1. Interchangeability and study design Drs. Jan Welink Training workshop: Training of BE assessors, Kiev, October 2009

2. 2 |2 | Guidance documents http://apps.who.int/prequal/ * Note to applicants on the choice of comparator products for the prequalification project * Guideline on generics - Annex 7 (Multisource (generic) pharm. products: guidelines on registration requirements to establish interchangeability) - Annex 11 (Guidance on the selection of comparator pharm. products for equivalence assessment of interchangeable multisource (generic) products)

3. Training workshop: Training of BE assessors, Kiev, October 2009 3 |3 | Guidance documents

4. Training workshop: Training of BE assessors, Kiev, October 2009 4 |4 | Guidance documents Europe: http://www.emea.europa.eu - Note for guidance on the investigation of bioavailability and bioequivalence - Note for guidance on modified release oral and transdermal dosage form: section II. - Question and answer documents ……… ………

5. Training workshop: Training of BE assessors, Kiev, October 2009 5 |5 | Bioequivalence Bioequivalence: Two medicinal products are bioequivalents if they are pharmaceutical equivalents or alternatives and if their bioavailabilities (rate and extent) after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essential the same.

6. Training workshop: Training of BE assessors, Kiev, October 2009 6 |6 | Bioequivalence ReferenceTest Pharmaceutical Equivalent Products Possible Differences Drug particle size,.. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence

7. Training workshop: Training of BE assessors, Kiev, October 2009 7 |7 | Bioequivalence Concept of interchangeability includes the equivalence of the dosage form as well as for the indications and instructions for use. Therapeutic equivalence of a multiscource product can be assured when the multiscource product is both pharmaceutically equivalent/alternative and bioequivalent.

8. Training workshop: Training of BE assessors, Kiev, October 2009 8 |8 | Bioequivalence Pharmaceutical equivalent does not necessarily imply therapeutic equivalence: - difference excipients - difference manufacturing process - other variables drug performance?

9. Training workshop: Training of BE assessors, Kiev, October 2009 9 |9 | Bioequivalence Therapeutic equivalent does not necessarily imply bioequivalence: - sensitivity - different formulations (IR/CR) - different active substance equivalence?

10. Training workshop: Training of BE assessors, Kiev, October 2009 10 | Bioequivalence acceptance criteria: comparative rate and extent of absorption pharmaceutical equivalence method: in principle comparative pharmacokinetics (AUC, C max )

11. Training workshop: Training of BE assessors, Kiev, October 2009 11 | Bioequivalence BA and BE are generally required for approvals of innovator and generic (multiscource) products. BE based on blood level determination of Cmax and AUC has become the most commonly used and successful biomarker for safety and efficacy of the drug product. BE products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring.

12. Training workshop: Training of BE assessors, Kiev, October 2009 12 | Bioequivalence Bioequivalence studies necessary for : Oral Immediate Release products Oral modified release products Fixed-combination products with systemic absorption where at least one of the API requires an in vivo study Transdermal products with systemic action Inhalation products

13. Training workshop: Training of BE assessors, Kiev, October 2009 13 | Bioequivalence Cases when pharmaceutical equivalence is enough: Aqueous solutions –Intravenous solutions –Intramuscular, subcutaneous solutions –Oral solutions –Otic or ophthalmic solutions Powders for reconstitution as solution Gases

14. Training workshop: Training of BE assessors, Kiev, October 2009 14 | Studies PD studies clinical studies in vitro methods Different approach for establishing equivalence ONLY IN EXCEPTIONAL CASE !!

