The ACT Consortium All Party Parliamentary Group on Malaria and NTDs 20 th January 2015 David Schellenberg Professor of Malaria & International Health ACT Consortium Director London School of Hygiene and Tropical Medicine Answering key questions on malaria drug delivery 1

2 Artemisinin Combination Treatment First line treatment for the most severe form of malaria, caused by Plasmodium falciparum

3 Goal of the ACT Consortium To develop and evaluate mechanisms to improve ACT delivery 25 projects in 10 countries, working on: ACCESS TARGETING SAFETY QUALITY

4 Four Research Themes ACCESS: Poorest have worst access to malarial drugs How can this be improved ? TARGETING: Many ACTs used by people without malaria. Implications for ACT cost-effectiveness, drug resistance, non-malaria case management How can ACTs be used more efficiently? SAFETY: Drugs licensed with data in ≥6,000 people. Rare but important adverse events may not be detected pre-licensure Need to consolidate safety profile eg repeat dosing, subgroups (eg HIV), interactions (eg antiretrovirals) QUALITY: Substandard and fake ACTs common No system for quality assurance in endemic countries

5 Four Research Themes ACCESS: Poorest have worst access to malarial drugs How can this be improved ? TARGETING: Many ACTs used by people without malaria. Implications for ACT cost-effectiveness, drug resistance, non-malaria case management How can ACTs be used more efficiently? SAFETY: Drugs licensed with data in ≥6,000 people. Rare but important adverse events may not be detected pre-licensure Need to consolidate safety profile eg repeat dosing, subgroups (eg HIV), interactions (eg antiretrovirals) QUALITY: Substandard and fake ACTs common No system for quality assurance in endemic countries

6 The Private Sector Formal & informal Clinics & pharmacies, shops & street vendors Most malaria treatments are obtained from the private sector in some countries Eg DRC 85%, Nigeria 95% Nigeria + DRC generated 1/3 of African malaria cases in 2006 Novel financing mechanism - Affordable Medicines Facility for malaria (AMFm) – designed to improve affordability of and access to ACTs

7 Targeting of ACTs Private retail sector, Tanzania Briggs M et al (2014) PLoS ONE 9(4): e Fever patients attending private retail outlets in Tanzania 70%of those infected did not get ACTs 80% of those receiving ACTs were not infected

8 A Balancing Act ACCESS TARGETING Novel financing mechanism - Affordable Medicines Facility for malaria (AMFm)

9 Rapid Diagnostic Tests (RDTs) Point of care diagnostic No laboratory or electricity needed, minimum training Based on antigen capture - 2 main types HRP-2 – persists (weeks) after cure LDH – negative ~2 days after cure

RDTs in drug shops to improve the targeting of malaria treatment in Uganda Private health care sector:

11 Introducing RDTs in drug shops to improve the targeting of malaria treatment in Uganda Study methods: ● Randomized study introduced malaria RDTs in 65 registered drug shops in central Uganda. ● RDTs were offered at subsidized cost (~ US $ 0.20). ● MoH researchers trained drug shop vendors in RDT use, malaria case management, and referral. ● Community volunteers helped to raise awareness.

12 Introducing RDTs in drug shops to improve the targeting of malaria treatment in Uganda Study results: ● Uptake of RDTs was high. In one year, > 15,000 clients sought treatment, and 98% accepted to buy an RDT. ● > 85% of treatments were correct based on RDT results. ● Correct treatment was higher in shops where vendors used RDTs (73%), vs symptom-based treatment (34%; p<0.001 ). ● Vendors did not refer many patients to health facilities. ● The intervention changed the reputation of drug shops.

13 Before introduction of subsidized ACTs and vendor training Introducing RDTs in drug shops to improve the targeting of malaria treatment in Uganda After vendors trained to diagnose by clinical symptoms After vendors trained to use malaria RDTs

14 Introducing RDTs in drug shops to improve the targeting of malaria treatment in Uganda Study conclusions: ● RDTs are likely to be popular in the private heath care sector. ● Clients are willing to buy RDTs at subsidized prices. ● Trained drug shop vendors can use RDTs correctly. ● RDT training in drug shops can improve the quality of care; it can also change the reputation of drug shops. ● Programs may wish to plan for wider consequences, e.g. for treatment seeking and general standards of care in the private sector.

15 Diagnostics in the Private Sector Is it possible to incentivise the use of RDTs for patients & shopkeepers? Approximate prices: ● RDT $ 0.65 ● ACT $ 4.00 (without subsidy) ● ACT $ 0.25 (with AMFm subsidy) Opportunity (& challenge) to capture data Challenge of management of RDT negative patients

16 Mapping the causes of non-malaria fever

17 35 % (796) out of 2296 antimalarials from 21 countries in Sub Saharan Africa failed the content analysis Drug reports are lacking for 63 (60.3%) of 104 malaria endemic countries Antimalarial Drug Quality – how much of a concern?

