1. Examples of deficiencies in submitted data Drs. J. Welink Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

2. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 2 |2 | GCP overview Bioanalytical part Critical deviations in %

3. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 3 |3 | GCP overview Bioanalytical part Major deviations in %

4. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 4 |4 | 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

5. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 5 |5 | 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

6. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 6 |6 | Examples subjects Case: Report stated that 32 subjects were selected and included in the study.

7. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 7 |7 | 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

8. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 8 |8 | Examples subjects Case: Exclusion of subjects (1). Subject 26:

9. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 9 |9 | 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).

10. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 10 | Examples subjects Case: Exclusion of subjects (2). subject excluded!

11. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 11 | 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).

12. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 12 | 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%

13. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 13 | Examples Case: sampling scheme. Drug: literature reported t max 2 – 7 hours Blood sampling

14. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 14 | Case: t max. Blood sampling

15. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 15 | Examples Elimination half-life

16. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 16 | Examples Reference product Case: manufacturer. Protocol : Study report:

17. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 17 | 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!

18. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 18 | Examples Reference product Case: change manufacturing process.

19. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 19 | Examples Test product Case: formulation. Application: Studied:

20. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 20 | 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).

21. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 21 | Examples Case: LOQ (2). Analytical method

22. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 22 | Examples Specificity/selectivity: Analytical method

23. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 23 | Examples Case: stability (1). Analytical method

24. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 24 | Examples Case: stability (2). Case: stability (3). Analytical method

25. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 25 | Examples Results: Pharmacokinetic data - check PK results; also C-t curves - in line with to be expected - normal variability PK data

26. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 26 | Case: C max. PK data

27. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 27 | Examples Case: C-t curves. PK data

28. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 28 | 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

29. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 29 | Examples Case: testing. Statistical analysis

30. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 30 | 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

31. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 31 | Examples GCP/GLP criteria local market ≠ world market GLP fraud original data/documents not available

32. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 32 | Examples Case: reanalysis statistical analysis could not confirm values obtained by applicant GCP/GLP

33. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 33 | Examples Case: integration GCP/GLP

34. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 34 | Examples Case: improper documentation GCP/GLP

35. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 35 | Examples Case: manipulation GCP/GLP

36. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 36 | Examples Case: manipulation GCP/GLP

37. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 37 | Examples Case: manipulation GCP/GLP

38. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 38 | Example Case: remarkable data GCP/GLP

39. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 39 | Example Case: integration (1) GCP/GLP

40. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 40 | Example Case: integration (2) GCP/GLP

41. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 41 | Example Case: falsified data GCP/GLP

42. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 42 | Example Case: falsified data GCP/GLP

43. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 43 | End Thank you for your attention