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

2. Hanoi, 2006-01-19, H.Kemmler2 The Prequalification Project The Prequalification project, set up in 2001, is a service provided by the WHO to facilitate access to medicines that meet unified standards of quality, safety and efficacy for HIV/AIDS, malaria and tuberculosis.

3. Hanoi, 2006-01-19, H.Kemmler3 Overview Defining efficacy and safety of a medicine (finished pharmaceutical product = FPP) Dossier requirements Use of guidelines Overview results for HIV-drugs

4. Hanoi, 2006-01-19, H.Kemmler4 Defining Efficacy and Safety The “Clinical Quality” of a Medicine Efficacy and safety of the active ingredient Galenical formulation Information on the appropriate and safe use All aspects are assessed during prequalification

5. Hanoi, 2006-01-19, H.Kemmler5 Efficacy and Safety of the Active Ingredient Investigated and documented in preclinical and clinical trials of – possibly – different galenic formulations

6. Hanoi, 2006-01-19, H.Kemmler6 Galenic Formulation Has an influence on e.g. –Bioavailability Best active ingredient will be of no use if contained in a stainless steel capsule –(local) tolerability Because different formulations can have different bioavailability or tolerability, the information about which formulation has been used in which trial(s) is essential for the assessment of the FPP.

7. Hanoi, 2006-01-19, H.Kemmler7 Information on the Appropriate and Safe Use Best active ingredient in best galenical formulation will be of no use if used for wrong condition, e.g. antimalarial used to treat headache It will be even dangerous if safety relevant information is not complete Information in SPC and PIL must be justified by and referenced in the documented evidence.

8. Hanoi, 2006-01-19, H.Kemmler8 Dossier requirements Manufacturers interested in participating in the prequalification project have to submit a product dossier for assessment The product dossiers have to contain the required data and information as stipulated in the Guidelines Guidelines available: http://mednet3.who.int/prequal/

9. Hanoi, 2006-01-19, H.Kemmler9 Dossier requirements Particulars for HIV/AIDS FPP containing more than one active ingredient: Guideline for registration of fixed- dose combination medicinal products (WHO Technical Report Series No. 929, 2005)

10. Hanoi, 2006-01-19, H.Kemmler10 Use of Guidelines Guidelines are guidances, no law But: –It should be apparent that the relevant guidelines are known –deviations from guidelines should be based on scientific justification Guidelines make „life“ easier –especially for applicants

11. Hanoi, 2006-01-19, H.Kemmler11 Use of Guidelines No presentation, no training course can help to avoid the thorough study of guidelines To find all relevant guidelines is - to some degree - an art WHO website provides an excellent starting point

12. Hanoi, 2006-01-19, H.Kemmler12 Where to Find Guidelines In previous and following presentations some references to guidelines are given in distributed material many more are included or referenced see also the presentations of the previous workshop (Kiev, 2005) for many additional references in particular relevant for bioequivalence studies

13. Hanoi, 2006-01-19, H.Kemmler13 Other Useful Documents In distributed papers is a complete and detailed „Table of Contents“ (TOC) for a bioequivalence study report In my opinion, a very valuable help for scientists intending to conduct such a study also useful for other study reports to give an idea about the detailedness of a „Full Study Report“

14. Hanoi, 2006-01-19, H.Kemmler14 Other Useful Documents Also in distributed material: Annex 7 (a template): Presentation of bioequivalence trial information Together with the TOC, these documents should, if properly populated, help to avoid >90% of currently encountered deficits in submitted bioequivalence trials

15. Hanoi, 2006-01-19, H.Kemmler15 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

16. Hanoi, 2006-01-19, H.Kemmler16 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/ )

17. Hanoi, 2006-01-19, H.Kemmler17 Summary of Submissions for HIV/AIDS-Drugs Antibacterials56 Antimycotics24 Antiprotozoals 7 other Antivirals18 Anticancer 6 Nucleosid RTI86 NRTI Combi34 Non-Nucleosid RTI18 Prot.Inhibitors18

18. Hanoi, 2006-01-19, H.Kemmler18

19. Hanoi, 2006-01-19, H.Kemmler19

20. Hanoi, 2006-01-19, H.Kemmler20 Update, status Dec. 2005 316 submissions 73 under active assessment 142 cancelled 85 products prequalified

21. Hanoi, 2006-01-19, H.Kemmler21 NRTI prequalified

22. Hanoi, 2006-01-19, H.Kemmler22

23. Hanoi, 2006-01-19, H.Kemmler23 Update to last slide, status December 2005 6 Lamivudine combinations added + 2 Lamivudine mono + 3 Zidovudine mono

24. Hanoi, 2006-01-19, H.Kemmler24 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

25. Hanoi, 2006-01-19, H.Kemmler25 Prequalification Results of Protease Inhibitors All prequalified PI are from innovator companies, none is a generic

26. Hanoi, 2006-01-19, H.Kemmler26 WHY? Deficiencies in BE Studies ? YES About 50% of initial 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

27. Hanoi, 2006-01-19, H.Kemmler27 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

28. Hanoi, 2006-01-19, H.Kemmler28 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

29. Hanoi, 2006-01-19, H.Kemmler29 Conclusion in Project Some problems arise again and again, from many applicants More advice needed !! And is possible !

30. Hanoi, 2006-01-19, H.Kemmler30 Two New Documents are now available Note to Applicants on Choice of Comparator Products in the Prequalification Project Annex 7: Presentation of bioequivalence trial information BIOEQUIVALENCE TRIAL INFORMATION FORM (BTIF) link