The transitivity of bioequivalence testing: potential for drift

Area of Science:

• Pharmacokinetics and Drug Development
• Regulatory Science
• Pharmaceutical Manufacturing

Background:

• Bioequivalence studies are critical for drug product formulation refinement and generic drug approval.
• These studies compare a generic drug formulation to the innovator's product to ensure therapeutic equivalence.
• The transitivity of bioequivalence, where A is equivalent to B, and B to C, implies A is equivalent to C, is not fully understood.

Purpose of the Study:

• To investigate the transitivity of average bioequivalence under current regulatory standards.
• To determine the extent to which bioequivalence can be inferred across multiple formulation steps (A-B, B-C, etc.).
• To assess the impact of the number of bioequivalence steps and study power on transitivity.

Main Methods:

• Simulations were conducted considering 1, 2, 3, and 6 sequential bioequivalence steps.
• The analysis focused on average bioequivalence with the standard 80% to 125% equivalence criterion.
• The power of individual bioequivalence studies was varied to observe its effect on transitivity.

Main Results:

• Bioequivalence is suggested to be transitive for a small number of steps (e.g., A-C, A-D) when bioavailability differences are minimal.
• Confidence in bioequivalence decreases significantly with an increasing number of sequential steps (e.g., A-G).
• Higher statistical power in individual bioequivalence studies diminishes the overall transitivity of the bioequivalence relationship.

Conclusions:

• The transitivity of bioequivalence is limited and decreases with each additional step in the formulation or manufacturing chain.
• Regulatory reliance on sequential bioequivalence studies may require careful consideration, especially for extended chains.
• The findings highlight the importance of understanding the cumulative effect of bioequivalence assessments in drug development and generic approvals.