The Global Bioequivalence Harmonisation Initiative (GBHI): Report of the sixth international EUFEPS/PQRI conference

At the 6^th International Conference of the Global Bioequivalence Harmonisation Initiative (GBHI), co-organised by the European Federation of Pharmaceutical Sciences (EUFEPS) and the Product Quality Research Institute (PQRI), critical bioequivalence (BE) topics were discussed by pharmaceutical scientists from academia, industry and regulatory agencies, revealing the following main conclusions: (1) Physiologically based pharmacokinetic/biopharmaceutic modelling (PBPK/PBBM) for solid oral drugs: PBPK/PBBM gains increasing recognition for generic drug development, e.g. waivers of fed studies and drug interaction studies with proton pump inhibitors. However, especially for complex formulations containing low-solubility compounds, more data are needed for modelling-based conclusion regarding BE in fed state. (2) Narrow therapeutic index drugs: A progress towards harmonisation of BE criteria from US-FDA and EMA speakers was made as there is consensus in the usefulness of applying a mixed scale for BE acceptance range depending on variability, via either fully or partially replicated design. Differences still remain regarding variability comparison and the selection of regulatory constant (0.760 vs. 1.05361). All parties confirmed the importance of controlling type-I error. (3) Single- vs. multiple-dose studies for BE demonstration of modified-release (MR) products: To circumvent multiple-dose studies, model-informed approaches were discussed based on real-life data, e.g. to simulate steady-state profiles from single-dose data. To reduce the burden in patient trials for long-acting injectables promising modelling approaches were presented, extrapolating from incomplete steady-state scenarios. (4) BE demonstration for additional dose strengths of solid oral MR products: For multiple-unit dosage forms where strengths differ in number of units only, testing BE of the highest dose was considered sufficient. In addition, there was some consensus that, whenever extrapolation from one strength to the others is not easily established, the "bracket-approach" of the EMA focusing on the intake conditions in the label claim (fasted or fed), can help mitigating risks without adding significant cost and effort. (5) Partial AUC for BE demonstration: Clinical relevance is key to decide on the relevant PK metrics for BE assessment whenever possible. There was consensus that the BE criteria and evaluation strategy may be best specified in product-specific guidances - preferably with international harmonisation. (6) BE of orally inhaled drug products (OIDPs): The "weight-of-evidence" approach of US-FDA and the stepwise approach of EMA largely differ. The auditorium was in favour of combining data on in-vitro characteristics and PK exposure. For prediction of comparable efficacy of two OIDPs, there is good trust in PK exposure data whenever they present concentrations being absorbed via the lung. GBHI has a strong role in scientifically supporting official harmonisation efforts including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use since the first conference in 2015.