Scaling or wider bioequivalence limits for highly variable drugs and for the special case of C(max)

To illustrate that bioequivalence (BE) can be effectively evaluated for highly variable (HV) drugs and drug products and for the special case of C(max) by using average BE. To demonstrate that either scaling or wider regulatory limits need not result in large observed ratios of the geometric means (GMR) of the 2 drug products.

Two- and 4-period crossover BE investigations with 24 subjects were simulated. Variabilities of 15, 25 or 35% were assumed in special studies of C(max) and 40% in the general investigations of HV drugs. Acceptance of BE was analyzed in each study by various procedures and regulatory criteria. Under each condition, the percentage of simulated investigations accepting BE was recorded as the simulated GMR was gradually raised from 1.00.

Scaled average BE for HV drugs (in both 2- and 4-period studies) and expanding limits for C(max) increased substantially, as expected, the proportion of investigations accepting BE. An additional secondary regulatory criterion constrained the simulated GMR to 1.25 and limited the possibility of large deviations between the mean metrics of the 2 formulations. Acceptance of BE by the composite regulatory expectation never exceeded the acceptances by the separate component criteria.

The sample size required for the evaluation of BE for HV drugs and drug products can be substantially reduced by applying the approach of scaled average BE. The same conclusion is reached from the determination of BE for the C(max) metric by expanding the regulatory limits to 0.75 - 1.33 or even to 0.70 - 1.43. Concerns for observations of high GMR values can be eased by imposing constraints with a secondary regulatory criterion.