Using Product Development Information to Address the Bioequivalence Challenges of Highly-variable Drugs

1. Using Product Development Information to Address the Bioequivalence Challenges of Highly-variable Drugs Lawrence X. Yu, Ph. D. Director for Science Office of Generic Drugs Food and Drug Administration Advisory Committee for Pharmaceutical Science May 4, 2005

2. Bioequivalence of Highly Variable Drugs Lawrence X. Yu, Ph.D. Director for Science Office of Generic Drugs, OPS, CDER, FDA ACPS Meeting, April 14, 2004

3. Objectives • Explore and define bioequivalence issues of highly variable drugs • Discuss potential approaches

4. Bioequivalence of Highly Variable Drugs • Introduction (5 min) Lawrence Yu, Ph.D. • Why Bioequivalence of Highly Variable Drugs Is an Issue? (20 min) Charlie Diliberti, Barr Lab • Highly Variable Drugs: Sources of Variability (20 min) Gordon L. Amidon, Ph.D. • Clinical Implications of Highly Variable Drugs (20 min) Leslie Benet, Ph.D. • Bioequivalence Methods for Highly Variable Drugs (20 min) Laszlo Endrenyi, Ph.D. • Bioequivalence of Highly Variable Drugs (30 min) Barbara Davit, Ph.D., Sam Haidar, Ph.D. • BE of HV Drugs Q & A Dale Conner, Pharm.D.

5. Bioequivalence of Highly Variable (HV) Drugs: Clinical ImplicationsWhy HV Drugs are Safer Leslie Z. Benet, Ph.D. Professor of Biopharmaceutical Sciences University of California San Francisco FDA Advisory Committee for Pharmaceutical Science Rockville, MD April 14, 2004

6. Highly Variable Drugs For wide-therapeutic index highly variable drugs we should not have to study an excessive number of patients to prove that two equivalent products meet preset (one size fits all ) statistical criteria. This is because, by definition, highly variable approved drugs must have a wide therapeutic index, otherwise there would have been significant safety issues and lack of efficacy during Phase 3 Highly variable narrow therapeutic index drugs are dropped in Phase 2 since it is not possible to prove either efficacy or safety.

7. ln Concentration AUC Time Bioavailability: Rate and Extent of Drug Absorption Cmax Concentration Tmax- time of maximum concentration Time

8. Possible Outcome of BE Studies Demonstrate BE Fail to Demonstrate BIE Fail to Demonstrate BE Demonstrate BIE Demonstrate BIE 80% 125% T/R (%)

9. What is a Highly Variable Drug? • Within subject CV > 30% Charles DiLiberti

10. ProgesteroneThe Poster Drug for High Variability • A repeat measures study of Prometrium® 2x200 mg capsules in 12 healthy post-menopausal females yielded: Intrasubject CV for AUC of 61% Intrasubject CV for Cmax of 98% • A generic company calculated that a 2 period crossover BE study for Progesterone Capsules, 200 mg would require dosing in 300 postmenopausal women to achieve adequate statistical power

11. ACPS Recommendation, April 14, 2004 • “The Committee suggested the need to understand where the variability originated. The members added that prior knowledge of all biostudies may help set more appropriate specifications to make decisions.” • Mechanistic Understanding of Variability • Drug Substance • Common between RLD and generic • Formulation • Generic could be lower or higher • Using Product Development Information to help understand sources of variability

12. Therapeutic Equivalence • Drug products are considered to be therapeutic equivalents only • they are approved as safe and effective, • they are pharmaceutical equivalents, • they are bioequivalent, • they are adequately labeled, and • they are manufactured in compliance with CGMP regulations.

13. Pharmaceutical Equivalence • Same active ingredient(s) • Pharmaceutical solid polymorphism • Same dosage form • QbD; design to be equivalent • Same route of administration • Identical in strength or concentration • May differ in characteristics such as shape, excipients, packaging...

14. Why Does Pharmaceutical Equivalence Matter? • User experience and expectation • Bioequivalence tests • Healthy subjects • Assumption: Equivalence in healthy subjects = Equivalence in patients • Pharmaceutical Equivalence • OGD has approved over 7000 generic products • Novel drug delivery systems

15. Highly Variable Drugs • Often have wide therapeutic index • Les Benet April 2004 ACPS • Clinical trials of the RLD have established the acceptable level of variability • Under an ideal system it should be easier to determine equivalence (wide target) • Design + Demonstration = Therapeutic equivalence • We must rely on the design side

16. Possible Outcome of BE Studies Demonstrate BE Fail to Demonstrate BIE Fail to Demonstrate BE Demonstrate BIE Demonstrate BIE 80% 125% T/R (%)

17. Product Design for an ANDA of a Highly Variable Drug • Understand what the RLD is supposed to do and origin of variability • Design for equivalence • Directly evaluate equivalent product performance: verify the design • Use bioequivalence study design for highly variable drugs

18. Share with FDA • Product Development Report • CTD section • ICH Q8 • OGD Question based Review • What is the formulation intended to do? (MR,CR) • What mechanism does it use to accomplish this? • Were any other formulation alternatives investigated and how did these perform? • Is the formulation design consistent with the dosage form classification in the label?

19. Why Provide Design Process to FDA? • Quality by Design paradigm • Product development report is where you demonstrate the drug is highly variable • Source of variability • Justify use of bioequivalence study design other than 80-125% confidence interval • Product development report is where you justify equivalence of design

20. Example: Product A • Variability in active ingredient • Formulation design: rapid release • Demonstrate by dissolution comparison under physiologically relevant conditions • Waive if BCS class I • Confirm with in vivo study

21. Example: Product B • Variability in the formulation of RLD • Design for equivalence begins with characterization of RLD • Generic product should target the mean • Current system: no reward for generic that is less variable

22. Product B: Within Subject

23. What is this product supposed to do? • Coated to release at the target pH • If physiological pH fluctuates observe significant variations in pharmacokinetics • Addition to pharmacokinetics • directly evaluate design • show that test and reference release at pH target

24. Tablet to Tablet Variability

25. Design Goal • Given dissolution variability what should a generic sponsor do? • Recognize variability is an issue • Target mean performance

26. Quality by Design • Pharmaceutical Development Report will help • “Understanding what the problem is, as well as the real fundamentals i.e. physical and chemical parameters.” • “Making coherent, science based decisions.”