1. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 1 |1 | Prequalification programme: Priority essential medicines Training Workshop for evaluators from National Medicines Regulatory Authorities in the East African Community: Evaluation of quality and inter-changeability of medicinal products. Dar Es Salaam United Republic of Tanzania 10 – 14 September 2007

2. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 2 |2 | Training Workshop on Evaluation of quality and interchangeability of medicinal products. Marketing authorisation trough equivalence documentation Presenter: Drs. J. Welink Senior pharmacokineticist Medicines Evaluation Board, NL WHO adviser E-mail: j.welink@cbg-meb.nl

3. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 3 |3 | Guidance documents

4. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 4 |4 | Guidance documents http://mednet3.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)

5. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 5 |5 | Guidance documents Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (1) Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms (2) Additional guidance for organizations performing in vivo bioequivalence studies (3)

6. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 6 |6 | Guidance documents Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (1) Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms (2) Additional guidance for organizations performing in vivo bioequivalence studies (3) Guidance on the selection of comparator pharmaceutical products for equivalence

7. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 7 |7 | Guidance documents

8. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 8 |8 | Regulatory Authority Mission “Assure that SAFE and EFFECTIVE drugs are marketed in the country and are available to the people”

9. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 9 |9 | Bioequivalence Bioavailability Pharmaceutical equivalent Pharmaceutical alternatives

10. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 10 | 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.

11. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 11 | 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)

12. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 12 | Bioequivalence Dissolution, solubility, and intestinal permeability are the three major factors that govern the rate and extent of absorption of a drug that is stable in the GI tract TIME (hours) Fluid volume pH hydrodynamics surface tension other….

13. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 13 | 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. TE = PE + BE

14. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 14 | Bioequivalence Pharmaceutical equivalent does not necessarily imply therapeutic equivalence: - difference excipients - difference manufacturing process - other variables drug performance?

15. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 15 | Bioequivalence Therapeutic equivalent does not necessarily imply bioequivalence: - sensitivity - different formulations (IR/CR) - different active substance equivalence?

16. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 16 | Bioequivalence acceptance criteria: comparative rate and extent of absorption pharmaceutical equivalence method: in principle comparative pharmacokinetics IR tablets and capsules considered the same pharmaceutical form

17. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 17 | 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.

18. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 18 | 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.

19. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 19 | 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

20. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 20 | Plasma concentration time profile C max T max AUC time concentration

21. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 21 | Bioequivalence Studies necessary: Oral Immediate Release products –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

22. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 22 | 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

23. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 23 | Studies PD studies clinical studies in vitro methods Different approach for establishing equivalence

24. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 24 | PD studies Comparative PD studies Not recommended when: - active ingredient is absorbed into the systemic circulation - pharmacokinetic study can be conducted In case of local action/ no systemic absorption

25. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 25 | PD studies Comparative PD studies PD measures more variable than PK response relevant efficacy/safety placebo effect method: validated

26. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 26 | PD studies-example

27. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 27 | Clinical studies Comparative clinical studies However: - requires large number of subjects - methodology establishing equivalence has not yet evolved extensively as for PK BE trials in case PK or PD studies can not be performed - insensitive

28. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 28 | Clinical studies-example dissolution matrix diffusion to skin penetration str. corneum diffusion and penetration epidermis penetration sebum diffusion trough dermis too blood capillair absorption blood Topical/local acting:

29. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 29 | In vitro studies Comparative in vitro studies However: - acceptability in general? - currently no biowaiver in prequalification project, except for additional strength and solutions BCS approach for biowaivers

30. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 30 | Bioequivalence – single dose minimize variability not attributable to formulations Basic design considerations: goal: compare performance 2 formulations minimize bias

31. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 31 | Bioequivalence – single dose single dose, two-period, crossover Golden standard study design: Reference (comparator)/ Test (generic) healthy volunteers

32. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 32 | Bioequivalence – single dose

33. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 33 | Bioequivalence – multiple dose More relevant clinically? Multiple dose: Less sensitive to formulation differences!

34. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 34 | 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

35. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 35 | Bioequivalence – parallel design Crossover design preferred: - intra-subject comparison - lower variability - fewer subjects required Crossover: Parallel: R R T

36. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 36 | 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

37. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 37 | Bioequivalence – replicate vs. non-replicate non-replicate Standard approach BE study: average bioequivalence single administration R and T

38. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 38 | 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

39. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 39 | 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

40. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 40 | Bioequivalence – replicate design Disadvantages: Bigger commitment volunteers More administrations per subject More expensive

41. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 41 | Bioequivalence – fast/fed no change in absorption:delay in absorption: increase in absorption:decrease in absorption: Food effect:

42. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 42 | Bioequivalence – fast/fed Food effect due to change in: gastric emptying time acid secretion intestinal motility bile secretion enzyme secretion active absorption process

43. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 43 | Bioequivalence – fast/fed 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

44. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 44 | 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.

45. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 45 | Bioequivalence – fast/fed The composition of the meal should be described and taken into account, since a light meal might sometimes be preferable to mimic clinical conditions, especially when the fed state is expected to be less sensitive to differences in pharmacokinetics. For products with release characteristics differing from conventional immediate release (e.g. improved release, dissolution or absorption), even if they cannot be classified as modified release products with prolonged or delayed release, bioequivalence studies may be necessary in both the fasted and fed states.

46. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 46 | Bioequivalence – fast/fed Different modified release formulations of the same drug substance may differ with respect to food interaction. Hence, the influence of food on the bioavailability of oral modified release formulations must be investigated for safety and efficacy purposes. The optimal experimental conditions to produce a food effect include the ingestion of a predefined high fat meal immediately before dosing. For the assessment of food effect besides AUC and Cmax, it may also be valuable to compare the modified release characteristics.

47. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 47 | Bioequivalence – fast/fed example Diclofenac 50 mg studies Study I: 2-way cross-over study administered after intake of a high fat breakfast, sampling for 12 hours Study 2: 2-way cross over study administered after intake of a high fat breakfast, sampling for 24 hours

48. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 48 | Bioequivalence – fast/fed example Diclofenac 50 mg short study

49. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 49 | Bioequivalence – fast/fed example Diclofenac 50 mg short study

50. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 50 | Bioequivalence – fast/fed example Diclofenac 50 mg long study Reference

51. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 51 | Bioequivalence – fast/fed example Diclofenac 50 mg long study Test

52. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 52 | Bioequivalence – fast/fed example Diclofenac 50 mg normalised on Tlag

53. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 53 | Bioequivalence – fast/fed

54. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 54 | End