1. Ensuring Access to Antimalarial Drugs Dr Clive O Ondari Essential Drugs and Medicines Policy Dept. World Health Organization October 2002

2. WHO - EDM 2 Roll Back Malaria (RBM) n Global partnership n Founded by Member States, WHO, UNDP, UNICEF, World Bank n Secretariat in WHO (HQ)

3. WHO - EDM 3 Current Status: n Quality of antimalarial drugs has been declining. n The efficacy of (affordable) antimalarial drugs has been declining and high cost of replacement options. n Over 50% of the population does not have regular access to most vital essential drugs. n 60-90% of the population seek initial treatment from unqualified sources, i.e. street vendors, kiosks. n Supply of drugs is often inefficient and unreliable. n Use of ineffective drugs leads to inadequate treatment and leads to drug resistance.

4. WHO - EDM 4 Malaria as cause of death of children under 5 yrs, by WHO region, 2000 % of all deaths Rank AFRO120.3 EMRO132.5 SEARO230.2 WPRO–0.0 AMRO–0.0 EURO–0.0

5. WHO - EDM 5 % of all deaths Rank Malaria1 20.3 Respiratory inf. 217.2 Diarrhoea 312.3 HIV/AIDS4 9.0 Measles5 8.4 Low birth weight6 5.8 Leading causes of death for children under 5 yrs, in the WHO African Region, 2000

6. WHO - EDM 6 WestCentralEast SP Therapeutic Failures (1996-2001) ALERT PHASE ACTION PHASE

7. WHO - EDM 7 Problems of resistance to antimalarial drugs n Era of availability of cheap and effective drugs coming to an end n Both CQ & SP cost <US$0.2/adult treatment course, but resistance to CQ widespread, and to SP increasing n Alternatives for multi-drug resistant falciparum malaria are x10 expensive

8. WHO - EDM 8 Drug-resistant malaria: an introduction n Globally, the pace at which Plasmodium falciparum is developing resistance to antimalarial drugs now exceeds the pace at which new antimalarial drugs are being developed. n It is essential that we find new ways of prolonging the Useful Therapeutic Life (UTL) of the drugs that we currently have

9. WHO - EDM 9 Factors leading to development of resistance n Lack of guidelines/poor drug treatment policies n Irrational prescribing n Irrational drug use n Drug concentration “tail” n Liberalized, uncontrolled drug market leading to poor quality products circulating in international and domestic markets

10. WHO - EDM 10

11. WHO - EDM 11 Who pays for malaria interventions? Out-of- pocket 71% Donors 9% Government 20% 1/3 on drugs 1/2 on bednets and insecticides United Republic of Tanzania

12. WHO - EDM 12 World Health Assembly Resolution WHA52. 19, May 1999 n WHO mandate in the areas of drug safety, quality and efficacy (Revised Drug Strategy) ä Urges member states to reaffirm their commitment: 1.“To developing, implementing and monitoring national policies…” 2.“To taking all necessary …measures in order to ensure equitable access to essential drugs”

13. WHO - EDM 13 The Abuja Declaration, African Summit on Roll Back Malaria (Abuja, Nigeria), April 2000 Call upon all member states to: 1.“Make treatment of malaria available as peripherally as possible including home treatment” 2.“Make appropriate treatment available and accessible to the poorest groups in the community” Pledge to: 1.“Reduce or waive taxes and tariffs for …antimalarial drugs” 2.“Explore and develop traditional medicine in the area of malaria control”

14. WHO - EDM 14 Recently changed 1st line antimalarial treatment guidelines

15. WHO - EDM 15 Access Framework 1. Rational Selection & Use 4. Reliable health and supply systems 2. Affordable prices 3. Sustainable financing ACCESS

16. WHO - EDM 16 Rational Antimalarial Drug Selection

17. WHO - EDM 17 Rationale of combination therapy in malaria n Mutual protection = parasites with mutations conferring resistance to one compound will be killed by the other compound(s). n This killing requires unlinked resistance mechanisms = independent modes of action

