1. Guidance Update: Average, Population, and Individual Approaches to Establishing Bioequivalence Mei-Ling Chen, Ph.D. Associate Director Office of Pharmaceutical Science Center for Drug Evaluation and Research Food and Drug Administration Advisory Committee for Pharmaceutical Science November 16, 2000

2. Statistical Guidances on Bioequivalence u 1992 Guidance Statistical Procedures for Bioequivalence Studies Using Standard Two-Treatment Crossover Design u 1997 Preliminary Draft Guidance In Vivo Bioequivalence Studies Based on Population and Individual Bioequivalence Approaches u 1999 Draft Guidance Average, Population and Individual Approaches to Establishing Bioequivalence

3. The 1999 Draft Guidance u Incorporates 1992 Guidance u Updates 1997 Preliminary Draft Guidance u Focuses on various study designs, statistical criteria and methodologies for establishing bioequivalence u Does not deal with the question of “when to use” a specific criterion

4. Regulatory Application u Replicate designs are recommended for modified release dosage forms and highly variable drug products. u Average BE is recommended for comparison of bioavailability measures in most BE studies. u Sponsors/applicants have the option to provide rationale for using another criterion, e.g., individual BE for highly variable drug products. u Currently, population BE is used for the in vitro testing of nasal and oral inhalation drug products.

5. Statistical Guidance Outline u Introduction u Background u Statistical Model u Bioequivalence Criteria u Study Design u Statistical Analysis u Miscellaneous Issues u Appendices

6. Types of Bioequivalence  Average Bioequivalence (Current) - Population means (    R )  Population Bioequivalence - Population means (    R ) - Total variances (  TT 2,  TR 2 )  Individual Bioequivalence - Population means (    R ) - Within-subject variances (  WT 2,  WR 2 ) - Subject-by-formulation interaction (  D 2 )

7. Bioequivalence Criteria [ Criterion ]  BE Limit  Average BE: (  T -  R ) 2  A 2 (  T -  R ) 2 +  D 2 + (  WT 2 -  WR 2 )  Individual BE: -------------------------------------------   I  WR 2 (  T -  R ) 2 + (  TT 2 -  TR 2 )  Population BE: -----------------------------------   P  TR 2

8. Distance Concept u A key concept for the population and individual BE criteria is to compare the distance measure between the T and R formulations, T-R, with that of the reference formulation against itself, R-R´. The distance measure is expressed by the expected squared difference and this comparison is denoted as a ratio of the two measures indicated below. E (T - R) 2 --------------------- E (R - R´) 2

9. General Form  Derived from the distance concept, both population and individual BE criteria compare the distribution (combination of mean and variance) between the T and R products, and result in a general form as follows: (Average Difference) 2 + Variance Terms ------------------------------------------------------  BE Limit Reference Variance u Both criteria are scaled to the variability of the reference product - this is referred to as reference-scaling.

10. Constraint on Mean Difference (Average Difference) 2 + Variance Terms ------------------------------------------------------  BE Limit Reference Variance u Concern for a possible large average difference due to the mean-variance tradeoff and reference-scaling u Resolution - In addition to the BE limits based on confidence bounds, the guidance recommends further constraint on the point estimate of the geometric T/R mean ratio to fall within 80-125%.

11. Guidance Status Draft Guidance August 1999 Review of Public Comments by Working Group (WG) Review of Public Comments by Working Group (WG) Revision of Draft Guidance by WG and BCC Revision of Draft Guidance by WG and BCC Public Comment Period Internal Clearance