Scaling of Bioequivalence Limits
RSABE (reference-scaled average bioequivalence): The limits are scaled based on the intra-subject variability of the reference drug. For drugs with higher variability, the acceptance criteria are relaxed, meaning the 90% confidence interval for the pharmacokinetic parameter ratios can be wider than the standard 80–125% used in ABE.
ABE (average bioequivalence): The bioequivalence criteria are fixed, with the 90% confidence interval needing to fall strictly within 80% to 125%, regardless of the drug’s variability.
Study Design
RSABE: typically involves a replicated crossover design, which is essential for accurately assessing within-subject variability. This design might be more complex and costly, but it is crucial for HVDs.
ABE: generally utilizes a standard two-period crossover design, which is simpler and less expensive but may not adequately address high variability in pharmacokinetic measures.
Applicability to Drug Variability
RSABE: is particularly useful for drugs with high intra-subject variability (over 30% CV). This approach reduces the likelihood of Type II errors, where bioequivalence is not demonstrated not due to actual differences but because of statistical power issues related to high variability.
ABE: Best suited for drugs with lower intra-subject variability, where the standard bioequivalence limits are appropriate and sufficient to demonstrate equivalence.
Regulatory Acceptance
RSABE: Accepted under specific conditions by major regulatory agencies like the FDA and EMA, especially for HVDs. These agencies have detailed guidelines on when and how RSABE should be employed.
ABE: is the universally accepted standard method for most drugs, supported by comprehensive regulatory guidance for its application.
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Resource Person: Chandramouli R