18. WHO - EDM 18 What is the ideal combination? n Two or more drugs with different modes of action n Rapid acting and rapid elimination [=no drug concentration “tail”] n At least one component should be gametocidal= reduced transmission

19. WHO - EDM 19 What drugs can we use in combination? Should at least contain artemisinin derivatives since: n Artemisinin derivatives are rapid acting[ = reduce infecting malaria biomass by approx. 10,000-fold per asexual life- cycle,compared with 1,000-fold for other antimalarials

20. WHO - EDM 20 Drugs to be used (cont) n Artemisinin derivatives decrease gametocyte carriage by approx. 90% n Artemisinin derivatives are rapidly eliminated =sustained sub-therapeutic concentrations never occur. Thus, if these compounds are used with an effective combination partner, no parasite “sees” either drug alone= Rationale for combination therapy

21. WHO - EDM 21 Developing and promoting interventions to improve access to good quality antimalarial drugs  Rational selection and use WHO will continue to work with member states to ensure that: 1)Evidence that is accumulated in the clinical practice is used to develop and update malaria treatment guidelines, 2)Treatment guidelines form the basis for the development of essential drugs list 3)Essential drugs list guide the procurement, distribution and use of antimalarial drugs 4)New antimalarial drugs, including novel combinations, are evaluated adequately and registered in a timely manner.

22. WHO - EDM 22 The costs n To the health system, nearly 1/4 of total health budget (US$ 3.19/pers/yr) allocated to drugs n US$ 2.14 malaria expenditures (2/3 covered by household out of pocket) n Increase from US$ 0.20 to US$ 2.0 per treatment in national drug budgets for next generation combination therapy (see next slide)

23. WHO - EDM 23 Cost implications of combination therapy Average cost per adult treatment (US$)

24. WHO - EDM 24 Global negotiation to reduce price of new antimalarials n Expert consensus that co-formulated artemisinin combination best option for use where multi-resistant malaria n Artemether/lumefantrine (Coartem) is only medicine of this type currently licensed n Novartis has agreed to provide drug at cost through WHO for 10 years – US$ 2.40 for adult treatment n Countries to request, direct or through NGOs

25. WHO - EDM 25 Developing and promoting interventions to improve access to good quality antimalarial drugs  Affordable prices 1)Implementation of an effective generic drugs policy 2) Policy guidance on pricing, impact of global trade agreements 3)Pooled bulk purchasing schemes, and price information dissemination 4)Equity pricing for new essential antimalarial drugs 5)No import taxes/duties and minimal distribution margins on essential drugs.

26. WHO - EDM 26 Who pays for malaria interventions? Malaria expenditure in United Republic of Tanzania: ~ US$ 2.14 /person/annum DFID-EA & RBM Expenditure Analysis - Jowett et al,. 2000 This represents 39% of all health expenditure Malaria accounts for 30% of the total disease burden

27. WHO - EDM 27 Developing and promoting interventions to improve access to good quality antimalarial drugs  Sustainable financing Efforts are directed towards: 1)Developing guidelines on sustainable financing 2)Dissemination and promotion of interagency guidelines on drug donation 3)Advocacy for increased budget allocation for essential drugs

28. WHO - EDM 28 Pilot Project on Quality of Antimalarial Products n Project Objectives: ä Provide answers/insight to the following questions: Is there a problem of poor quality chloroquine (CQ) and/or Sulphadoxine/pyrimethamine (SP) products in countries where they are used? If there is a problem of quality of CQ and SP products, what is the magnitude of the problem? If there is a problem of quality of CQ and SP products, is it limited to a particular level of the distribution channel?

