Novel scaled bioequivalence limits with leveling-off properties

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Pharmaceutical Sciences
• Regulatory Science

Background:

• Bioequivalence (BE) studies are crucial for generic drug approval.
• Current BE limits, such as 0.80-1.25, may not adequately address variability.
• Novel approaches are needed to refine BE limit setting.

Purpose of the Study:

• To develop novel scaled bioequivalence (BE) limits with levelling-off properties based on variability.
• To evaluate the performance of these new limits against established criteria (0.80-1.25, 0.75-1.33) and GMR-dependent limits (BELscW).

Main Methods:

• Two model functions were employed to achieve gradual changes in BE limits.
• Simulations of two-period crossover BE studies with varying subject numbers and coefficients of variation (CV) were conducted.
• Power curves and estimation accuracy were assessed using Geometric Mean Ratio (GMR) values.

Main Results:

• Four new scaled BE limits were developed, showing favorable performance for average BE evaluation.
• At low variability, two new limits matched the 0.80-1.25 criterion, while others were less permissive.
• At high CV values, new limits offered higher statistical power than 0.80-1.25, similar to 0.75-1.33, and were less permissive than BELscW.
• The new limits demonstrated more accurate estimation due to the absence of the GMR factor in their model functions.

Conclusions:

• The novel scaled BE limits are effective across all investigated variability levels.
• These limits provide satisfactory estimation accuracy for bioequivalence assessments.
• The findings support the use of variability-based scaled BE limits for improved drug evaluation.