1. 1 WHO Procurement, Quality and Sourcing Project: Access to Tuberculosis Drugs of Acceptable Quality Experience from the Evaluation of Drug Dossiers with Respect to Bioequivalence Data Hans Kemmler Swissmedic, Switzerland

2. 2 Invited Generic Products 1 Expressions of Interest were invited for First line drugs Ethambutol Hydrochloride 400mg tablets Pyrazinamide 400mg tablets Isoniazid 300mg tablets Rifampicin 150/300/450/600 mg tablets

3. 3 Invited Generic Products 2 Second line drugs Cycloserine 250mg tablets Ethionamide125 mg or 250mg tablets Ofloxacin 200 mg tablets Prothionamide 125 mg or 250mg tablets Para-Aminosalicylic Acid 100 g or 4 g granules or powder Moxifloxacin 400 mg tablets

4. 4 Invited Generic Products 3 Fixed-Dose-Combinations (FDC) 2FDC: Rifampicin 150 mg /Isoniazid 75mg tablets 2FDC: Rifampicin 150 mg /Isoniazid 150mg tablets 2FDC: Ethambutol Hydrochloride 400 mg /Isoniazid 150mg tablets

5. 5 Invited Generic Products 4 Fixed-Dose-Combinations (FDC) 3FDC: Rifampicin 150 mg / Isoniazid 75 mg / Ethambutol Hydrochloride 275 mg tablets 4FDC: Rifampicin 150mg /Isoniazid 75mg /Pyrazinamide 400mg /Ethambutol Hydrochloride 275mg tablets

6. 6 Invited Generic Products 5 FDC’s for children: 1)Rifampicin 60 mg /Isoniazid 60mg/ Pyrazinamide 150 mg (R60/H30/Z150) 2)Rifampicin 60 mg /Isoniazid 30mg (R60/H30) 3)Rifampicin 60 mg/ Isoniazid 60 mg (R60/H60)

7. 7 Invited Generic Products 6 Preparations for injection (no bioequivalence study needed) Streptomycin Sulfate 1g vial (injection) Water for injection 5ml vial (injection) Amikacin 500mg/2 ml vial (injection) Kanamycin 1g powder for injection, vial Capreomycin 1g powder for injection, vial

8. 8 Submitted Generic Products Of the 153 files submitted 7 files for solutions for injection requiring no BE study 146 files for tablets/capsules/oral suspensions requiring BE study Only 8 products up to now have been found acceptable, in principle, for procurement by UN agencies (included in list available : http://mednet3.who.int/prequal/ )

9. 9 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

10. 10 Current Status SCPQA 2-FDC (R, H) 29 8 3 18 Pyrazinamide (Z)19 12 1 6 Ethambutol (E)18 5 1 13 Isoniazid(H)16 6 0 10 4-FDC (R,H,Z,E)13 4 3 6 Rifampicin (R)12 5 0 7 3-FDC 8 3 0 5

11. 11 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

12. 12 Deficiencies in BE Studies Selected examples: Pyrazinamide: “Bioequivalence study report The report and protocol is not paged and is submitted completely randomised. “

13. 13 Identified Deficiencies in Applications Requiring 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

14. 14 Identified Deficiencies in Applications Requiring 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

15. 15 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)

16. 16 Identified Deficiencies in BE studies Minor deficiencies (information not presented, but easily accessible) Individual pharmacokinetic parameters not submitted Pharmacokinetic and statistical calculations not submitted Detailed description of study design not submitted

17. 17 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

18. 18 Conclusion in Project Some problems arise again and again, from many applicants More advice needed !! And is possible and here!

19. 19 Two New Documents soon available 1. Note to Applicants on Choice of Comparator Products in the Prequalification Project 2. Template: ASSESSMENT REPORT FOR PREQUALIFICATION OF MULTI- SOURCE (GENERIC) FINISHED PHARMACEUTICAL PRODUCTS (FPPS) NOT REGISTRED IN ICH REGIONS OR RELATED COUNTRIES

20. 20 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 –After receiving and evaluating comments, few changes to be expected

21. 21 Note on Choice of Comparators 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.

22. 22 Note on Choice of Comparators Background 1: The following information is already provided on the web site, see (http://mednet3. who.int/prequal/, Documents and Materials, Bio-equivalence)http://mednet3. who.int/prequal/ “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” !!!!!!

23. 23 Note on Choice of Comparators Background 2: 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]

24. 24 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.

25. 25 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.

26. 26 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.

27. 27 „Bio-Creep“ Interchangeable Not Interchangeable

28. 28 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.

29. 29 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 !!!

30. 30 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®

31. 31 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

32. 32 Note on Choice of Comparators: Example for FDC: However, even if approved in many countries, Rimstar ® is still not an acceptable reference, because approval was based exclusively on BE-studies In contrast, with Rifater ® (3FDC) and Rifinah ® (2FDC) extensive clinical studies have been done, these would be acceptable

33. 33 Note on Choice of Comparators: Example for FDC: Appear in List A of Annex 11:

34. 34 Note on Choice of Comparators: General comments, Principle: General principle for selection of an appropriate comparator: As near as possible in the chain of evidence to the product for which efficacy and safety has been directly shown.

35. 35 Note on Choice of Comparators: Schema Wherever possible, follow: 1. Marketing Authorization of Pharmaceutical Products with special Reference to Multisource (Generic) Products : a Manual for a Drug Regulatory Authority, WHO/DMP/RGS/98.5 2. Annex 11 (see above, slide 23)

36. 36 Note on Choice of Comparators: Schema However: The “Manual” and the “Annex 11” were developed for national regulatory agencies regulating single national markets Not all recommendations applicable to international markets The concept of a “national market leader” cannot be used for prequalification project

37. 37 Note on Choice How to choose 1. Innovator a) Easily identifiable for new drugs (only two for TB) b) Consult Annex 11, List A, also for Tb several drugs listed 2. Pharmaceutical products approved in the WHO prequalification project for which a full dossier for quality, safety and efficacy was submitted and evaluated. (currently only anti-malarials) 3. Try to find accepted comparator in “Note” 4. If no innovator and no product listed in Annex11 ?

38. 38 Note on Choice How to choose 4. No innovator, no List A product, nothing in „Note“: Difficult, extensive justification is necessary: The most important selection criterion will be based on extensive – documented – use in clinical trials reported in peer-reviewed scientific journals, and after this, approval in ICH- and associated countries.