1. Results from Replicate Design Studies in ANDAs Rabi Patnaik, Ph.D. Division of Bioequivalence Office of Generic Drugs Office of Pharmaceutical Science, CDER Advisory Committee for Pharmaceutical Science Meeting CDER Advisory Committee Conference Room 5630 Fishers Lane, Rockville, MD November 29, 2001.

2. ABE IBE < ABE & IBE Criteria and Parameters Lower BE Limit < Test Mean - Ref. Mean < Upper BE Limit (Test Mean - Ref. Mean) 2 + (Subj*Form) 2 + (Test within-subj. SD 2 - Ref. within-subj. SD 2 ) Upper BE Limit *(Ref. within-subj. SD) 2 or (Regulatory within- subj. SD) 2 *use Ref. within-subj. SD if Ref. within-subj. SD > 0.2 (Reference-scaled) use Regulatory within-subj SD (0.20) if Ref. within-subj SD < 0.2 (Constant-scaled)

3. Summary of Studies Purpose of Submission: Approval of generic drugs Number of Studies: 13 Study Design: 2-treatment, 2-sequence, 4-period Crossover Sequence Designs: ABAB/BABA and ABBA/BAAB Number of Subjects: 16 - 59 Demography: Controlled population (mostly young healthy male subjects) Dosage Forms: IR, MR (solid oral products), Suspension, Suppository Analyte: Parent Drug BE Measures: AUC(0-T), AUC(0-inf), CMAX

4. Summary of Results Individual Bioequivalence (IBE) Average Bioequivalence (ABE) Pass Fail PassFail 11/13 (AUCT) 12/13 (AUCI) 12/13 (CMAX) 1/13 (CMAX) 2/13 (AUCT) 1/13 (AUCI) BE Measure Within-subj. Std. Dev. Range - Ref. Drug Within-subj. Std. Dev. Test/Ref. Ratio - Range Subj.X Form. - Range Test/Ref G. Mean Ratio. - Range AUC(0-T)89.3 - 103.6%0.06 - 0.390.88 - 1.560 - 0.2 AUC(0-inf)89.3 - 103.9%0.08 - 0.380.77 - 1.540 - 0.12 CMAX88.5 - 115.1%0.11 - 0.450.69 - 1.340 - 0.2 Number of Data Sets Passing/Failing by IBE and ABE Criteria Summary of IBE Parameters NONE

8. Performance of the IBE Criterion - Some Examples 1. Failing ABE & Passing IBE: Drug #2 - IR (CMAX) - N=55 2. Passing IBE (Drug #1 - IR, N=29) & Failing IBE (Drug #4 - IR, N=59) - AUC(0-T) 3. Passing IBE (Drug #3 - SUP., N=57) & Failing IBE (Drug #6 - ER, N=27) - AUC(0-T)

9. Subject-by-Formulation Interaction (Drug #4) - AUC(0-T)

10. Subject-by-Formulation Interaction - CMAX (Drug #2)

11. Concluding Remarks 1. IBE approach is an aggregate criterion. The combination of all three parameters (differences in means, differences in within-subject variances, and subject*formulation) determines the outcome. 2. Scaling approach is particularly helpful for highly variable drugs with large within-subject variances. 3. Analysis of showed that important subject-by-formulation interactions occurred due to a few subjects. The reliability and the possible cause of such observed interactions need to be carefully investigated. 4. The studies received thus far during the interim period, have utilized controlled populations. The frequency of occurrence of important subject-by-formulation interactions and the utility of this approach will be better evaluated as BE studies using heterogeneous general populations become available to the Agency.