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. Examples of problems in bioequivalence studies 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 | Bioequivalence 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)

4. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 4 |4 | Bioequivalence Same pharmaceutical form; bioequivalence study needed

5. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 5 |5 | Bioequivalence Different pharmaceutical form; no registration on bioequivalence only

6. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 6 |6 | Bioequivalence Nearly identical; no bioequivalence study needed

7. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 7 |7 | Bioequivalence BIOEQUIVALENCE acceptance criteria: comparative rate and extent of absorption: 90% CI for the Test/Reference for C max and AUC within 80 – 125% pharmaceutical equivalence methods: in principle comparative pharmacokinetics; in specific cases pharmacodynamic, clinical or in vitro studies IR tablets and capsules considered the same pharmaceutical form

8. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 8 |8 | 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.

9. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 9 |9 | Assessment Expression of interest (EOI): HIV/AIDS medication Antimalarial and tuberculosis medicines Reproductive health

10. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 10 | Assessment 2006: appr. 280 expressions of Interest were 34 files for solutions for injection requiring no BE study 222 files for tablets/capsules/oral suspensions requiring BE study 19 submissions for oral solutions about 80 products up to now have been found acceptable …… …… …….

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

12. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 12 | Assessment

13. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 13 | Assessment Update June 2007: 3 solutions for injections 399 expressions of interest (+ 119) 13 oral solutions 103 tablets/capsules

14. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 14 | Assessment Update June 2007: 75 accepted of the additional 119 submissions 24 additional data requested 5 rejected 12 innovator products

15. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 15 | Assessment Update June 2007: 146 accepted of the total of 399 submissions 29 additional data requested 20 rejected 175 cancelled/withdrawn all prequalified PI are from innovator companies

16. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 16 | Deficiencies Overall: no bio-study submitted insufficient clinical data Test and Reference product outside the 90% confidence intervals Inadequate validation method of the bioanalysis no submission of dissolution test study design outliers GLP/GCP

17. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 17 | Examples GCP/GLP criteria local market ≠ world market GLP fraud original data/documents not available

18. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 18 | Examples Case: reanalysis statistical analysis could not confirm values obtained by applicant GCP/GLP

19. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 19 | Examples Subjects included: - subjects: normal healthy volunteers, male, 18-55 years * report all demographic data * report all withdrawals from study and reasons why * protocol: handling! Exclusion only when: - subject had vomited shortly after intake of product - analytical problem subjects

20. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 20 | Examples subjects Case: Protocol stated that 32 subjects were selected and included in the study.

21. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 21 | Examples subjects Case: Exclusion of subjects (1). - protocol 28 subjects enrolled - PK data 24 subjects used as defined by protocol - two drop-outs (for personal reason) - 26 subjects completed the study - selection procedure replacements not defined!! - replacements subjects 25 and 27

22. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 22 | Examples subjects Case: Exclusion of subjects (1). Subject 26:

23. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 23 | Examples - number of subjects: 36 - used for statistical analysis: 35 - reason: low drug plasma levels in one subject calculated 90% CI: AUC 0-t 0.83 – 1.07 C max 0.82 – 1.04 Conclusion: Bioequivalent! subjects Case: Exclusion of subjects (2).

24. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 24 | Examples subjects Case: Exclusion of subjects (2). subject excluded!

25. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 25 | Examples - number of subjects: 36 - used for statistical analysis: 36 calculated 90% CI: AUC 0-t 0.76 – 1.03 C max 0.79 – 1.02 Conclusion: not bioequivalent! subjects Case: Exclusion of subjects (2).

26. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 26 | Examples Food can affect the rate and extent of absorption!! Food effect delay in absorption: increase in absorption: decrease in absorption:

27. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 27 | Examples Food effect Case: Fasting: Fed:

28. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 28 | Examples Blood sampling Adequate sampling times and period. - reliable estimation of Cmax - reliable estimation of extent of absorption (AUC) AUC 0-t / AUC inf > 80%

29. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 29 | Examples Case: sampling scheme. Drug: literature reported t max 2 – 7 hours Blood sampling

30. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 30 | Examples Case: sampling period. - AUC 0-t = 1600 +/- 346; AUC inf = 1989 +/- 378; t elim. = 3.4 hours; sampling period 8 hours Blood sampling

31. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 31 | Examples Case: t max. Blood sampling

32. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 32 | Examples Reference product Case: manufacturer. Protocol : Study report:

33. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 33 | Examples Reference product Case: change manufacturing process. - normal crossover bioequivalence study - number of subjects 38 - Test: ethionamide 250 mg capsule - Reference: Trecator-SC 250 mg tablet - 90% CI: AUC 0-t 0.95 – 1.28 C max 1.02 – 1.51 Conclusion: Not bioequivalent!

34. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 34 | Examples Reference product Case: change manufacturing process.

35. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 35 | Examples Test product Case: formulation. Application: Studied:

36. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 36 | Examples Case: batch size. Test product

37. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 37 | Examples - LOQ: 10 ng/ml, sampling period 96 hours - AUC 0-t : 639 +/- 258 ng.h/ml - AUC inf : 1367 +/- 379 ng.h/ml - C max : 31 +/- 14 ng/ml Analytical method Case: LOQ (1).

38. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 38 | Examples Case: LOQ (2). Analytical method

39. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 39 | Examples Case: stability (1). Analytical method

40. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 40 | Examples Case: stability (2). Case: stability (3). Analytical method

41. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 41 | Examples Results: Pharmacokinetic data - check PK results; also C-t curves - in line with to be expected - normal variability PK data

42. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 42 | Examples Case: C max. PK data

43. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 43 | Examples Case: C-t curves. PK data

44. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 44 | Examples -Parent or metabolite? Parent normally to be used as representative for the rate of absorption. metabolite: 90% CI AUC and C max within 80 – 125% but parent..! Statistical analysis Case: analyte.

45. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 45 | Examples - number of subjects: 24 - used for statistical analysis: 24 - non-parametric testing - reason: non normal distribution calculated 90% CI: AUC inf 0.98 – 1.23 C max 0.99 – 1.24 Conclusion: Bioequivalent! Case: testing. Statistical analysis

46. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 46 | Examples Case: testing. Statistical analysis

47. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 47 | Examples Case: testing. - number of subjects: 24 - used for statistical analysis: 24 - parametric testing !!!!!!!!!! - reason: detection of an outlier considered not acceptable calculated 90% CI: AUC 0-t 0.98 – 1.23 C max 1.01 – 1.38 Conclusion: Not bioequivalent! non parametric testing considered not acceptable! Statistical analysis

48. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 48 | Last example Case: PK variable. - t elim. : 15 h - sampling period 120 hours - parametric testing calculated 90% CI: AUC 0-t 0.96 – 1.26 (n=26) AUC inf 0.98 – 1.23 (n=25) C max 0.92 – 1.23 (n=26) Conclusion applicant: Bioequivalent based upon AUCinf Statistical analysis

49. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 49 | Last example Case: PK variable. Conclusion assessor: Not bioequivalent! AUC 0-t most reliable for extent of absorption n=25 for AUC inf because for 1 subject AUC inf could not be calculated Statistical analysis

50. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 50 | End Thank you for your attention