Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System.

1. Multisource (generic) products and Interchangeability Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. Hotel Bratislava 1 Malyshko Street Kyiv, Ukraine Date: 25 to 27 June 2007

2. Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. WHO guidance: Choice of comparator product for establishing bioequivalence Presenter: Drs. J. Welink Senior pharmacokineticist Medicines Evaluation Board, NL WHO adviser E-mail: j.welink@cbg-meb.nl

3. Guidance documents

4. Guidance documents http://mednet3.who.int/prequal/ * Note to applicants on the choice of comparator products for the prequalification project * Guideline on generics - Annex 7 (Multisource (generic) pharm. products: guidelines on registration requirements to establish interchangeability) - Annex 11 (Guidance on the selection of comparator pharm. products for equivalence assessment of interchangeable multisource (generic) products)

5. Introduction * Note to applicants ….... the prequalification project generics QUALITY

6. Introduction Incorrect ingredient 16% Incorrect amount 17% No active ingredient Other errors 60% 7% Quality problem?!! Percentage breakdown of data on 325 cases of substandard drugs - reported from around the world to WHO database

7. Introduction Daily mail…… dare thinking off day, am got as talked you changed did? Certified OnlinePharmacyGenuine Quality Ingredient &All Countries Shipping

8. Introduction Multi-source (generic) drug products must satisfy the same standards as those applicable to the originator’s product. In addition, reasonable assurance must be provided that they are, as intended, clinically interchangeable with nominally equivalent market products.

9. 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.

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

11. Comparator Choice of the comparator:

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

13. 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

14. 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! ……………………………… ………………………………

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

16. Decision tree Comparator pharmaceutical product of known quality, safety and efficacy Innovator product known? Consider innovator product as comparator Consider obtaining innovator: List A Innovator product available? Available on local market? Consider innovator product as comparator Consider market leader product + + - + -

17. Decision tree Comparator pharmaceutical product of known quality, safety and efficacy Innovator product known? Present on List B? Follow compendial standard approach Acceptable results? Quality market leader known? Consider market leader product as comparator Consider market leader product Conduct comparative compendial tests on multisource and market leader products Consider second market leader product Consider market leader product as comparator - - + - + + -

18. 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!?

19. Bio-creep Interchangeable Not Interchangeable

20. EMEA Differentiate between use for single market or many countries! EMEA: EMEA: 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.

21. EMEA The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form with respect to the legal basis of the application. However, ‘appropriate bioequivalence data’ means that for the national reference products bioequivalence has to be demonstrated. Where the reference product has the same pharmaceutical form in all Member States normally one bioequivalence study is sufficient. When there are different pharmaceutical forms of oral immediate-release formulations it is the responsibility of the applicant to demonstrate bioequivalence of his product with the different pharmaceutical formulations in the Member States.

22. EMEA Whether an additional bioequivalence study or additional dissolution data are needed has to be decided on a case by case basis. For each Member State bioequivalence of the generic medicinal product and reference product has to be demonstrated because generics and reference products are considered to be interchangeable. Capsules and immediate release tablets differ considerably in composition and properties and in accordance with the Guideline on bioavailability, a bioequivalence study is required for each pharmaceutical form unless the applicant can justify otherwise that the reference product is bioequivalent with all pharmaceutical formulations in the Concerned Member States.

23. Innovator bio-creep Line extension of innovator bioequivalent bioequivalent Test: generic Innovator

24. Innovator bio-creep Line extension of innovator bioequivalent bioequivalent bioequivalent Test: generic Test: generic Innovator ?

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

26. Example Fixed dose combination (FDC): Comparator: Combination of the acceptable reference products with only one drug! WHY?

27. Example • Bioequivalence study, 1999, accepted in EU, Switzerland and by WHO:   Rimstar 4-FDC® versus Rimactane ® + Isozid ® + Rolab Pyrazinamide ® + Myambutol®

28. Example Rimstar 4-FDC® (Rifampicin 150, Isoniazid 75, Pyrazinamide 400, Ethambutol 275mg) 4 tablets given in a single dose versus Rimactane ® (Novartis, Switzerland*) 4 capsules each containing 150mg rifampicin Isozid ® (Fatol, Germany) 3 tablets each containing 100 mg isoniazid Rolab Pyrazinamide ® (Rolab, South Africa) 3 tablets each containing 500 mg Pyrazinamide Myambutol® (Lederle Arzneimittel GmbH & Co) 2 tablets containing 400mg and 3 tablets containing 100mg ethambutol BIOEQVALENCE PROVEN

29. Example • Such FDC’s should normally not be used as comparators – even if approved by ICH countries (bio-creep phenomenon) • Instead again the individual components should be used as comparators. • However, there are also some fixed-dose-combinations which were used as such extensively in clinical trials, thus direct, “own” evidence for their efficacy and safety is available. These can be used !!!

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

31. Conclusion Thank you for your attention