WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010

1. WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010 Selection of comparators Compiled by Jan Welink WHO Workshop on Assessment of Bioequivalence Data, 31. August - 3.September 2010, Addis Ababa

2. Introduction Quality of generics:

3. Comparator Introducing the comparator: * a pharmaceutical product with which the multi-source product is intended to be interchangeable in clinical practice. * the selection of the comparator product is usually made at the national level by the drug regulatory authority.

4. Comparator Quality Clinical Pre-clinical Introducing the comparator: innovator product, approved on full documentation: - established safety and efficacy

5. WHAT IS THE DIFFERENCE BETWEEN INNOVATOR AND GENERIC? Physically:

6. BE WHAT IS THE RELATION BETWEEN INNOVATOR AND GENERIC? Scientifically: INNOVATOR GENERIC

7. Choice of the comparator:

8. Comparator Selection by the DRA: • select national granted innovator for which quality, safety and efficacy has been established (nationally authorised innovator) • select WHO comparator product from the comparator list (WHO comparator product) • select innovator product from well-regulated country (ICH et al. innovator) • if no innovator can be identified, choice must be justified

9. Comparator Justification if no innovator can be identified: • approval in ICH- and associated countries • pre-qualified by WHO • extensive documented use in clinical trials (reports) • long and unproblematic post-market surveillance

10. List A and B WHO provides a list with comparator products - information DRA/pharmaceutical companies List A: WHO model list of Essential Drugs - ‘best’ innovator products on national markets List B: Products for which no innovator product could be identified - no equivalence test can be performed - quality, safety and efficacy based upon local, national, or regional pharmacopoeia - innovator products with insufficient information No innovator, but market leader available! ……………………………… ………………………………

11. Decision tree Choosing comparator complex WHO provides criteria decision tree NO YES ? ? YES NO NO ?

12. Bio-creep Annex 11 also written for a single market WHO: cannot be translated in case other countries are at stake national comparator may be the national market leader no problem in that market but others!?

13. Bio-creep Interchangeable Not interchangeable

14. EMEA (Europe) Differentiate between use for single market or many countries! EMA: For an abridged application claiming essential similarity to a reference product, application to numerous Member States based on bioequivalence with a reference product from one Member State can be made.

15. Prequalification project List of acceptable reference products for the prequalification project for reproductive health List of acceptable reference products for the prequalification project for reproductive health

16. Guidance documents Recommended comparator products: Reproductive Health medicines Comparator products should be obtained from a well regulated market with stringent regulatory authority i.e., from countries participating in the International Conference on Harmonization (ICH) Countries officially participating in ICH are the ICH members European Union, Japan and USA; and the ICH observers Canada and Switzerland.

17. Guidance documents

18. Guidance documents

19. Guidance documents

20. Guidance documents

21. Guidance documents http://apps.who.int/prequal/ * Note to applicants on the choice of comparator products for the prequalification project * Guideline on generics - WHO TRS 937 Annex 7 (Multisource (generic) pharm. products: guidelines on registration requirements to establish interchangeability) - WHO TRS 902 Annex 11 (Guidance on the selection of comparator pharm. products for equivalence assessment of interchangeable multisource (generic) products)

22. Guidance documents http://apps.who.int/prequal/ * updated documents on the choice of comparator products for the prequalification project • Comparator for anti-tuberculosis medicines • Comparator for anti-malarial medicines • Comparator for Influenza-specific antiviral medicines • Comparator for medicines for HIV/AIDS and related diseases • Comparator for reproductive health products

23. Guidance documents http://apps.who.int/prequal/ * a word on Dose Equivalence • “In case the invited product has a different dose compared to the available acceptable comparator product, it is not always necessary to carry out a bioequivalence study at the same dose level; if the active substance shows linear pharmacokinetics, extrapolation between similar doses may be applied by dose normalisation.”

24. Guidance documents http://apps.who.int/prequal/ * a word on Fixed-dose Combination Products • “The bioequivalence of fixed-dose combination (FDC) product should be established following the same general principles. The submitted FDC product should be compared with the respective innovator FDC product as listed above. In cases where a FDC comparator product is not listed above, individual component products administered in loose combination should be used as a comparator. The principles of dose normalization as mentioned above are applicable.”

25. Conclusion - Let quality rules - Comparators helps you into quality - Do not fall in the bio-creep

26. End Thank you for your attention