Aim: 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 with respect to 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 both, originator and generic product. Moreover, the necessity of the negative control proposed in the draft guideline is more as questionable. From the results presented, there were indications that a reduced number of skin donors would be sufficient in order to achieve statistically significant equivalence in the comparison of all applied formulations, decreasing simultaneously the degree of biodiversity. Moreover, a higher number of independent replicates (n>2) is proposed for proper statistics. Conclusion: This bioequivalence study shows insufficient parameters in the EMA draft guideline, which should be discussed.