15. Training workshop: Training of BE assessors, Kiev, October 2009 15 | EXPERIMENTAL DESIGN

16. Training workshop: Training of BE assessors, Kiev, October 2009 16 | Bioequivalence Important PK parameters AUC: area under the concentration-time curve  measure of the extent of absorption Cmax: the observed maximum concentration of a drug  measure of the rate of absorption tmax: time at which Cmax is observed  measure of the rate of absorption

17. Training workshop: Training of BE assessors, Kiev, October 2009 17 | Plasma concentration time profile C max T max AUC time

18. Training workshop: Training of BE assessors, Kiev, October 2009 18 | Bioequivalence – single dose minimize variability not attributable to formulations Basic design considerations: goal: compare performance 2 formulations minimize bias

19. Training workshop: Training of BE assessors, Kiev, October 2009 19 | Bioequivalence – single dose single dose, two-period, crossover Golden standard study design: Reference (comparator)/ Test (generic) healthy volunteers

20. Training workshop: Training of BE assessors, Kiev, October 2009 20 | Bioequivalence – single dose Single dose, two-period crossover: Subjects receive in Period I and II Test/Reference Subjects: Healthy volunteers –randomisation –Inclusion/exclusion criteria –Number of subjects

21. Training workshop: Training of BE assessors, Kiev, October 2009 21 | Bioequivalence – variability Number of subjects: variability!! Controllable variation: - carry-over effects (use of other medicines etc.) - time-factors (sampling time etc.) - physiological factors (gastric emptying etc.) Inescapable variation: - subject difference (inter- and intra variability) - formulations differences - random error

22. Training workshop: Training of BE assessors, Kiev, October 2009 22 | Bioequivalence – fast/fed Administration of Test/Reference: Normally fasted state –overnight fast –drug administration ca. 240 ml water SPC !!!!! –with or without food –reason: pharmacokinetic adverse events

23. Training workshop: Training of BE assessors, Kiev, October 2009 23 | Sampling Number of samples. Blood sampling: Time of sampling (extrapolated AUC max. 20%). Washout phase long enough. Sampling times (Cmax!). knowledge drug substance

24. Training workshop: Training of BE assessors, Kiev, October 2009 24 | Bioequivalence – multiple dose More relevant clinically? Multiple dose: Less sensitive to formulation differences!

25. Training workshop: Training of BE assessors, Kiev, October 2009 25 | Bioequivalence – multiple dose Multiple dose studies in case of….. Drug too potent/toxic for healthy volunteers –patients/ no interruption therapy Extended/modified release formulations – accumulation / unexpected behavior Non-linear PK at steady state Analytical assay sensitivity

26. Training workshop: Training of BE assessors, Kiev, October 2009 26 | Bioequivalence – parallel design Crossover design preferred: - intra-subject comparison - lower variability - fewer subjects required Crossover: Parallel: R R T

27. Training workshop: Training of BE assessors, Kiev, October 2009 27 | Bioequivalence – parallel design Parallel design may be useful: Drug with very long elimination half-life –Crossover design not practical Number of subjects Parallel design considerations: Adequate sample collection –Complete absorption –72 hours sufficient in general

28. Training workshop: Training of BE assessors, Kiev, October 2009 28 | Bioequivalence – replicate vs. non-replicate non-replicate Standard approach BE study: average bioequivalence single administration R and T

29. Training workshop: Training of BE assessors, Kiev, October 2009 29 | Bioequivalence – replicate vs. non-replicate T and/or R administered twice Replicate (RRTT or RRT or TTR): Subject X formulation interaction Intra-subject variability average bioequivalence/ individual bioequivalence

30. Training workshop: Training of BE assessors, Kiev, October 2009 30 | Bioequivalence – replicate design Scientific advantages: Comparison within-subject variances T and R Indicate whether T exhibits lower or higher within-subject variability More information (performance/S*F interaction) Reduce number of subjects

31. Training workshop: Training of BE assessors, Kiev, October 2009 31 | Bioequivalence – replicate design Disadvantages: Bigger commitment volunteers More administrations per subject More expensive

32. Training workshop: Training of BE assessors, Kiev, October 2009 32 | Bioequivalence Single dose studies. Most submitted bioequivalence studies are: Crossover design. Non replicate. Fasted conditions. depends on drug substance!

33. Training workshop: Training of BE assessors, Kiev, October 2009 33 | End