29. WHO - EDM 29 Pilot Project on Quality of Antimalarial Products n Project Design : ä Country selection criteria: “spot light countries” in AFRO and EMRO ä Evaluation of the most widely used antimalarials products in the regions ä Sampling from various levels of the distribution chain (household, private sector pharmacy, peripheral health units, district hospital, teaching/referral hospital and district and/or central medical store ä Evaluation of samples on a rapid assessment kit (Mini-lab) and central laboratory (pharmacopeal tests) in CENQAM, South Africa

30. WHO - EDM 30 Pilot Project on Quality of Antimalarial Products n Project initiated in 2000 in 8 African Countries: ä Countries selected: Gabon, Ghana, Kenya, Mali, Mozambique, Sudan, Tanzania, Zimbabwe ä Products selected in the study: CQ (tablets), CQ (syrup), SP (tablets) ä Countries that have completed study: Gabon, Ghana, Kenya, Mali, Mozambique, Zimbabwe ä Countries in the 2nd phase of the study: Sudan (recently completed sampling), Tanzania (starting sample collection in 05/02)

31. WHO - EDM 31 Failure rates (%) - Content

32. WHO - EDM 32 Failure Rates (%) - Dissolution

33. WHO - EDM 33 Pre-qualification of ACT Manufacturers and Products n Objectives: ä To accelerate sustained access to, and use of, good quality ACTs ä To ensure that adequate and effective treatment reaches significantly greater numbers of people in need ä To assist/support the implementation of ACTs in ways that respond to the specific needs and requests of individual countries ä To support drug regulatory agencies in regulating ACTs

34. WHO - EDM 34 Pre-qualification of Manufacturers and Products n Processes of Pre-qualification of manufacturers (of artemisinin-based combination antimalarial drug products) ä Preparatory Phase Drafting of specifications and guidelines (products and product files) Publication of Expression of Interest (EOI) - IHT and WWW ä Documentation Review Phase Receiving of EOI (letter+files) Screening, assessing, and reviewing dossiers  Report ä Plant Inspection (GMP compliance) Phase Team of inspectors appointed by QSM/EDM Inspections carried out jointly with respective DRA ä Reporting Phase Results in a “white” list of products and manufacturers

35. WHO - EDM 35 Pre-qualification of Manufacturers and Products n Expression of Interest (EOI) - Artemisinin-based ACTs ä Products selected for Phase I: Artesunate (oral preparations) Dihydroartemisinin (tablets, capsules, granules, suppositories) Artemether (oral preparations) Artemether + lumefantrine (oral preparations) Artesunate (injection for IV and IM) Artemotil (injection forms) Dihydroartemisinin + piperaquine

36. WHO - EDM 36 Pre-qualification of Manufacturers and Products n Expression of Interest (EOI) for AS+AQ Blister Packs ä WHO calling for EOI - for MOH/Zanzibar ä Paediatric and Adult blister packs ä Process of pre-qualification similar to ARV Project - (WHO/HQ Procurement Services - led) ä Tender will be issued by WHO/Procurement Services (07/02) ä Awards of tenders expected around 08/02 ä Programme incorporates elements of monitoring of deliveries and use of the product (incorporating issues of IND status)

37. WHO - EDM 37 RBM/EDM Planned Activities - Biennium 2002- 2003 n Rational Selection and Use ä Develop training materials ä Assist in the dissemination of training materials ä Provide assistance in training activities n Affordable Prices for Antimalarial Drugs ä Collect information on pricing/prices of antimalarials ä Assist countries in the procurement of antimalarials ä Collect data on domestic manufacturing - capacity etc

38. WHO - EDM 38 RBM/EDM Planned Activities - Biennium 2002- 2003 n Providing assistance in ensuring sustainable financing ä Develop a database on national budgets/expenditures on AM ä Develop a database on the availability of AM (esp. ACTs) n Strengthening drug supply, quality assurance and regulatory systems ä Develop common guidelines for registration of antimalarials ä Assist countries to evaluate quality and monitor inspection activities (including pre-qualification of sources of products) ä Provide support to training in the areas of pharmaceutical inspection (GMP) - manufacturing and distribution channels ä Initiate the development of monographs for new AM