1. Interchangeability and study design Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

2. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 2 |2 |

3. 3 |3 | 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)

4. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 4 |4 | Guidance documents

5. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 5 |5 | Regulatory Authority Mission “Assure that SAFE and EFFECTIVE drugs are marketed in the country and are available to the people”

6. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 6 |6 | Bioavailability Bioavailability means the rate and extent to which the active substance or therapeutic moiety is absorbed from a pharmaceutical form and becomes available at the site of action. plasma

7. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 7 |7 | Bioavailability relative bioavailability absolute bioequivalence food-effect different formulations interactions

8. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 8 |8 | 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.

9. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 9 |9 | Bioequivalence Bioavailability Pharmaceutical equivalent Pharmaceutical alternatives

10. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 10 | Bioequivalence ReferenceTest Pharmaceutical Equivalent Products Possible Differences Drug particle size,.. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution specifications)

11. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 11 | 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.

12. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 12 | Bioequivalence Pharmaceutical equivalent does not necessarily imply therapeutic equivalence: - difference excipients - difference manufacturing process - other variables drug performance?

13. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 13 | Bioequivalence Therapeutic equivalent does not necessarily imply bioequivalence: - sensitivity - different formulations (IR/CR) - different active substance equivalence?

14. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 14 | Bioequivalence acceptance criteria: comparative rate and extent of absorption pharmaceutical equivalence method: in principle comparative pharmacokinetics (AUC, C max )

15. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 15 | 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.

16. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 16 | Bioequivalence ref. BRIDGING STUDIES clinical batchcomm.batchchanged batch scale up variations ref.test approval innovator approval generic acceptance variations innovator generic bioequiv.batchcomm. batchchanged batch test ref.test scale upvariations acceptance variations ref.

17. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 17 | Bioequivalence Studies necessary for : Oral Immediate Release products –In general –Critical use medicines/Narrow therapeutic range drug products –Documented BA or BE problems related to API –Scientific evidence suggesting polymorphs of API, excipients, and/or process affecting BA –Non-oral, non-parenteral products designed to act systemically Oral Modified Release products Fixed-combination products with systemic absorption where at least one of the API requires an in vivo study

18. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 18 | Bioequivalence Cases when pharmaceutical equivalence is enough: Aqueous solutions –Intravenous solutions –Intramuscular, subcutaneous solutions –Oral solutions –Otic or ophthalmic solutions –Topical products prepared as solutions –Aqueous solution for nebulizer inhalation or nasal sprays Powders for reconstitution as solution Gases

19. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 19 | Studies PD studies clinical studies in vitro methods Different approach for establishing equivalence ONLY IN EXCEPTIONAL CASE !!

20. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 20 | EXPERIMENTAL DESIGN

21. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 21 | 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

22. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 22 | Plasma concentration time profile C max T max AUC time

23. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 23 | Bioequivalence – single dose minimize variability not attributable to formulations Basic design considerations: goal: compare performance 2 formulations minimize bias

24. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 24 | Bioequivalence – single dose single dose, two-period, crossover Golden standard study design: Reference (comparator)/ Test (generic) healthy volunteers

25. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 25 | 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

26. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 26 | Bioequivalence – single dose Number of subjects!! - Sample size calculation: e.g. Eur J Drug Metab Pharmacokinet 30 (2005) 41

27. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 27 | Bioequivalence – fast/fed Administration of Test/Reference: Normally fasted state –overnight fast –drug administration ca. 240 ml water If the SPC of the reference product contains specific recommendations in relation with food intake related to food interaction effects the study should be designed accordingly

28. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 28 | Bioequivalence – fast/fed no change in absorption:delay in absorption: increase in absorption:decrease in absorption: Food effect:

29. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 29 | Bioequivalence – fast/fed If the recommendation of food intake is based on pharmacokinetic properties such as higher bioavailability, then a bioequivalence study under fed conditions is generally required If the recommendation of food intake is intended to decrease adverse events or to improve tolerability, a bioequivalence study under fasting conditions is considered acceptable although it would be advisable to perform the study under fed conditions. If the SPC leaves a choice between fasting and fed conditions, then bioequivalence should preferably be tested under fasting conditions as this situation will be more sensitive to differences in pharmacokinetics.

30. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 30 | Bioequivalence – fast/fed In general: follow SPC.

31. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 31 | Sampling Number of samples. Blood sampling: Time of sampling (extrapolated AUC max. 20%). Washout phase long enough. Sampling times (Cmax!). knowledge drug substance

32. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 32 | Extrapolated AUC < 20% time

33. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 33 | Extrapolated AUC < 20% time

34. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 34 | Bioequivalence – multiple dose More relevant clinically? Multiple dose: Less sensitive to formulation differences!

35. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 35 | 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

36. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 36 | Bioequivalence – parallel design Crossover design preferred: - intra-subject comparison - lower variability - fewer subjects required Crossover: Parallel: R R T

37. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 37 | 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

38. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 38 | Bioequivalence – replicate vs. non-replicate non-replicate Standard approach BE study: average bioequivalence single administration R and T

39. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 39 | 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

40. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 40 | 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

41. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 41 | Bioequivalence – replicate design Disadvantages: Bigger commitment volunteers More administrations per subject More expensive

42. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 42 | Bioequivalence Single dose studies. Most submitted bioequivalence studies are: Crossover design. Non replicate. Fasted conditions. depends on drug substance!

43. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 43 | End