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

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

Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November |3 | Bioequivalence minimize variability not attributable to formulations Basic design considerations: goal: compare performance 2 formulations minimize bias

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

Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November |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 % (regulatory control of specified limit)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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