PREQUALIFICATION OF ANTIMALARIA L DRUG PRODUCTS

1. Hans Kemmler Clinical Reviewer Antibacterials and Antimalarials Swissmedic Bangkok, 19 October 2004 PREQUALIFICATION OF ANTIMALARIAL DRUG PRODUCTS Assessment of product dossiers – Clinical and Bioequivalence part H.Kemmler - Bern

2. Overview • Prequalification Requirements for Finished Pharmaceutical Products (FPPs) • Clinical issues • The „basic requirements“ • Results of evaluation • Conclusions H.Kemmler - Bern

3. 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 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

4. 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

5. 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 H.Kemmler - Bern

6. Problems for applicant (1) Is my FPP an innovator product? Then, since 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

7. 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! • (But: Help from WHO‘s side maybe coming) H.Kemmler - Bern

8. 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

9. 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

10. 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

11. Problems of assessors (1) • Evidence of efficacy and safety of active ingredient is not sufficient evidence for FPP, each has to be evaluated on its 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

12. 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 -> assessors developed draft SOP for specific problem H.Kemmler - Bern

13. Clear deficiencies in many submissions received: • No characterisation of pharmacokinetic properties of FPP: For innovators and generics as well unacceptable • 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

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

15. Clear deficiencies: • Far from complete toxicological documentation: Literature easily available e.g. „ARTEMISININ-COMPOUNDS LITERATURE LIST“: • 1. Abdin MZ, Israr M, Rehman RU, Jain SK. Artemisinin, a novel antimalarial drug: biochemical and molecular approaches for enhanced production. Planta Med 69(4):289-299, 2003. To • 352. Zheng GQ: Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med 60:54-57, 1994. • 353. Ziffer H, Highet RJ, Klayman DL: Artemisinin: an endoperoxidic antimalarial from Artemisia annua L. Fortschr Chem Org Naturst 72:121-124, 1997. H.Kemmler - Bern

16. Toxicological data • In contrast to ICH guidelines full documentation not required in these cases • Are well investigated for API, only FPP specific data (e.g. local tolerance) should be presented • Expert report is sufficient, emphasis on tox-data with possible relevance for adverse events H.Kemmler - Bern

17. Lessons learned during assessment • Applicants: • Several applicants submit very small bits and pieces of information relating to their FPP • Additional pieces of information nearly every month • Assessors • Bits assessed with each new round of meetings and letters sent to applicant • Very time consuming and inefficient • Increasingly difficult to have all relevant information at hand H.Kemmler - Bern

18. Note to applicants.... • 1.Demonstrate bio-equivalence with an established, acceptable reference product. A suitable reference product has to be identified by the applicant and must be one that is acceptable to WHO assessors. • 2. Provide direct evidence in support of the product’s efficacy and safety, which in most cases will be based on both of the following • a. general information pertaining to the active ingredients pharmacologic properties, including toxicological, pharmacokinetic, and efficacy and safety data as published, and resulting from investigations with preparations different from the FPP applied for • b. specific information emerging from clinical studies performed with the proposed product H.Kemmler - Bern

19. Note to applicants.... • 2.Provide direct evidence in support of the product’s efficacy and safety, which in most cases will be based on both of the following • a. general information pertaining to the active ingredients pharmacologic properties, including toxicological, pharmacokinetic, and efficacy and safety data as published, and resulting from investigations with preparations different from the FPP applied for • b. specific information emerging from clinical studies performed with the proposed product H.Kemmler - Bern

20. Basic requirements • Complete list of all clinical trials performed with the proposed FPP (compare ICH CTD M4E , section 2.7.3.2 and 2.7.3.6 and tables 2.7.3.1 and 2) • If different galenical formulations of the FPP have been marketed or used in clinical trials, a galenical development history should be provided with clear identification of the respective formulations used in the trials included in the list (see°1.) • Basic pharmacokinetic characterisation of the FPP • Summary of Product Characteristics and Package Insert • Expert reports on pharmaco-toxicological and clinical evidence for the active ingredient as well as the FPP H.Kemmler - Bern

