Choice of comparators An Introduction to Bioequivalence Studies Presented by: Hans Kemmler, Consultant to WHO Accra, 5.

1. Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data which are submitted to regulatory authorities Choice of comparators An Introduction to Bioequivalence Studies Presented by: Hans Kemmler, Consultant to WHO Accra, 5.Nov. 2008

2. Note on Choice of Comparator Products: Current status • Note to Applicants on Choice of Comparator Products in the Prequalification Project: • First draft (Jan. 2005) was circulated among experienced assessors from several countries • Now published on the WHO website

3. Note on Choice of Comparator • Objective: • This note is intended to provide to applicants some additional guidance and clarification on existing guidance documents how to select an appropriate comparator product for a bioequivalence study necessary for generic products submitted into the WHO prequalification project .

4. Note on Choice of Comparator • The following information is already provided on the web site,see (http://www.who.int/prequal/ , Documents and Materials, Bio-equivalence): • “What data and information needs to be submitted in a dossier for a generic product?” • “A set of bio-equivalence study data is required for all oral preparations” !!!!!!

5. Note on Choice of Comparator • With regard to the choice of comparator products reference is made on the website to “International comparator products for bio-equivalence testing" • Annex 11 of Thirty-sixth Report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. WHO Technical Report Series, No. 902, 2002: 161-180:Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products. [Annex 11]

6. Note on Choice of Comparators: General comments: • The innovator pharmaceutical product is usually the most logical comparator product for a multisource pharmaceutical product because its quality, safety and efficacy should have been well assessed and documented in premarketing studies and post-marketing monitoring schemes.

7. Note on Choice of Comparators: General comments: • Whenever possible the innovator products should be obtained from a well regulated market with stringent regulatory authority (countries such as Australia, Canada, European Union Member States, Japan, USA, Switzerland) , and the Product Information (or Summary of Product Characteristics) of the respective country should be used for reference.

8. Note on Choice of Comparators: General comments: • Never should a generic drug be used as comparator as long as an innovator drug is available, because this could lead to a “bio-creep” phenomenon, resulting in progressively less reliable similarity of future multisource products and to lack of interchangeability with the innovator.

9. „Bio-Creep“ Interchangeable Not Interchangeable

10. Note on Choice of Comparators: General comments, FDC: • Similar considerations apply to the use of fixed-dose-combinations, which were approved exclusively on the basis of bioequivalence studies comparing with the individual components, which were used as free combinations (i.e. individual products co-administered) in efficacy and safety studies.

11. Note on Choice of Comparators: General comments, FDC: • Such FDC’s should normally not be used as comparators – even if approved by ICH countries – 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 !!!

12. Note on Choice of Comparators: Example for 4-FDC: • Bioequivalence study, 1999, accepted in EU, Switzerland and by WHO:   • Rimstar 4-FDC® versus • Rimactane ® + Isozid ® + Rolab Pyrazinamide ® + Myambutol®

13. Note on Choice of Comparators: Example for 4-FDC: • 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

14. Thank you for your attention