Reflection paper on the APV workshop on in vitro performance testing of topically applied and topically acting substances

Abstract

With great anticipation, the European Medicines Agency (EMA) guideline titled “Quality and Equivalence of Locally Applied, Locally Acting Cutaneous Products” officially came into effect on April 2, 2025. This regulatory document establishes the legal and scientific framework for the evaluation of generic topical medicinal products, particularly those for which systemic bioavailability is not a relevant endpoint. The guideline is designed to replace conventional clinical trials with scientifically justified alternative methodologies for demonstrating therapeutic equivalence to reference products in the context of generic marketing authorization. These methodologies include, most notably, in vitro release testing (IVRT), in vitro permeation testing (IVPT), stratum corneum sampling via tape stripping (TS), and the vasoconstriction assay for corticosteroids. Based on the draft guideline version released in 2018, preliminary experience has been gathered in recent years regarding the implementation and practical applicability of some testing parameters proposed. However, this early engagement also exposed several ambiguities and limitations in the draft guidance, prompting expectations that the finalized version would address these deficiencies and offer more comprehensive direction on the use of these methods. The present paper is intended to summarize these known limitations and critically examine selected aspects of the guideline. Thereby, it seeks to provide an informed perspective on the scope, robustness, and regulatory utility of the final guideline, and to facilitate a dialogue on its practical implementation in regulatory and industrial settings.