1. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 1 |1 | Prequalification programme: Priority essential medicines Training programme on pharmaceutical quality, good manufacture practice and bioequivalence with a focus on TB products. Jiaxing Peoples’ Republic of China 5 – 9 November 2007

2. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 2 |2 | Training Workshop on Evaluation of quality and interchangeability of medicinal products. Sample analysis for a comparative bioavailability study 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 - WHO Training workshop / 5-9 November 2007 3 |3 | Bioequivalence minimize variability not attributable to formulations Basic design considerations: goal: compare performance 2 formulations minimize bias

4. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 4 |4 | Bioequivalence single dose, two-period, crossover Golden standard study design: Reference (comparator)/ Test (generic) healthy volunteers

5. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 5 |5 | Statistical considerations Average Bioequivalence: two drug products are bioequivalent ‘on the average’ when the (1-2α) confidence interval around the Geometric Mean Ratio falls entirely within 80-125% (regulatory control of specified limit)

6. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 6 |6 | Sample analysis include: Randomisation scheme Summary drug concentrations Summary estimates of the parameters Formal statistical analysisSummary of potency correction

7. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 7 |7 | Sample analysis Randomisation scheme cross-over design: Comparison Reference and Test All subjects should be included, including non completers Subject numbers on inform consent and reporting forms Sequence should be included Dosing periods and dates should be included

8. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 8 |8 | Sample analysis Summary of drug concentrations: Reference and Test Missing values should be identified Reason missing values e.g. lost sample, sample not collected Formal statistical analysis not required, but recommended

9. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 9 |9 | Sample analysis Summary of drug concentrations: Reference

10. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 10 | Sample analysis List of parameters: + definitions + other not standard parameters (if applicable)

11. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 11 | Sample analysis Summary of parameters estimates: Test Arithmic means or medians (tmax also range preferred) + standard deviations + CV

12. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 12 | Sample analysis Summary of parameters estimates: Reference

13. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 13 | Sample analysis Analysis of AUC 0-t : Estimates on raw scale Estimates on log scale Ratio AUC 0-t / AUC inf (%) Summary statistics

14. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 14 | Sample analysis Analysis of variance (ANOVA) on AUC 0-t : ln AUC 0-t Estimation ANOVA CV

15. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 15 | Sample analysis Analysis of variance (ANOVA) on AUC 0-t : Calculation of 90% CI

16. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 16 | Sample analysis Analysis of C max :

17. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 17 | Sample analysis Analysis of variance (ANOVA) on C max + 90% CI calculations:

18. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 18 | Sample analysis Analysis of AUC inf :

19. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 19 | Sample analysis Analysis of variance (ANOVA) on AUC inf : Calculation of 90% CI not shown

20. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 20 | Sample analysis Analysis on t max :

21. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 21 | Sample analysis Analysis on λ:

22. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 22 | Sample analysis Potency correction:

23. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 23 | Sample analysis C-t profiles: All individual C-t profiles Mean curves (arithmic + ln scale)

24. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 24 | Sample analysis C-t profiles: All individual C-t profiles ln scale including regression lines from which the terminal disposition rate constants ( λ ) were estimated

25. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 25 | Example Case: C-t curves. PK data

26. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 26 | End