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Geometric mean ratio-dependent scaled bioequivalence limits with leveling-off properties
Vangelis Karalis1, Panos Macheras, Mira Symillides
1Laboratory of Biopharmaceutics-Pharmacokinetics, School of Pharmacy, University of Athens, Panepistimiopolis, Athens 157 71, Greece.
Summary
Novel bioequivalence (BE) limits scale with variability, combining classic and expanded criteria. These new limits offer a balanced approach, performing similarly to classic criteria at low variability and providing greater certainty than expanded limits at high variability.
Area of Science:
- Pharmacokinetics and Pharmaceutical Sciences
- Biostatistics
- Drug Regulatory Science
Background:
- Bioequivalence (BE) studies are crucial for demonstrating therapeutic equivalence between generic and reference drugs.
- Current BE limits, such as 0.80-1.25 and expanded criteria (0.70-1.43, 0.75-1.33), have limitations in handling varying levels of intrasubject variability.
- There is a need for flexible BE limits that adapt to intrasubject variability while maintaining regulatory stringency.
Purpose of the Study:
- To develop and evaluate novel approaches for designing bioequivalence (BE) limits.
- To create a single BE criterion that integrates classic and expanded limits, scaling with intrasubject variability.
- To assess the performance of these novel BE limits against existing criteria using simulated data.
Main Methods:
- Development of novel BE limits that scale with intrasubject variability up to a geometric mean ratio (GMR)-dependent plateau.
- Simulation of two-period crossover BE studies with varying numbers of subjects (12, 24, 36) and coefficients of variation (CV: 10%, 20%, 30%, 40%).
- Comparison of the novel BE limits' performance against classic (0.80-1.25) and expanded (0.70-1.43, 0.75-1.33) limits based on simulated data.
Main Results:
- Novel BE limits perform similarly to classic 0.80-1.25 limits at low CV values.
- Expanded BE limits (0.70-1.43) are found to be overly permissive, even at high GMR values.
- For high CV (30%, 40%), novel limits show a higher probability of declaring BE when GMR=1 compared to classic limits.
- Novel limits demonstrate a lower acceptance rate than expanded 0.70-1.43 limits when drug products differ by >25%.
Conclusions:
- The novel BE limits offer a gradual expansion with variability up to a GMR-dependent plateau, providing a balanced approach.
- Their continuity and leveling-off properties make them suitable for diverse BE study scenarios, regardless of variability levels.
- These new limits address limitations of current criteria, offering improved assessment of bioequivalence across different variability conditions.