draft guidance for future in vivo bioequivalence studies. The guidance suggested specific criteria for new drug sponsors to show individual bioequivalence (IBE). The criteria use a mixed-scaling aggregate strategy. It has been generally accepted that, under some particular situations, the proposed criteria would result in a relaxation of the current bioequivalence standard set by the average bioequivalence (ABE) criterion. Here we study the magnitude of this relaxation under three scenarios: when the conditions for an ABE investigation are met; when the drugs are highly variable, and when the experiments are poorly conducted. The magnitude of relaxation we report here may be surprisingly large to many. For example, when a drug is highly variable (with the intrasubject coefficient of variation reaching 40 per cent), the allowable limit for the ratio of the formulation means could reach 55-180 per cent in an IBE investigation. In comparison, the usual allowable limit in an ABE investigation is 80-125 per cent. Our investigation raises doubts on whether the implied standard of the new proposed IBE criteria would adequately ensure switchability in highly variable drugs. Copyright (C) 2000 John Wiley & Sons, Ltd.