PREQUALIFICATION OF ANTIMALARIA L DRUG PRODUCTS

1. Hans Kemmler Clinical Reviewer Anti-bacterials and Anti-malarials Swissmedic Geneva, 03 May 2004 PREQUALIFICATION OF ANTIMALARIAL DRUG PRODUCTS Assessment of product dossiers – Clinical and Bioequivalence part H.Kemmler - Bern

2. Overview • Background • Prequalification Requirements for Finished Pharmaceutical Products (FPPs) • Clinical issues • Status • Conclusions H.Kemmler - Bern

3. Background • See previous presentation • http://mednet3.who.int/prequal/default.htm H.Kemmler - Bern

4. Prequalification Requirements for Finished Pharmaceutical Products (FPPs) • Website WHO: • 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 http://www.who.int/medicines/library/qsm/manual-on-marketing/who-dmp-rgs-985.doc • Innovator: „What data and information needs to be submitted in a dossier for an innovator product?“ H.Kemmler - Bern

5. Artemisinin- Generics for Malaria? • Currently only very few innovators (artemisinin derivatives) approved in ICH- and associated countries • No reference product available for bioequivalence studies H.Kemmler - Bern

6. Artemisin - 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 H.Kemmler - Bern

7. Problems for applicant (1) • Is my FPP an innovator product? • Then (toxicological and clinical issues): • Not approved in ICH countries • Full documentation of preclinical and clinical efficacy and safety according to ICH requirements has to be provided, all claims in SPC have to be substantiated • fully documented clinical studies!! (abstracts and even publications normally not sufficient) H.Kemmler - Bern

8. Problems for applicant (2) • I want my FPP to be evaluated as generic! Which reference product can I use for BE-studies? • Currently no recommendations possible • Applicant has to research literature for suitable reference product, and prove that this product has sufficient efficacy and safety data available: • Very difficult! H.Kemmler - Bern

9. Questions of applicants (1) • The active ingredient of my FPP is listed in the WHO - Essential Drugs List: • http://www.who.int/health_topics/essential_medicines/en/ : “Essential medicines are those that satisfy the priority health care needs of the population. They are selected with due regard to public health relevance, evidence on efficacy and safety, and comparative cost-effectiveness.” http://www.who.int/medicines/organization/par/edl/eml2002core.doc • http://www.who.int/medicines/organization/par/edl/eml2002comp.doc : The complementary list presents essential medicines for priority diseases which are efficacious, safe and cost-effective but not necessarily affordable, or for which specialised health care facilities or services may be needed. • Why do I have to prove efficacy and safety again? H.Kemmler - Bern

10. Model List of Essential Medicines(13th list) • artemether (2) (injection) P01BE02 • artemether + lumefantrine * (1)(tablets) P01BE52 • artesunate (2) (tablets) P01BE03 • (1): core list, (2): complementary list H.Kemmler - Bern

11. Questions of applicants (2) • WHO has invited Expression of Interest, so efficacy and safety are already known and documentation already at WHO? • Innovators: Why do I have to prove efficacy and safety again? • Generics: Which is possible reference product? H.Kemmler - Bern

12. Problems of assessors (1) • Evidence of efficacy and safety of active ingredient is not sufficient evidence for FPP, each has to be evaluated on ist own merits • With one exception, the FPP‘s which have been used for inclusion of API in Essential Drugs List, are not known to assessors -> thus even not possible to provide guidance for reference product H.Kemmler - Bern

13. Problems of assessors (2) • Within time frame for assessment, no possibility to perform own literature review -> has to be provided by applicant for his FPP • No guidance documents or SOP‘s from WHO applicable -> In process of developing draft SOP for specific problem H.Kemmler - Bern

14. Clear deficiencies: • No characterisation of pharmacokinetic properties of FPP: For innovators and generics as well inacceptable • General statements: • No interaction known -> clearly not true • No (or minimal) adverse events: information has to be provided through literature survey • Too broad efficacy claims H.Kemmler - Bern

15. Clear deficiencies: • Galenical development history not provided -> Do results of earlier studies apply to current formulation? • List of all clinical trials performed with • specific FPP (including information on formulation, if possible) • Active ingredient H.Kemmler - Bern

16. CONCLUSIONS • Initially, only a small number of FPPs have met the required standards: • }Malaria }List of prequalified products and manufacturers • Date: 26 April 2004 • 018 Artesunate 50mg Tablets Sanofi-Synthelabo, Gentilly, France Guilin Pharmaceutical Co., Ltd, Guangxi China Blister 25 blister of 12 • 026 Artemether/ • Lumefantrine 20/120mg Tablets Novartis Pharma, Basel, Switzerland Beijing Novartis Pharma, Beijing China Blister 30 blisters of 6, 12, 18 or 24 H.Kemmler - Bern