18 Drug Samples LSHTM (UK) Harparkash Kaur All samples logged Scanned & tablet dimensions noted HPLC analysis for % API content Results compiled into a report CDC (Atlanta) Mike Green ~10 %of samples tested to confirm HPLC analysis from partner (LSHTM) GT (Atlanta) Facundo Fernandez Mass spec analysis I NFORMATION ON QUALITY OF DRUGS DISSEMINATED TO M O H All collected samples Samples sent for validation Samples sent for mass analysis Results sent Report complied and sent Schematic Flow of Sample Processing All information is logged on to a database mAU min Artemether – 3.8 Lumefantrine – 4.6 ACT Consortium Drug Quality project: Principal Investigator Dr H Kaur

19 The importance of the sampling strategy Types of providers – pharmacy, patent medicine vendors and public health facilities SAMPLING METHODS Convenience – collect drugs from outlets which are easy to access Representative sample of outlets Mystery client - collect drugs from outlets by pretending to be a patient Overt sample collection – inform shop keepers of interest in drug quality A drug quality survey in Enugu, Nigeria ACT Consortium Drug Quality project: Principal Investigator Dr H Kaur

20 OutletsAuthenticSubstandardDegradedFalsified Convenience (n = 200; total brands = 49; brands per outlet = 2.1) All outlets (23) 169 (84.5%)21 (10.5%)4 (2.0 %)6 (3.0 %) Mystery clients (n = 1919; total brands = 102; brands per outlet = 0.4) All outlets (279) 1748 (91.1%)112 (5.8%)25 (1.3%)24 (1.2%) Overt (n = 905; total brands = 79; brands per outlet = 0.7) All outlets (119) 828 (91.5%)63 ( 6.9%)9 (1.0%)5 (0.6%) Chemical analyses of ACTs purchased using convenience, mystery client and overt sampling approaches in Enugu, Nigeria; n = 3024 The importance of the sampling strategy - Results Appropriate sampling: important for reliable estimates & monitoring change Pros & cons of mystery versus overt sampling Overt sampling: more samples, additional information (risk factors): possibly biased estimate ACT Consortium Drug Quality project: Principal Investigator Dr H Kaur ACT Consortium Drug Quality project: Principal Investigator Dr H Kaur

21 > 5 % falsified ACTs < 5 % falsified ACTs 0 falsified found Countries where Falsified Drugs were Found In 4 of 6 countries NO falsified ACTs found ACT Consortium Drug Quality project: Principal Investigator Dr H Kaur ACT Consortium Drug Quality project: Principal Investigator Dr H Kaur

22 Need to bring epidemiology & analytical chemistry together - Large sample sizes, representative surveys, a range of settings - Corroboration between laboratories (3) and detection methods (2) Overall reassuring results, but no room for complacency - Falsified & substandard drugs prevalent in Nigeria and Bioko – Monotherapy tablets still available A need for National Regulatory Authorities to have systems & capacity for routine drug quality monitoring Drug Quality Conclusions ACT Consortium Drug Quality project: Principal Investigator Dr H Kaur Assortment of ACTs purchased in one west African town Picture H Kaur (Aug 2009) ACT Consortium Drug Quality project: Principal Investigator Dr H Kaur

23 Working as a Consortium Co-ordinated approach Enhanced standardisation Methodology, endpoints, indicators Quality assurance Robust safety and effectiveness data for pooled analyses Involves academics, policy makers & programme managers Reliable, policy relevant outputs

ACT Consortium Members Centres for Disease Control and Prevention, (CDC) USA College of Medicine, University of Malawi, Malawi College of Medicine, University of Nigeria, Nigeria Dangme West District Health Directorate, Ghana Georgia Institute of Technology, Georgia, USA Heath Protection and Research Organisation, Afghanistan Ifakara Health Institute, Tanzania Infectious Disease Research Collaboration, Uganda Karolinska Institutet, Sweden Kilimanjaro Christian Medical Centre, (KCMC), Tanzania Kintampo Health Research Centre, Ghana Liverpool School of Tropical Medicine, UK London School of Hygiene and Tropical Medicine, UK National Institute for Medical Research, Tanzania University of Cape Town, South Africa University of Copenhagen, Denmark University of Yaoundé, Cameroon Coordinated by the London School of Hygiene and Tropical Medicine Funded by the Bill and Melinda Gates Foundation Answering key questions on malaria drug delivery