1. Guilin, 9-13, January 2006 1 PREQUALIFICATION OF ANTIMALARIAL DRUG PRODUCTS Hans Kemmler Consultant to WHO Guilin, 11.Jan. 2006 Frequently Encountered Deficits in Expression of Interest for Originators

2. Guilin, 9-13, January 2006 2 Overview Prequalification Requirements for Finished Pharmaceutical Products (FPPs) Clinical issues The „basic requirements“ Results of evaluation Conclusions

3. Guilin, 9-13, January 2006 3 Artemisinin-Generics for Malaria? Currently only very few innovators (artemisinin derivatives) approved in ICH- and associated countries –No reference product available for bioequivalence studies (one exception: Artesunate from Guilin Pharma)

4. Guilin, 9-13, January 2006 4 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

5. Guilin, 9-13, January 2006 5 The main deficiency Insufficient reporting of the evidence about the clinical efficacy and safety..... –No fully documented trial reports –No full evaluation of published literature

6. Guilin, 9-13, January 2006 6 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

7. Guilin, 9-13, January 2006 7 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

8. Guilin, 9-13, January 2006 8 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.

9. Guilin, 9-13, January 2006 9 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 Consultant to WHO is currently preparing an Expert Report for all artemisins = Artemisinin part may be omitted in close future Attention: Some assessment of toxicology of combinations is still necessary

10. Guilin, 9-13, January 2006 10 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

11. Guilin, 9-13, January 2006 11 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

12. Guilin, 9-13, January 2006 12 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

13. Guilin, 9-13, January 2006 13 Basic requirements 1. 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) 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.) 3. Basic pharmacokinetic characterisation of the FPP 4. Summary of Product Characteristics and Package Insert 5. Expert reports on pharmaco-toxicological and clinical evidence for the active ingredient as well as the FPP

14. Guilin, 9-13, January 2006 14 Basic requirements Ia 1. 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).

15. Guilin, 9-13, January 2006 15 Basic requirements Ib 1. 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.

16. Guilin, 9-13, January 2006 16 Basic requirements II 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 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.

17. Guilin, 9-13, January 2006 17 Basic requirements III 3. 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

18. Guilin, 9-13, January 2006 18 Basic requirements IV 4. 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 )

19. Guilin, 9-13, January 2006 19 Basic requirements V 5. 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

20. Guilin, 9-13, January 2006 20 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 assessment will 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.

21. Guilin, 9-13, January 2006 21 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 Guilin Pharma Artesunate 50mg Tablets Sanofi-Synthelabo Artemether/Lumefantrine Novartis

22. Guilin, 9-13, January 2006 22 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

23. Guilin, 9-13, January 2006 23 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 more reference products –remove the need for Toxicology Expert Report

24. Guilin, 9-13, January 2006 24 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 no F inished P harmaceutical P roduct will pass the prequalification.