Regulatory Approaches for Bioequivalence Study of Highly Variable Drugs (HvD)

HvD pose a unique challenge in generic drug development due to their high intra-subject variability (CV > 30%) in pharmacokinetics. This variability complicates BE studies, requiring different regulatory agencies to adopt distinct approaches to ensure therapeutic equivalence without clinical hurdles.

Key Regulatory Approaches for HvD Generic Drug Approval

USFDA Approach – Reference-Scaled Average Bioequivalence (RSABE)

• Introduced to address high variability without excessive study subjects.
• Uses scaled bioequivalence criteria based on within-subject standard deviation (SDw) of the reference product.
• Allows wider bioequivalence limits (e.g., 75-133% instead of 80-125%) if intra-subject variability is high.
• Requires fully replicate crossover study design (e.g., 4-period or 3-period design).
• Example: Montelukast, Venlafaxine, and Omeprazole formulations often qualify under RSABE.

EMA Approach – Reference-Scaled Average Bioequivalence (RSABE) with Constraints

• Similar to USFDA but with a cap on widening limits to prevent excessive deviations.
• BE limits can be widened up to 69.84-143.19%, but additional pharmacodynamic or safety considerations may apply.
• EMA requires applicants to justify that variability is an intrinsic property of the drug and not formulation-dependent.
• Example: EMA often evaluates drugs like Tacrolimus with stricter acceptance criteria due to narrow therapeutic index (NTI) concerns.

Health Canada Approach – Alternative Bioequivalence Limits for HvD

• Allows bioequivalence limits to be widened up to 70-143% but requires larger study sizes if variability is >30%.
• Prefers two-sequence, four-period crossover or full replicate design to estimate within-subject variability.
• Accepts scaled BE for drugs with high variability in Cmax but generally maintains standard 80-125% AUC criteria.

TGA (Australia) & ANVISA (Brazil) Approaches – Hybrid Models

• TGA follows EMA-aligned criteria but with more flexibility on study design.
• ANVISA applies scaled BE only for Cmax while keeping AUC within 80-125% limits.
• Challenges & Considerations in HvD Drug Generic Approvals

Regulatory Variability – Different agencies have different acceptance criteria, requiring multiple BE strategies

• Study Design Impact: Choice of 2×2 crossover vs. replicate design significantly impacts variability assessment.
• Narrow Therapeutic Index (NTI) Complications: For drugs with high variability but NTI (e.g. Tacrolimus), stricter requirements may apply.

Conclusion – A Tailored Strategy for Global Generic Approval

• Developing generics for HvD drugs requires region-specific strategies to align with USFDA, EMA, Health Canada, and TGA/ANVISA requirements.
• For USFDA: Use fully replicated study and RSABE.
• For EMA: Apply scaled BE with constraints and justify variability origins.
• For Canada & Others: Optimize study design while maintaining standard AUC limit.

Read Also:

• Factors Affecting Bioequivalence (BE) Results
• Formulation Development Strategies for Biologics Product

Resource Person: Moinuddin syed. Ph.D, PMP®