1. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 1 |1 | Prequalification programme: Priority essential medicines Training Workshop for evaluators from National Medicines Regulatory Authorities in the East African Community: Evaluation of quality and interchangeability of medicinal products. Dar Es Salaam United Republic of Tanzania 10 – 14 September 2007

2. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 2 |2 | Training Workshop on Evaluation of quality and interchangeability of medicinal products. 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. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 3 |3 | 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)

4. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 4 |4 | Introduction * Note to applicants ….... the prequalification project generics QUALITY

5. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 5 |5 | 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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7. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 7 |7 | 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.

8. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 8 |8 | 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.

9. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 9 |9 | Comparator Introducing the comparator: innovator product, approved on full documentation: - established safety and efficacy Quality Pre-clinical Clinical

10. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 10 | Comparator Choice of the comparator:

11. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 11 | 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

12. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 12 | 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

13. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 13 | 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! ……… ………

14. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 14 | Decision tree Choosing comparator complex WHO provides criteria decision tree YES NO YES NO ? ? ?

15. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 15 | 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? + + - + -

16. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 16 | 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 - + + + - - -

17. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 17 | 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!?

18. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 18 | Bio-creep Interchangeable Not Interchangeable

19. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 19 | 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.

20. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 20 | 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.

21. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 21 | 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.

22. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 22 | EMEA registration procedure risk for differences centralised MRP national

23. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 23 | Innovator Line extension of innovator bioequivalent Test: generic bioequivalent Innovator bio-creep

24. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 24 | Innovator Line extension of innovator bioequivalent Test: generic bioequivalent Innovator bio-creep Test: generic bioequivalent ?

25. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 25 | Prequalification project List of acceptable reference products for the prequalification project for reproductive health

26. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 26 | Example Fixed dose combination (FDC): Comparator: Combination of the acceptable reference products with only one drug! WHY?

27. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 27 | Example Bioequivalence study, 1999, accepted in EU, Switzerland and by WHO: Rimstar 4-FDC® versus Rimactane ® + Isozid ® + Rolab Pyrazinamide ® + Myambutol®

28. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 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. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 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. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 30 | Conclusion - Let quality rules - Comparators helps you into quality - Do not fall in the bio-creep

31. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 31 | Conclusion Thank you for your attention