Individual bioequivalence--a European perspective

Area of Science:

• Pharmacokinetics and Pharmaceutical Sciences
• Biostatistics and Regulatory Science

Background:

• International harmonization exists for average bioequivalence regulatory requirements.
• Individual bioequivalence lacks standardized regulatory approaches.
• Highly variable drugs present challenges for setting appropriate bioequivalence ranges.

Purpose of the Study:

• To address the complexities of individual bioequivalence, particularly for highly variable drugs.
• To highlight the limitations of standard crossover designs in detecting subject-by-formulation interactions.
• To advocate for broader international understanding and adoption of advanced statistical methods for replicate designs.

Main Methods:

• Discussion of replicate designs and advanced bioequivalence criteria.
• Exploration of scaling bioequivalence criteria by intrasubject variability.
• Reference to Schall's unified statistical procedures for replicate designs.

Main Results:

• Standard 2x2 crossover designs are insufficient for detecting subject-by-formulation interactions.
• Replicate designs offer a more robust approach for assessing individual bioequivalence.
• Proposed statistical methods exist but have limited accessibility and understanding.

Conclusions:

• More complex replicate designs are necessary for individual bioequivalence, especially for highly variable drugs.
• There is a need to increase international awareness and understanding of these advanced statistical procedures.
• Further dissemination of knowledge on individual bioequivalence statistical methods is crucial for regulatory science.