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TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD MANUFACTURING PRACTICE AND BIOEQUIVALENCE WITH A FOCUS ON ARTEMISININ

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. The Prequalification Project.

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TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD MANUFACTURING PRACTICE AND BIOEQUIVALENCE WITH A FOCUS ON ARTEMISININ

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  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 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. TANZANIA 21 - 25 AUGUST 2006

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

  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 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 TANZANIA 21 - 25 AUGUST 2006

  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 assessmentof the FPP. 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. 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) 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. • Generics: If innovators exist and are approved: Bioequivalence study, assessed with WHO Technical Report 937: WHO EXPERT COMMITTEE ON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONSTRS 937 • Innovator: „What data and information needs to be submitted in a dossier for an innovator product?“ 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 TANZANIA 21 - 25 AUGUST 2006

  11. Dossier requirements Particulars for artemisinin containing FPP: • 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: • Guideline for registration of fixed-dose combination medicinal products (WHO Technical Report Series No. 929, 2005) 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 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 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 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 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 forbioequivalence studies 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“ 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 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) 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!!! 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 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 noFinished Pharmaceutical Product will pass the prequalification. TANZANIA 21 - 25 AUGUST 2006

  23. Thank you For inviting usFor listeningFor many questions TANZANIA 21 - 25 AUGUST 2006

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