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. Experimental design of 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 - WHO Training workshop / 5-9 November 2007 3 |3 | Bioequivalence – single dose 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 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 | Bioequivalence – single dose

6. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 6 |6 | Bioequivalence – multiple dose More relevant clinically? Multiple dose: Less sensitive to formulation differences!

7. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 7 |7 | Bioequivalence – multiple dose Multiple dose studies in case of….. Drug too potent/toxic for healthy volunteers –patients/ no interruption therapy Extended/modified release formulations – accumulation / unexpected behavior Non-linear PK at steady state Analytical assay sensitivity

8. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 8 |8 | Bioequivalence – parallel design Crossover design preferred: - intra-subject comparison - lower variability - fewer subjects required Crossover: Parallel: R R T

9. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 9 |9 | Bioequivalence – parallel design Parallel design may be useful: Drug with very long elimination half-life –Crossover design not practical Number of subjects Parallel design considerations: Adequate sample collection –Complete absorption –72 hours sufficient in general

10. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 10 | Bioequivalence – replicate vs. non-replicate non-replicate Standard approach BE study: average bioequivalence single administration R and T

11. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 11 | Bioequivalence – replicate vs. non-replicate T and/or R administered twice Replicate (RRTT or RRT or TTR): Subject X formulation interaction Intra-subject variability average bioequivalence/ individual bioequivalence

12. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 12 | Bioequivalence – replicate design Scientific advantages: Comparison within-subject variances T and R Indicate whether T exhibits lower or higher within-subject variability More information (performance/S*F interaction) Reduce number of subjects

13. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 13 | Bioequivalence – replicate design Disadvantages: Bigger commitment volunteers More administrations per subject More expensive

14. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 14 | Bioequivalence – fast/fed no change in absorption:delay in absorption: increase in absorption:decrease in absorption: Food effect:

15. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 15 | Bioequivalence – fast/fed Food effect due to change in: gastric emptying time acid secretion intestinal motility bile secretion enzyme secretion active absorption process

16. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 16 | Bioequivalence – fast/fed If the SPC of the reference product contains specific recommendations in relation with food intake related to food interaction effects the study should be designed accordingly

17. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 17 | Bioequivalence – fast/fed If the recommendation of food intake is based on pharmacokinetic properties such as higher bioavailability, then a bioequivalence study under fed conditions is generally required If the recommendation of food intake is intended to decrease adverse events or to improve tolerability, a bioequivalence study under fasting conditions is considered acceptable although it would be advisable to perform the study under fed conditions. If the SPC leaves a choice between fasting and fed conditions, then bioequivalence should preferably be tested under fasting conditions as this situation will be more sensitive to differences in pharmacokinetics.

18. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 18 | Bioequivalence – fast/fed

19. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 19 | Bioequivalence – fast/fed The composition of the meal should be described and taken into account, since a light meal might sometimes be preferable to mimic clinical conditions, especially when the fed state is expected to be less sensitive to differences in pharmacokinetics. For products with release characteristics differing from conventional immediate release (e.g. improved release, dissolution or absorption), even if they cannot be classified as modified release products with prolonged or delayed release, bioequivalence studies may be necessary in both the fasted and fed states.

20. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 20 | Bioequivalence – fast/fed Different modified release formulations of the same drug substance may differ with respect to food interaction. Hence, the influence of food on the bioavailability of oral modified release formulations must be investigated for safety and efficacy purposes. The optimal experimental conditions to produce a food effect include the ingestion of a predefined high fat meal immediately before dosing. For the assessment of food effect besides AUC and Cmax, it may also be valuable to compare the modified release characteristics.

21. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 21 | Bioequivalence – fast/fed example Diclofenac 50 mg studies Study I: 2-way cross-over study administered after intake of a high fat breakfast, sampling for 12 hours Study 2: 2-way cross over study administered after intake of a high fat breakfast, sampling for 24 hours

22. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 22 | Bioequivalence – fast/fed example Diclofenac 50 mg short study

23. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 23 | Bioequivalence – fast/fed example Diclofenac 50 mg short study

24. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 24 | Bioequivalence – fast/fed example Diclofenac 50 mg long study Reference

25. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 25 | Bioequivalence – fast/fed example Diclofenac 50 mg long study Test

26. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 26 | Bioequivalence – fast/fed example Diclofenac 50 mg normalised on Tlag

27. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 27 | End