1. Individual Bioequivalence: Strengths and Weaknesses of the Current Approach: View from the Generic Pharmaceutical Association by MDS Pharma Services FDA Advisory Committee Pharmaceutical Sciences November 29, 2001 Mario Tanguay, BPharm, PhD Associate Director, Pharmacokinetics

2. Individual Bioequivalence Collaborators GPhA Science and CRO/Biopharmaceutics Committees MDS Pharma Services –Murray P. Ducharme, PharmD, FCCP, FCP –Marika Pasternyk DiMarco, MSc, PhD –Diane Potvin, MSc

3. Individual Bioequivalence Advantages of IBE Enables one to capture the advantages of giving the same formulation twice –Replicate design has no real benefit when ABE is used IBE may be ethically advantageous –Smaller sample size needed for highly variable drugs due to the scaling component

4. Individual Bioequivalence Disadvantages of IBE How robust is the assessment of switchability with current IBE approach? –BE studies are primarily designed to prove bioequivalence based on Cmax and AUCs calculations –Current BE studies are not designed to allow proper determination of a Subject * Form interaction  Reason(s) for Subject * Form interaction cannot be identified properly

5. Individual Bioequivalence Disadvantages of IBE Enrollment of a heterogeneous population may not be helpful –BE Studies are not properly designed to evaluate Gender differences in PK Age differences in PK Race differences in PK etc...

6. Individual Bioequivalence Disadvantages of IBE In clinical research, conclusions based on posteriori statistical subgroup evaluations have many times been proven to be wrong when verified in properly designed prospective studies. These lessons should apply to switchability measurement in BE studies

7. Individual Bioequivalence Conclusion The BE of 2 formulations of a highly variable drug will be better assessed by giving a formulation more than once to the same subject However, it is not appropriate to assume that switchability is robustly assessed with IBE –Posteriori subgroup calculations (study not designed for this) –Contrary to the lessons we have learned over the years in Clinical Pharmacology