Discussion of EMA Draft Guideline on Quality and Equivalence of Topical Products Based on Comparison of Approved Mometasone Furoate Drugs

• Published in: Dermatology and therapy Vol. 14; no. 8; pp. 2153 - 2169
• Main Authors: Eichner, Adina, Mrestani, Yahya, Hukauf, Martin, Wohlrab, Johannes
• Format: Journal Article
• Language: English
• Published: Cheshire Springer Healthcare 01-08-2024; Springer; Adis, Springer Healthcare
• Subjects: Comparative analysis; Dermatology; EMA draft guideline on quality and equivalence of topical products; Generic drugs; Health aspects; In vitro penetration test (IVPT); Internal Medicine; Medicine; Medicine & Public Health; Mometasone; Mometasone furoate; Oral and Maxillofacial Surgery; Original Research; Plastic Surgery; Product introduction; Quality management; Quality of Life Research; Skin; Topical bioequivalence; Topical medication; Germany; In vitro penetration test (IVPT); Mometasone furoate; EMA draft guideline on quality and equivalence of topical products; Topical bioequivalence
• ISSN: 2193-8210; 2190-9172
• DOI: 10.1007/s13555-024-01222-z

Introduction
Today, the approval for a generic topical product includes the presentation of therapeutic equivalence to the originator based on clinical trials. To facilitate this procedure, in 2018 the European Medicines Agency (EMA) published a draft guideline on quality and equivalence of topical products, which includes request parameters regarding the quality of the newly developed generic product and test protocols for the implementation of equivalence tests regarding efficacy.
Methods
To date, no data are available on the quality and evidence of the proposed test conditions. In this study, we performed an in vitro penetration test (IVPT) following the terms of the EMA draft guideline on two authorized topical products for which therapeutic equivalence was already proven during the approval process.
Results
The complex biometric data processing revealed that in vitro equivalence could not be observed for all skin sections for either originator or generic product. Moreover, the necessity of the negative control proposed in the draft guideline is more than questionable. From the results presented, there were indications that a reduced number of skin donors would be sufficient to achieve statistically significant equivalence in the comparison of all applied formulations. Here,
n
 = 7 donors was proposed instead of
n
≥
12 as the EMA draft guideline demands, decreasing the degree of biodiversity simultaneously. Moreover, a higher number of independent replicates (
n
 > 2) was proposed for proper statistics.
Conclusion
This bioequivalence study shows insufficient parameters, which should be discussed together with the EMA draft guideline.
Plain Language Summary (PLS)
Today in Europe the approval of generic drugs requires clinical trials to present therapeutic equivalence to the originator. To facilitate this time- and cost-intensive process, the European Medicines Agency (EMA) published a draft guideline in 2018 proposing test protocols for carrying out equivalence tests for drugs applied on human skin. Although its publication is over 5 years old, it is still in a draft version; moreover, so far no evidence has been presented on whether the experimental settings in the test protocols can prove equivalence. This study should prove the EMA test protocol for in vitro permeation tests (IVPT) as closely as possible on two authorized topical products for which therapeutic equivalence was already proven during the approval process to determine whether their equivalence could be observed by this pharmacokinetic approach as well. Due to the experimental setup, a penetration test was performed to survey the drug diffusion behavior over the skin cross section instead of the amount of drug which permeates through the skin. To the best of our knowledge, this study is the first work published regarding that topic. Here, bioequivalence of the preparations applied, which were equivalent when they were tested on patients during their approval, was not found overall. We recommend reducing the number of donors and increasing the number of replicates to achieve a higher power for the statistical data evaluation. Moreover, an evaluation of the drug amount at the pharmaceutical place of action should be considered in the EMA guideline.