An Approach for Widening the Bioequivalence Acceptance Limits in the Case of Highly Variable Drugs

Abstract

Purpose. Highly variable drugs pose a problem in bioequivalence assessment because they often fail to meet current regulatory acceptance criteria for average bioequivalence (80–125%). This paper examines alternative approaches to establishing bioequivalence. Methods. Suggested solutions have included alternate study designs, e.g., replicate and multiple dose studies, reducing the level of the confidence interval, and widening the acceptance limits. We focus on the latter approach. Results. A rationale is presented for defining wider acceptance limits for highly variable drugs. Two previously described methods are evaluated, and a new method having more desirable properties is proposed. Conclusions. We challenge the “one size fits all” current definition of bioequivalence acceptance limits for highly variable drugs, proposing alternative limits or “goal posts” which vary in accordance with the intrasubject variability of the reference product.