1. Deficiencies in Bioequivalence dossiers Overview and Examples

2. Guilin, 9-13, January 2006 2 Summary of Submissions for Tuberculosis-Drugs 2-FDC (R, H) 29 Pyrazinamide (Z)19 Ethambutol (E)18 Isoniazid(H)16 4-FDC (R,H,Z,E)13 Rifampicin (R)12 3-FDC 8

3. Guilin, 9-13, January 2006 3 Deficiencies in BE Studies Selected examples: Pyrazinamide: (19 submissions, 1 prequalified, 12 cancelled) For 13 products no BE study submitted For 3, BES were submitted, but major deficiencies in all aspects (reporting, reference product) Only 2 BE studies (for three products) acceptable -> one product prequalified 18 of 19 submissions with quality documentation deficits

4. Guilin, 9-13, January 2006 4 Deficiencies in BE Studies Selected examples: 4-FDC (R,H,Z,E): ( 13 submitted, 3 prequalified, 4 cancelled, 6 with deficits) For 3 products, no BES For 7, major deficits, 6 studies with unacceptable reference products 9 products with quality deficits

5. Guilin, 9-13, January 2006 5 Identified Deficiencies in BE studies Major deficiencies No bioequivalence study performed and no adequate justification for not performing a study Unacceptable reference product Inadequate validation data of bioanalytical method

6. Guilin, 9-13, January 2006 6 Identified Deficiencies in BE studies Major deficiencies (cont.) No verification that test product used in bioequivalence study is identical to product intended for marketing 90 % Confidence Intervals for pharmacokinetic parameters not presented (or more generally, no adequate statistical analysis)

7. Guilin, 9-13, January 2006 7 Identified Deficiencies in BE studies Minor deficiencies (cont.) No information on batch size of test product Certificate of Analysis of test batch not submitted In-vitro dissolution profiles not submitted –for test product –for reference product –for different strengths of the same product

8. Guilin, 9-13, January 2006 8 Advice: As the same problems arise again and again, from many applicants: Consider: 1. Note to Applicants on Choice of Comparator Products in the Prequalification Project 2. Template: Presentation of Bioequivalence trial information

9. Guilin, 9-13, January 2006 9 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

10. Guilin, 9-13, January 2006 10 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.

11. Guilin, 9-13, January 2006 11 Note on Choice of Comparator The following information is already provided on the web site, see (http://mednet3. 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” !!!!!!

12. Guilin, 9-13, January 2006 12 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]

13. Guilin, 9-13, January 2006 13 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.

14. Guilin, 9-13, January 2006 14 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.

15. Guilin, 9-13, January 2006 15 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.

16. Guilin, 9-13, January 2006 16 „Bio-Creep“ Interchangeable Not Interchangeable

17. Guilin, 9-13, January 2006 17 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.

18. Guilin, 9-13, January 2006 18 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 !!!

19. Guilin, 9-13, January 2006 19 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®

20. Guilin, 9-13, January 2006 20 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

21. Guilin, 9-13, January 2006 21 Thank you for your attention