1. WHO Training Course on Prequalification Introduction Efficacy and Safety Issues Hans Kemmler Consultant to WHO Accra, 5.Nov. 2008

2. Artemisinin combined medicines, Kampala, February 2009 2 |2 | The Prequalification Project The Prequalification Programme, set up in 2001, is a service provided by the World Health Organization (WHO) to facilitate access to medicines that meet unified standards of quality, safety and efficacy for HIV/AIDS, malaria and tuberculosis. From the outset, the Programme was supported by UNAIDS, UNICEF, UNFPA and the World Bank as a concrete contribution to the United Nations priority goal of addressing widespread diseases in countries with limited access to quality medicines.

3. Artemisinin combined medicines, Kampala, February 2009 3 |3 | Overview Defining efficacy and safety of a medicine (finished pharmaceutical product = FPP) Dossier requirements Use of guidelines Difficulties in understanding

4. Artemisinin combined medicines, Kampala, February 2009 4 |4 | 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. Artemisinin combined medicines, Kampala, February 2009 5 |5 | Efficacy and Safety of the Active Ingredient Investigated and documented in preclinical and clinical trials of – possibly – different galenic formulations

6. Artemisinin combined medicines, Kampala, February 2009 6 |6 | 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. Artemisinin combined medicines, Kampala, February 2009 7 |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.

8. Artemisinin combined medicines, Kampala, February 2009 8 |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://www.who.int/prequal

9. Artemisinin combined medicines, Kampala, February 2009 9 |9 | Dossier requirements Particulars for artemisinin containing FPP: 1.Note to applicants expressing interest for supplying artemisinin-containing drug products Because all products on current Expression of Interest list are combinations, the consideration of the combinations guideline is of utmost importance: 2.Guideline for registration of fixed-dose combination medicinal products (WHO Technical Report Series No. 929, 2005)

10. Artemisinin combined medicines, Kampala, February 2009 10 | Prequalification Requirements for Finished Pharmaceutical Products (FPPs) Website WHO: (http://www.who.int/prequal/default.htm) –Manufacturers are requested to submit a covering letter, sample and product dossier (generics -- innovator) including a completed checklist.genericsinnovatorchecklist Generics: If innovators exist and are approved: Bioequivalence study, assessed with WHO Technical Report 937: WHO EXPERT COMMITTEE ON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS TRS 937TRS 937 Innovator: „What data and information needs to be submitted in a dossier for an innovator product?“

11. Artemisinin combined medicines, Kampala, February 2009 11 | Artemisinin - Innovators? „What data and information needs to be submitted in a dossier for an innovator product?“ –For innovator products, registered/licensed in the USA, EU or Japan: Submit the following information: A WHO-type Certificate of a Pharmaceutical Product issued by one of the regulatory authority of ICH regions (or other stringent regulatory authorities), together with the summary of product characteristics (SmPC) Assessment report(s) issued by the respective regulatory authority........ Does not apply to most of Artemisinin-FPP for which Expression of Interest was invited

12. Artemisinin combined medicines, Kampala, February 2009 12 | 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

13. Artemisinin combined medicines, Kampala, February 2009 13 | 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

14. Artemisinin combined medicines, Kampala, February 2009 14 | Where to Find Guidelines In previous and following presentations some references to guidelines are given in distributed material (CD) many more are included or referenced see also the presentations of a previous workshop (Kiev, 2005) for many additional references in particular relevant for bioequivalence studies

15. Artemisinin combined medicines, Kampala, February 2009 15 | Other Useful Documents In distributed papers or CD 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“

16. Artemisinin combined medicines, Kampala, February 2009 16 | 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

17. Artemisinin combined medicines, Kampala, February 2009 17 | Other Useful Documents WHO Guidelines for registration of fixed- dose combination medicinal products !!! (see distributed material) Sample analysis for a comparative bioavailability study (see distributed material, and general hint: If questions about BE-studies arise, the website of the Canadian health authority should be one of the first places to look at)

18. Artemisinin combined medicines, Kampala, February 2009 18 | Difficulties in understanding Delays in prequalification by lack of mutual understanding Not only language problems, but –same words have different meanings for people with different previous experience e.g. A „full study report“ is obviously something different for an European assessor and for an employee of a Chinese company. This doesn‘t mean that one is right and the other not!!!

19. Artemisinin combined medicines, Kampala, February 2009 19 | Difficulties in understanding Talking and asking helps a lot, therefore one of our intentions for this workshop: Less presentations about something which is better read anyway More time for discussion in and about case studies

20. Artemisinin combined medicines, Kampala, February 2009 20 | Finally: The bare necessities Apart from the intrinsic efficacy/safety of the active ingredient, the bioavailability is THE clinical quality mark of a FPP, therefore: Without pharmacokinetic characterisation in humans, either through Phase I Studies for innovators or through bioequivalence studies (which may, in very exceptional cases be only in vitro bioequivalence studies) for „multi-source“ products no F inished P harmaceutical P roduct will pass the prequalification.

21. Thank you For inviting us For listening For active participation in the case studies