A002: A Comparative Review of Study Population & Dose Recommendations for In Vivo Bioequivalence Studies With Pharmacokinetic Endpoints Between FDA & EMA Guidances

Statement of Purpose, Innovation or Hypothesis: The US Food & Drug Administration (FDA)’s product-specific guidances (PSGs) describe the agency’s current thinking on the most appropriate method for establishing therapeutic equivalence between generic drugs and reference listed drugs (RLDs). The European Medicines Agency (EMA)’s product-specific bioequivalence (BE) guidances (also referred to as “PSG” in this abstract) summarize the relevant study design principles for demonstration of BE to meet EMA’s regulatory expectations. Understanding the major areas of differences in recommendations on BE study design between the FDA’s and EMA’s PSGs is important to address challenges from generic applicants seeking approval from both agencies. Therefore, this study evaluated the underlying factors leading to these differences in recommendations between FDA and EMA on study population and dose for BE studies with pharmacokinetic (PK) endpoints for immediate release (IR) oral drug products.

Description of Methods & Materials: A list of EMA’s PSGs of oral IR drug products were retrieved from the EMA website. Subsequently, the corresponding PSGs for products with the same active pharmaceutical ingredients (APIs) and dosage forms were retrieved from the FDA PSG website. The recommended study population and dose in these guidances were then compared for each drug product. Information on the highest approved strength was retrieved from the approved labeling.

Data & Results: Seventy-eight oral drug products (66 APIs) have PSGs available from both agencies (66 from EMA, 78 from FDA). Of PSGs for the 78 drug products, five have discordance in study population. FDA recommends patients for BE assessment of imatinib, pazopanib, and sunitinib products while EMA recommends HVs. For asenapine, FDA recommends patients while EMA recommends either patients or HVs. For lapatinib, FDA recommends HVs while EMA recommends patients. In general, risks due to toxicities including carcinogenicity, hemodynamic effects, cardiotoxicity, and/or hepatotoxicity, may be considered for the recommendation of the appropriate study population. For the study dose selection in HVs, the two agencies recommend a different dose in 11 EMA and 13 FDA PSGs corresponding to 13 drug products. Four EMA PSGs recommend BE studies using more than one strength in HVs due to PK characteristics (e.g., non-dose-proportionality or differential food-effect) while FDA recommends a single strength. When compared between the agencies, FDA recommends a higher dose for ursodiol capsule and cobicistat; elvitegravir; emtricitabine; tenofovir disoproxil fumarate tablets, while EMA recommends a higher dose for bosutinib, colchicine, dasatinib, everolimus, memantine, ursodiol tablet, and vandetanib (Table 1).

Interpretation, Conclusion or Significance: There are some discordances in the selection of the study population (HV vs patients) and/or recommended dose for BE studies with PK endpoints between EMA and FDA PSGs. The discordances in study population and/or recommendation may reflect the two agencies’ different approaches in assessing the safety considerations, which may still be a challenge after harmonization of general BE guidances such as ICH M13A. In addition, the selection of recommended study dose may be guided by the differences in approved strengths and differences in safety considerations. Ongoing efforts to harmonize the recommendations of study population and dose are warranted to facilitate generic drug development.

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