By Taís Gratieri and Kelen Carine Costa Soares
A recent data collection performed by our group showed that 75% of topical dermatological products registered in Brazil are copies. Drugs of this class are supposed to penetrate the skin and exert a local pharmacological effect. The problem is, several studies in literature show differences between copies and reference products, evidencing the importance of increasing the number of studies to prove bioequivalence. The difficulty is, traditional bioequivalence methods—measuring concentrations of drug in blood samples—are not applicable due the low systemic absorption. So other studies should be employed; however, there is not yet a consensus about the ideal methodology.
Some regulatory authorities require clinical or pharmacodynamic studies to prove the efficacy and safety of the topical generic formulations. In literature, we can find different in vitro and in vivo approaches for bioequivalence assessment of topical dermatological drug products. Nevertheless, only four regulatory authorities (Canada, EMA [PDF], Japan [PDF], and the U.S. [PDF]) have specific guidance documents for topical drug products.
However, other regulatory authorities such as the Brazilian Health Surveillance Agency (ANVISA) don’t have any specific requirement for efficacy demonstration of copies. According to Resolution RDC n. 37 (PDF) (August 3, 2011), topical medicines, i.e., those not intended for systemic effects, are granted a biowaiver if: (i) the generic product contains the same active ingredient, (ii) in the same concentration as that of the reference product (pharmaceutical equivalents), and (iii) the generic product contains excipients with the same function as those of the reference formulation. The process of cutaneous absorption is complex and highly correlated with both drug physicochemical properties and the formulation. Excipients exerting “the same function” do not necessarily interact with the skin in the same manner; different excipients can promote skin absorption or hinder drug release. Hence, clinical efficacy of a topical medication depends largely on formulation components, as detailed in our recent AAPS Journal Regulatory Note. To test that the bioequivalence is essential and could not be waived, instead, how reliable would topical generic on the market be?
Successful approaches implemented for some authorities show that it is possible to require some tests that can improve the efficacy of topically administered generic formulations and ensure real interchangeability between these types of formulations. In this way, regulators, who still don’t ask for any proof of bioequivalence, should start thinking about updating their regulatory recommendations for topical dermatological drug products. Our group is currently evaluating different methodologies for in vitro skin permeation studies. The goal is to propose a protocol that could be recommended by ANVISA. For this, study design should be easily reproduced; the test should be robust and capable of detecting formulations differences that could affect performance.