Population and individual bioequivalence: lessons from real data and simulation studies.

Area of Science:

• Pharmacokinetics and Drug Development
• Regulatory Science
• Statistical Analysis in Bioequivalence

Background:

• The U.S. Food and Drug Administration (FDA) proposed shifting from average bioequivalence (ABE) to population and individual bioequivalence (PBE & IBE).
• This proposal generated significant debate among experts in regulatory affairs, academia, and industry.
• The FDA's final guidance in 2000 maintained ABE as the primary criterion but recommended replicate designs for specific drug classes.

Purpose of the Study:

• To analyze existing bioequivalence study databases to evaluate the utility of a data collection period for PBE & IBE assessment.
• To provide an update on the authors' previous analysis of bioequivalence data.
• To explore the operating characteristics of PBE & IBE criteria.

Main Methods:

• Analysis of 28 datasets from 20 replicate cross-over bioequivalence studies (n=12-96).
• Application of statistical methodologies from the latest FDA draft guidance.
• Exploration of subject-by-formulation interaction sensitivity through simulation studies.

Main Results:

• Inconsistent results were observed within datasets across ABE, PBE, and IBE criteria.
• ABE criteria passed in 23/19 cases, while PBE & IBE passed in 21/17 cases.
• Failures for PBE and IBE criteria were observed in 0/3 and 6/8 cases, respectively.

Conclusions:

• Additional simulation assessments are crucial for evaluating the value of data collection for PBE & IBE.
• A combination of data-driven hypotheses and simulation studies can yield definitive conclusions on PBE & IBE operating characteristics.
• Recommendations for future data collection are proposed to further assess PBE & IBE.