1. TANZANIA 21 - 25 AUGUST 2006 1 TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD MANUFACTURING PRACTICE AND BIOEQUIVALENCE WITH A FOCUS ON ARTEMISININS Introduction Efficacy and Safety Issues Hans Kemmler Consultant to WHO White Sands, 23.Aug. 2006

2. TANZANIA 21 - 25 AUGUST 2006 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.

3. TANZANIA 21 - 25 AUGUST 2006 3 Overview Defining efficacy and safety of a medicine (finished pharmaceutical product = FPP) Dossier requirements Use of guidelines

4. TANZANIA 21 - 25 AUGUST 2006 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. TANZANIA 21 - 25 AUGUST 2006 5 Efficacy and Safety of the Active Ingredient Investigated and documented in preclinical and clinical trials of – possibly – different galenic formulations

6. TANZANIA 21 - 25 AUGUST 2006 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. TANZANIA 21 - 25 AUGUST 2006 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. TANZANIA 21 - 25 AUGUST 2006 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 Prequalification Project Guidelines (Presentation Dr. Sterzik) Guidelines available: http://mednet3.who.int/prequal/ (all on CD-ROM 1)

9. TANZANIA 21 - 25 AUGUST 2006 9 Prequalification Requirements for Finished Pharmaceutical Products (FPPs) Website WHO: (http://mednet3.who.int/prequal/default.htm) –Manufacturers are requested to submit a covering letter, sample and product dossier (generics -- innovator) including a completed checklist.genericsinnovator checklist 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?“

10. TANZANIA 21 - 25 AUGUST 2006 10 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 FPP for which Expression of Interest was invited

11. TANZANIA 21 - 25 AUGUST 2006 11 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)

12. TANZANIA 21 - 25 AUGUST 2006 12 Focus of Today’s Lectures Artemisinins based generics Orally applied products on the EoI-List: All are combinations: –Artesunate + amodiaquine –Artemether/lumefantrine –Artesunate + mefloquine –Artesunate + sulphadoxine/pyrimethamine

13. TANZANIA 21 - 25 AUGUST 2006 13 Wanted for BE-Studies A generic FPP An acceptable comparator BUT: Choice of comparator is not trivial On WHO-Prequalification Project Website follow: Selection of comparator product: Note to Applicants on the Choice of Comparator Products for the Prequalification Project (on CD-ROM 1) One big problem still to be solved: Only one of the combinations is already approved in ICH region and prequalified: Not a topic today

14. TANZANIA 21 - 25 AUGUST 2006 14 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

15. TANZANIA 21 - 25 AUGUST 2006 15 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

16. TANZANIA 21 - 25 AUGUST 2006 16 Where to Find Guidelines In previous and following presentations some references to guidelines are given in distributed material (CD-ROMs) many more are included or referenced see in particular the presentations of the previous workshop (Kiev, 2005, on CD-ROM 1) for many additional references in particular relevant for bioequivalence studies

17. TANZANIA 21 - 25 AUGUST 2006 17 Other Useful Documents On the accompanying CD-ROM 2 will be 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“

18. TANZANIA 21 - 25 AUGUST 2006 18 Other Useful Documents Also on CD-ROM 1 : 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

19. TANZANIA 21 - 25 AUGUST 2006 19 Other Useful Documents WHO Guidelines for registration of fixed-dose combination medicinal products !!! (see CD-ROM 1) Sample analysis for a comparative bioavailability study (see CD-ROM 2, 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)

20. TANZANIA 21 - 25 AUGUST 2006 20 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!!!

21. TANZANIA 21 - 25 AUGUST 2006 21 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

22. TANZANIA 21 - 25 AUGUST 2006 22 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 for „multi-source“ products no F inished P harmaceutical P roduct will pass the prequalification.

23. TANZANIA 21 - 25 AUGUST 2006 23 Thank you For inviting us For listening For many questions