WHO Procurement, Quality and Sourcing Project: Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality

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

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

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

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

6. Galenic Formulation • Has an influence on e.g. • Bioavailability • Best active ingredientwill be ofno 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. Hanoi, 2006-01-19, H.Kemmler

7. 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. Hanoi, 2006-01-19, H.Kemmler

8. 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/ Hanoi, 2006-01-19, H.Kemmler

9. 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) Hanoi, 2006-01-19, H.Kemmler

10. 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 Hanoi, 2006-01-19, H.Kemmler

11. 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 Hanoi, 2006-01-19, H.Kemmler

12. 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 forbioequivalence studies Hanoi, 2006-01-19, H.Kemmler

13. 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“ Hanoi, 2006-01-19, H.Kemmler

14. 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 Hanoi, 2006-01-19, H.Kemmler

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

16. Submitted Generic Products Of the appr. 280 Expressions of Interest were • 34 files for solutions forinjection 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/ ) Hanoi, 2006-01-19, H.Kemmler

17. Summary of Submissions for HIV/AIDS-Drugs • Antibacterials 56 • Antimycotics 24 • Antiprotozoals 7 • other Antivirals 18 • Anticancer 6 • Nucleosid RTI 86 • NRTI Combi 34 • Non-Nucleosid RTI 18 • Prot.Inhibitors 18 Hanoi, 2006-01-19, H.Kemmler

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

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

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

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

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

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

26. 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 Hanoi, 2006-01-19, H.Kemmler

27. Other Identified Deficiencies in BE studies Minor deficiencies (informationnot presented, but easily accessible) • Individual pharmacokinetic parameters not submitted • Pharmacokinetic and statistical calculations not submitted • Detailed description of study design not submitted Hanoi, 2006-01-19, H.Kemmler

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

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

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