Topical bioequivalence design studies: An update

Hitherto, the regulatory authorities required that the evaluation of therapeutic equivalence of a topical generic product (TGP) be documented primarily through comparative clinical endpoint studies. Although waivers could sometimes be equated, for most formulations these circumstances did not apply. The variability inherent to topical drug delivery makes comparative clinical studies insensitive, time-consuming, and costly. Their economic burden, coupled with the typically low market price of the reference product (RP) has limited the development of TGPs, as their chance of economic return is lower. These limitations have sparked considerable attention of academia, industry and regulators, having resulted in new regulatory recommendations. The key documents reflecting this paradigm shift are the FDA non-binding product-specific draft guidances, and the EMA draft guideline on quality and equivalence of topical products. Both guidelines clearly establish a regulatory background for in vitro release testing (IVRT), as well as in vitro permeation testing methods. These methods, if properly validated, can be used to infer on topical generic product bioequivalence. Due to the paramount importance of these studies, this chapter outlines a practical and regulatory oriented framework for the development, validation and performance of pivotal IVRT/IVPT studies.