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 1

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 Implications Why 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. Bioavailability: Rate and Extent of Drug Absorption
ln Concentration
AUC
Time
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. Progesterone The 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, 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 OGD Question based Review
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 % 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.”