2. 1 WHO Procurement, Quality and Sourcing Project: Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality Experience from the Evaluation of Drug Dossiers with Respect to Bioequivalence Data Hans Kemmler Swissmedic, Switzerland

3. 2 Invited Generic Products Expressions of Interest were invited for Nucleoside Reverse Transcriptase Inhibitors –7: Zidovudine, Didanosine, Lamivudine etc. Non-nucleoside Reverse Transcriptase Inhibitors –3 : Nevirapine, Efavirenz, Delarvidine Protease Inhibitors –6 : Amprenavir, Saquinavir, Ritonavir etc. Other Anti-infective drugs: Antibacterials, Antimycotics, Antiprotozoals, other Antivirals, Anti-cancer drugs

4. 3 Submitted Generic Products Of the appr. 280 Expressions of Interest were 34 files for solutions for injection requiring no BE study 222 files for tablets/capsules/oral suspensions requiring BE study 19 submissions for oral solutions About 80 products up to now have been found acceptable, in principle, for procurement by UN agencies (included in list available : http://mednet3.who.int/prequal/ )

5. 4 Summary of Submissions for HIV/AIDS-Drugs Antibacterials56 Antimycotics24 Antiprotozoals 7 other Antivirals18 Anticancer 6 Nucleosid RTI86 NRTI Combi34 Non-Nucleosid RTI18 Prot.Inhibitors18

6. 5

7. 6

8. 7 NRTI prequalified

9. 8

10. 9 Prequalification results of NRTI 120 submissions for NRTI and combinations with NRTI 36 prequalified Of 36 NRTI prequalified, only 14 are generics Of 98 submissions for generic NRTI, 84 not (yet) prequalified

11. 10 Prequalification Results of Protease Inhibitors All prequalified PI are from innovator companies, none is a generic

12. 11 WHY? Deficiencies in BE Studies ? YES About 50% of submissions without bioequivalence study Of submitted studies: – About 50% with inadequate method validation –~ 50% without verification that test product is exactly same as applied-for-product –~ 35% without basic statistical evaluation

13. 12 Other 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

14. 13 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

15. 14 Conclusion in Project Some problems arise again and again, from many applicants More advice needed !! And is possible !

16. 15 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

17. 16 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

18. 17 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.

19. 18 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” !!!!!!

20. 19 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]

21. 20 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.

22. 21 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, EU Member States, Japan, USA, Switzerland), and the Product Information (or Summary of Product Characteristics) of the respective country should be used for reference for future up-dates of safety relevant informations.

23. 22 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. Lacking of availability on local market is no excuse

24. 23 „Bio-Creep“ Interchangeable Not Interchangeable

25. 24 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 ( individual components were, however, used as free combinations (i.e. individual products co- administered) in comprehensive efficacy and safety studies)

26. 25 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. (otherwise „bio-creep“) 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 !!!

27. 26 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®

28. 27 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

29. 28 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

30. 29 Note on Choice of Comparators: Example for FDC: Appear in List A of Annex 11:

31. 30 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.

32. 31 Note on Choice of Comparators: Schema Wherever possible, follow: 1. “Blue book” 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 19)

33. 32 Note on Choice of Comparators: Schema However: The “Blue book” 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

34. 33 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 ?

35. 34 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.

36. 35 Template: ASSESSMENT REPORT FOR PREQUALIFICATION OF MULTI- SOURCE (GENERIC) FPPS Used by assessors of BE-studies for harmonisation of approach and completeness of evaluation In project used since appr. July 2004 Derived with small adjustments from template of Canadian drug regulatory authority (there used since many years)

37. 36 Template

38. 37 Template

39. 38 Template Section 3.2 3.2 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE (a) Name of principal investigator(s) (State location of C.V. in the submission) (b) Clinical Facility (Name and full mailing address) (c) Clinical Laboratories (Name and full mailing address) (d) Analytical Laboratories (Name and full mailing address) (e) Company performing pharmacokinetic/statistical analysis (Name and full mailing address)

