Batch Selection via In Vitro/In Vivo Correlation in Pharmacokinetic Bioequivalence Testing.

Pharmacokinetic differences between manufacturing batches, well established for inhaled drug products, preclude control of patient risk in the customary two-way (single batch) pharmacokinetic bioequivalence crossover design if batches are randomly chosen. European regulators have recommended selecting a "typical" in vitro batch to represent each product in pharmacokinetic bioequivalence testing. We explored the feasibility of this approach to control patient risk (the "false equivalence", or Type I, error rate). The probability of achieving a Test/Reference 90% confidence interval within (0.80, 1.25) for a true (non-equivalent) value of 1.25 was simulated for a two-way crossover design using the median in vitro batch across a range of number of in vitro batches, in vitro/in vivo correlation (IVIVC) quality (correlation coefficient, r, of zero to one), and within-subject between-batch pharmacokinetic variability. Even under extremely optimistic conditions, e.g., r=0.95 and >100 batches per product screened in vitro, patient risk for typical between-batch variability levels remained at least threefold higher than the 5% regulatory expectation for the significance level (the false equivalence error rate) of the pharmacokinetic bioequivalence test. This elevated error rate in bioequivalence decision-making occurs because of incomplete confidence that the true product average has been identified, and, importantly, omission of this uncertainty from the bioequivalence confidence interval.