What regulatory bioequivalence acceptance criterion for AUC and Cmax is commonly used, and what is the rationale behind it?

• A. 90% CI for T/R ratios within 80–125%; it reflects no clinically meaningful difference in systemic exposure
• B. 95% CI within 70–130%
• C. P-value < 0.05 for PK parameters
• D. No variability allowed

Answer: (A)

The main idea is that regulatory bioequivalence is shown by demonstrating that the systemic exposure from the test product is essentially the same as the reference. For AUC and Cmax, the standard criterion is that the 90% confidence interval for the ratio of the test to reference geometric means (usually calculated after log transformation) falls within the 80–125% range. This ensures that, on average, the test product yields exposure within about 20% of the reference, which regulators deem not to produce a clinically meaningful difference in safety or efficacy.

Why this approach makes sense: pharmacokinetic data are typically skewed, so using a log scale and the 90% CI corresponds to the two one-sided tests framework, providing a robust assessment of equivalence with a reasonable sample size. A ratio near 1 indicates similar peak and overall exposure, which are the exposures most tied to therapeutic effect and risk. The 80–125% bounds reflect a balance between allowing normal inter-subject variability and maintaining clinical similarity.

Why the other options don’t fit: a 95% CI within 70–130% is not the standard regulatory criterion for BE; P-values alone don’t define bioequivalence; and insisting no variability is achievable is unrealistic and not how BE is determined. In some contexts, highly variable drugs may use scaled approaches, but the common standard remains the 90% CI for the T/R ratio within 80–125%.