40. 39 Template Section 3.4 3.4 INVESTIGATIONAL PLAN 3.4.1 Overall Study Design and Plan – Description (Describe the type of study design employed in 1-2 sentences) 3.4.2 Selection of Study Population 3.4.2.1 Inclusion Criteria 3.4.2.2 Exclusion Criteria (List the exclusion criteria applied to subjects) 3.4.2.3 Removal of Patients from Therapy or Assessment (a)Number of subjects enrolled in the study (All subjects including alternates, withdrawals, and dropouts) (b)Withdrawals (Identify each withdrawal by subject and provide the reason for withdrawal and at what point in the study the withdrawal occurred)

41. 40 Template Section 3.4 3.4.2 Treatments Administered 3.4.3.1 Test Product (a) Batch number and date of manufacture for the test product (b) Potency (measured content) of test formulation as a percentage of label claim (This information should be cross-referenced to the location of the certificate of analysis in the submission)

42. 41 Template Section 3.4.3.2 Reference Product (a) Name and manufacturer of the reference product (b) Batch number and expiry date for the reference product (c) Potency (measured content) of the reference formulation as a percentage of label claim (This information should be cross- referenced to the location of the certificate of analysis in the submission) (d) Justification of choice of reference product (Provide short summary here and cross-reference to location of comprehensive justification in study protocol)

43. 42 Template Section 3.4.6 Blinding 3.4.6.1 Identify which of the following were blinded. If any of the groups were not blinded, provide a justification for not doing so (a) study monitors (b) subjects (c) analysts 3.4.6.2 Identify who held the study code and when the code was broken

44. 43 Template Section 3.4.7 3.4.7 Drug Concentration Measurements 3.4.7.1 Biological fluid(s) sampled 3.4.7.2 Sampling Protocol (a) Number of samples collected per subject (b) Volume of fluid collected per sample (c) Total volume of fluid collected per subject per phase of the study (d) List the study sampling times (e) Identify any deviations from the sampling protocol (State location of summary in the submission) (Describe and explain reasons for deviations from sampling protocol. Comment on impact on study. Indicate whether the deviations were accounted for in the pharmacokinetic analyses)

45. 44 Template Section 3.5 3.5 Comments from review of Section 3.0 – WHO use only

46. 45 Template Section 5 5.0 PROTOCOL DEVIATIONS 5.1 Protocol deviations during the clinical study (Describe any such deviations and discuss their implications with respect to bioequivalence) 5.2 Comments from review of Section 5.0 – WHO use only

47. 46 Template Section 7 7.0 EFFICACY EVALUATION – Efficacy Results and Tabulations of Individual Patient Data 7.1 Presentation of Data (a) State location in submission of tables of mean and individual subject concentrations (b) State location in submission of (mean and individual) linear and semi-logarithmic subject drug concentration vs. time plots

48. 47 Template Section 7.1

49. 48 Template Section 8 Must always be provided !!

50. 49 Template Section 8.6 Must always be provided !! 8.6 Chromatograms (State the location in the submission where the sample chromatograms can be found. The chromatograms should be obtained from a minimum of two analytical batches and include at least 20% of the subjects, up to a maximum of five. A complete set includes standards, QC samples, pre-dose and post-dose subject samples for both phases. Each chromatogram should be clearly labelled with respect to the following: date of analysis; subject ID number; study period; sampling time; analyte; standard or QC, with concentration; analyte and internal standard peaks; peak heights and/or areas)

51. 50 Template Section 9 Must always be provided !! 9.0 ANALYTICAL VALIDATION REPORT 9.1 Precision and Accuracy (a) Summarize inter-day and intra-day accuracy and precision during assay validation (b) Summarize inter-day and intra-day accuracy and precision during assay re-validation (If applicable)

52. 51 Template Section 10 10.0 QUALITY ASSURANCE 10.1 Internal quality assurance methods (State locations in the submission where internal quality assurance methods and results are described for each of study sites (see 3.2 b-d) 10.2 Monitoring, Auditing, Inspections (Provide a list of all monitoring and auditing reports of the study, and of recent inspections of study sites by regulatory agencies. State locations in the submission of the respective reports for each of study sites (see 3.2 b-d)

53. 52 Wanted !