Critical Remarks on Reference-Scaled Average Bioequivalence

Area of Science:

• Pharmaceutical Sciences
• Regulatory Science
• Biostatistics

Background:

• Reference-scaled average bioequivalence (RSAE) is used for highly variable drugs.
• Current regulatory approaches vary by jurisdiction and may yield inconsistent conclusions.
• Operating characteristics of implemented RSAE methods have not been directly compared.

Purpose of the Study:

• To compare the operating characteristics of different RSAE methods.
• To assess consumer risk and clinically relevant differences under regulatory settings.
• To evaluate the impact of varying jurisdictional approaches on bioequivalence assessment.

Main Methods:

• Monte Carlo simulations were employed.
• Simulations assessed Type I Error and statistical power.
• Consumer risk and clinically relevant differences were evaluated.

Main Results:

• All RSAE methods showed potential for Type I Error inflation.
• Consumer risk was compromised in implemented RSAE methods.
• Clinically relevant differences varied across studies using the same reference product.

Conclusions:

• Average bioequivalence with fixed, widened limits ensures consumer risk and defines a clear clinically non-relevant difference.
• Until fixed limits are adopted, adjusting the test level alpha is recommended.
• Standardized approaches are needed for consistent bioequivalence assessment of highly variable drugs.