1. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 1 Statistical Considerations Evaluation of Quality and Interchangeability of Medicinal Products 10 – 14 September 2007 Dar Es Salaam, Tanzania Dr. Henrike Potthast; Temporary Advisor to WHO

2. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 2 Statistical Considerations  Bioequivalence – equivalent bioavailability within pre-set acceptance ranges  Bioequivalence  therapeutic equivalence

3. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 3 Statistical Considerations F“The primary concern in bioequivalence assessment is to limit the risk of a false declaration of equivalence. Statistical analysis of the bioequivalence trial should demonstrate that the clinically significant difference in bioavailability is unlikely…..” [WHO Working Document Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability November 2005]

4. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 4 Statistical Considerations HOW SIMILAR IS SIMILAR?

5. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 5 Statistical Considerations  basic measures ♦AUC area under the plasma concentration curve

6. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 6

7. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 7 Statistical Considerations  basic measures ♦Cmax – observed peak concentration ♦tmax – the time after administration at which Cmax is observed (highly dependent on the sampling schedule!) ♦t1/2 – half-life ♦…a.o.

8. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 8 Statistical Considerations  log transformation…. ♦….for all concentration dependent pharmacokinetic parameters (e.g. AUC and Cmax) ♦analysis of log-transformed data by means of ANOVA (analysis of variances)

9. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 9 Statistical Considerations  ANOVA model includes…. ♦….usually formulation, period, sequence or carry- over, and subject factors

10. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 10 Statistical Considerations  Parametric (normal-theory)…. ♦….to construct a 90 % confidence interval for µT-µR ♦….which is equivalent to carrying out two-one sided tests of hypothesis at the 5 % level of significance.

11. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 11 Statistical Considerations  …the constructed 90% confidence interval has to meet the pre-set acceptance criteria FAUC – 80 – 125 % FCmax – 80 – 125 % (75 – 133 % may be possible if prospectively justified in terms of safety and efficacy) Ftmax – therapeutic relevance of mean difference

12. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 12

13. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 13 Statistical Considerations  ‘Outliers’ Fdefinition – explanation – handling?! ♦aberant/irregular values (e.g. no plasma concentration, late high concentrations….)

14. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 14 Statistical Considerations  ‘Outliers’ Fdefinition – explanation – handling?! ♦vomiting? ♦non-compliant volunteers? ♦bioanalytical failure? ♦individual pharmacokinetics? ♦protocol violations? ♦……

15. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 15 Statistical Considerations  ‘Outliers’ Fdefinition – explanation – handling?! ♦“…pharmacokinetic data can only be excluded based on non-statistical reasons that have been … defined previously in the protocol…Exclusion of data can never be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because it is impossible to distinguish between formulation effects and pharmacokinetic effects…Results of statistical analyses with and without the ….excluded subjects should be provided.” (excerpt from Q&A Doc Ref: EMEA/CHMP/EWP/40326/2006)

16. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 16 Statistical Considerations  ‘carry-over’ Fdefinition – explanation – handling?!

17. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 17 Statistical Considerations Fdifferential ‘carry-over’ … ♦…is coming from the drug given at the previous period ♦…in a 2x2 crossover it occurs if the carry-over is not the same for the sequence TR and RT ♦…a non-differential carry-over translates into a period effect ♦…a poor randomization can be wrongly interpreted as a carry-over ♦…no valid study with a significant carry-over

18. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 18 Statistical Considerations F… to avoid a ‘carry-over’ … ♦…the wash-out period should be sufficiently long (appr. 5 x t1/2)

19. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 19 Statistical Considerations F… a sequence effect may occur… ♦…if the two groups of volunteers (TR and RT) are really different (unlikely by correct selection) ♦…due to a different carry-over effect from the formulations (may be visible by non-zero samples at the second period) ♦…due to a formulation-period interaction (minimized by the same standardized conditions for both periods)

20. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 20 Statistical Considerations THANK YOU FOR YOUR ATTENTION