21. Basic requirements Ia • Complete list of all clinical trials performed with the proposed FPP • The applicants should provide a complete list of all clinical trials (phase I, II and III) they are aware of and for which their product was used. It should be indicated whether the study was sponsored by the applicant. As a first step in the identification of studies not sponsored by the applicant, a consultation of the review of the Cochrane database may be useful: Artemisinin derivatives for treating uncomplicated malaria. (McIntosh HM, Olliaro P., In: The Cochrane Library, Issue 2, 2003 Oxford). H.Kemmler - Bern

22. Basic requirements Ib • Complete list of all clinical trials performed with the proposed FPP This list should be updated each time when substantial new information, i.e. new clinical studies with the FPP, is submitted Existing full study reports and publications based on these studies should be submitted. If no study report or publication exists for any of the aforementioned clinical trials, the applicants should comment on reasons known to them and either confirm that they are not aware of any negative findings in unpublished trials or comment on all unreported and unpublished evidence. H.Kemmler - Bern

23. Basic requirements II • If different galenical formulations of the FPP have been marketed or used in clinical trials, a galenical development history should be provided with clear identification of the respective formulations used in the trials included in the list • If different galenical forms were manufactured in the development history of the product, then the applicant should provide a list in order to clearly identify the different forms used in the respective studies. If the applicant is not able to identify the specific galenical form (e.g. for an independently performed trial) then they should comment on which form was most likely used.It should be confirmed unambiguously if only one galenical formulation was ever used in humans. H.Kemmler - Bern

24. Basic requirements III • Basic pharmacokinetic characterisation of the FPP • In most cases, the most important part of the evidence about the pharmacokinetic properties of the active ingredient will come from the (abundant!!) literature. However, at least some information about the pharmacokinetics/bioavailability of the FPP is absolutely necessary, too, in order to allow a judgement as to whether results from clinical trials with other FPPs can at least to a sufficient degree be extrapolated to the FPP applied for. This information may come from studies in healthy volunteers or in patients. In all cases the results will have to be discussed and compared to results from published studies in the Clinical Expert Report. The results from pharmacokinetic investigations must be described briefly in the SPC of the product. • Statements that plasma levels of artemisinin derivatives are too difficult to measure and not necessary only show lack of knowledge of recent literature H.Kemmler - Bern

25. Basic requirements IV • Summary of Product Characteristics and Package Insert • The SPC and package insert should be specific with regard to the infections which can be reasonably treated with the FPP. • In most cases the FPP will not be equally well suited for both uncomplicated and complicated malaria, or for all species of Plasmodia. • Efforts should be made to keep the SPC up to date, especially with regard to safety-relevant information. (compare e.g. to Co-Artem ) H.Kemmler - Bern

26. Basic requirements V • Expert reports on pharmaco-toxicological and clinical evidence for the active ingredient as well as the FPP • Expert reports will have to be updated – just like the list of all trials – as soon as new substantial information is added H.Kemmler - Bern

27. Basic requirements:Consequences for assessment All documentation, new or additional, provided with current or future Expressions of Interest will first be checked whether these basic requirements are fulfilled. If the basic requirements are not met then no assessmentwill be conducted on the clinical data. The applicant will be notified of the deficiencies. When the basic requirements are met an assessment of the data provided will commence and more comprehensive communications will be sent to the applicant as required. H.Kemmler - Bern

28. Results of evaluation • Initially, only the documentation of a small number of FPPs has fulfilled “basic requirements” and for even less the documentation could be considered sufficient : • Artesunate 50mg Tablets Sanofi-Synthelabo • Artemether/Lumefantrine Novartis H.Kemmler - Bern

29. Conclusions Past • Artemisinin derivatives could not be evaluated according to published WHO ”Prequalification Requirements for Finished Pharmaceutical Products“ • In the beginning uncertainties on both sides, assessors and applicants • Very insufficient dossiers of many “want-to-be” innovators • No bioequivalence studies submitted for “multi source” products • No reference products identified H.Kemmler - Bern

30. Conclusions: Presence and Future • Draft SOP for evaluation developed • “Basic requirements” for innovator products published • WHO experts working on literature survey, which should • Provide help for innovators • Enable WHO to name possible reference products H.Kemmler - Bern

31. And 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. H.Kemmler - Bern