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

2. WHO Prequalification Programme June 2007 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. WHO Prequalification Programme June 2007 Guidance documents

4. WHO Prequalification Programme June 2007 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. WHO Prequalification Programme June 2007 Introduction * Note to applicants ….... the prequalification project generics QUALITY

6. WHO Prequalification Programme June 2007 Introduction Incorrect amount 17% No active ingredient 60% Other errors 7% Incorrect ingredient 16% Percentage breakdown of data on 325 cases of substandard drugs - reported from around the world to WHO database Quality problem?!!

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8. WHO Prequalification Programme June 2007 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. WHO Prequalification Programme June 2007 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. WHO Prequalification Programme June 2007 Comparator Introducing the comparator: innovator product, approved on full documentation: - established safety and efficacy Quality Pre-clinical Clinical

11. WHO Prequalification Programme June 2007 Comparator Choice of the comparator:

12. WHO Prequalification Programme June 2007 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. WHO Prequalification Programme June 2007 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. WHO Prequalification Programme June 2007 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. WHO Prequalification Programme June 2007 Decision tree Choosing comparator complex WHO provides criteria decision tree YES NO YES NO ? ? ?

16. WHO Prequalification Programme June 2007 Decision tree Comparator pharmaceutical product of known quality, safety and efficacy Innovator product available? Consider innovator product as comparator Consider obtaining innovator: List A Consider market leader product Consider innovator product as comparator Available on local market? Innovator product known? + + - + -

17. WHO Prequalification Programme June 2007 Decision tree Comparator pharmaceutical product of known quality, safety and efficacy Quality market leader known? Consider second market leader product Acceptable results? Consider market leader product as comparator Follow compendial standard approach Present on List B? Innovator product known? Consider market leader product Consider market leader product as comparator Conduct comparative compendial tests on multisource and market leader products - + + + - - -

18. WHO Prequalification Programme June 2007 Bio-creep WHO: Annex 11 also written for a single market 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. WHO Prequalification Programme June 2007 Bio-creep Interchangeable Not Interchangeable

20. WHO Prequalification Programme June 2007 EMEA Differentiate between use for single market or many countries! 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. WHO Prequalification Programme June 2007 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. WHO Prequalification Programme June 2007 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. WHO Prequalification Programme June 2007 Innovator Line extension of innovator bioequivalent Test: generic bioequivalent Innovator bio-creep

24. WHO Prequalification Programme June 2007 Innovator Line extension of innovator bioequivalent Test: generic bioequivalent Innovator bio-creep Test: generic bioequivalent ?

25. WHO Prequalification Programme June 2007 Prequalification project List of acceptable reference products for the prequalification project for reproductive health

26. WHO Prequalification Programme June 2007 Example Fixed dose combination (FDC): Comparator: Combination of the acceptable reference products with only one drug! WHY?

27. WHO Prequalification Programme June 2007 Example Bioequivalence study, 1999, accepted in EU, Switzerland and by WHO: Rimstar 4-FDC® versus Rimactane ® + Isozid ® + Rolab Pyrazinamide ® + Myambutol®

28. WHO Prequalification Programme June 2007 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. WHO Prequalification Programme June 2007 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. WHO Prequalification Programme June 2007 Conclusion - Let quality rules - Comparators helps you into quality - Do not fall in the bio-creep

31. WHO Prequalification Programme June 2007 Conclusion Thank you for your attention