TRANSLATION FROM WHO RECOMMENDATION TO IMPLEMENTATION INTO NATIONAL POLICY Ellis S 1, Musa A 2, Burza S 3, Alirol E 4, 5, Lima M A 3, Chappuis F 4, 5, Hailu A 6, Khalil E 2, Olobo J 7, Strub N 1, Wasunna M 1, 8, Sharma B 1, Balasegaram M 9, Author Affiliation: 1 Drugs for Neglected Diseases initiative, Switzerland; 2 Institute of Endemic Diseases, University of Khartoum, Sudan; 3 Médicos Sin Frontieras, Spain; Hôpitaux Universitaires de Genève, Switzerland; Médecins Sans Frontières, Switzerland, 6 Addis Ababa University School of Medicine, Ethiopia; 7 Makerere University, Uganda; 8 Kenya Medical Research Institute, Nairobi; 9 MSF Access Campaign Switzerland; Together for Impact World Leish 2013
2 Phase III Policy Implementation
India - Phase III Clinical trial efficacy 3 S Sundar study VL Combo study AmB SD Ampho B Ampho B AmB+M AmB+PM M+PM ITT 304 108 157 160 157 158 Cure at M6 291 95.7% 104 96.3% 146 93.0% 156 97.5% 153 97.5% 155 98.7% PP 304 106 156 158 155 158 Cure at M6 291 95.7% 104 98.1% 146 93.6% 155 98.1% 153 98.7% 156 98.7% Source:Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW: Single-dose liposomal amphotericin B for visceral leishmaniasis in India.. N Engl J Med. 2010 Feb 11;362(6):504-12. Source: Sundar S, Sinha PK, Rai M, Verma DK, Nawin K, Alam S, Chakravarty J, Vaillant M, Verma N, Pandey K et al: Comparison of shortcourse multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet 2011, 377(9764):477-486. 3
Clinical Trial Real life 4 Photo: DNDi, DNDi and sally Ellis Photo: DNDi, DNDi and Catherine Royce
India 5 All drugs are registered VL Treatments in use: Miltefosine monotherapy: 28 days conventional Amphotericin B: up to 30 days WHO Recommendation: No published data in Primary Health Care Setting Implementation plan conducted in PHC to evaluate treatments in a wider patient population in Bihar, India Assess the effectiveness Evaluate the safety profile Single dose AmB 10mg/kg on D 1 Combination: AmB 5mg/kg on D1 + MF D 2-8 MF + PM Day 1-10 AmB 5mg/kg on D1 + PM D 2-11 Assess if there are any important adverse outcomes in specific patient groups
6 Project Implementation with Partners Key Implementing Partners State Health Society Bihar: All the Doctors and supporting staff from Government, working at the District Hospital and PHCs. Rajendra Memorial Research Institute Patna, as site and training support Médecins Sans Frontières partners in Vaishali district LSHTM, ITM-Antwerp
Sites participating in VL PV 001 7 Saran: District Hospital: Chhapra PHCs: Maraurah, Dariyapur, Baniyapur and Parsa Vaishali: District Hospital: Hajipur PHCs: Vaishali, Garaul, Mahua, Raghopur, and Mahnar
Project Design 8 Open label, prospective, non randomised, non comparative, multicentre, observational study assessing safety & effectiveness of new treatment PHC District Hospital/ Referral centre Sites 10-15 PHCs in 2-3 districts in Bihar eg Vaishali, Saran 5+ PHC 5+ PHC 1-2 sites eg. District Hospital Referral Centres (special cases) Treatments Milt + PM for 10 d AmB (5) + Milt for 7d SDA Other VL treatments if SDA contraindicated Sample Size Safety: 2000 patients - 86% probability and 3000 patients - 95% probability that 1 ADR will be detected (expected incidence of 1/1000) Effectiveness: 300 patients treated, a failure risk of 5% could be estimated with at least 5% precision.
Key components of the project 9 Step 1- initial piloting Active monitoring & evaluation Surveillance register Safety (PV) Treatment Compliance Duration: 1-2 years Sites: 1-2 District hospitals and 10+ PHCs No. of patients: At least 1000 (300 per treatment) Follow up: 6 & 12 month follow up visit for efficacy Data review Step 2 consolidation/reporting Continue Surveillance register Continue PV Duration: 2-3 years Sites: Potential for implementation in other endemic areas by NCP and SHS. No. of patients: approximately 6000 6 monthly PUR. Long term reporting of AEs will be handed over to the NPP
Status - India 10 S.No Dates Training Venue Participants 1 7-10 Dec 2011 MSF Team- study protocol & GCP, informed consent & pharmacovigilance Hajipur, Vaishali, Bihar 42 2 30-31 Jan 2012 3 9-10 April 2012 Medical professional of PHCs, Allopathic doctors and AYUSH ANM Training school, Chappra, Saran, Bihar Sadar hospital, Hajipur, Vaishali 75 49 4 24-25 May 2012 GCP Training Saran (24) & Vaishali (25) 42 + 38 600 500 400 300 200 100 0 Recruitment Pilot Study 465 495 395 306 250 190 140 92 28 Aug 12 Sep Oct Nov Dec Jan Feb Mar Apr Total SDA Total A+M Total P+M Total Recruited Classifications Number of Patients Paediatric patient <12 130 Severe disease 3 Severely Malnourished 4 TB +ve 1 Age less than 2 years 0 Pregnant 0 HIV +ve 9 PKDL 1
East Africa 11 WHO Recommendation Country Recommendation Kenya Sudan & Ethiopia Uganda Revised Guidelines launched SSG & PM Combination 17 Days Guidelines revised but not launched SSG Registration status PM Registration status Registered- Nov 08 Not registered Registered 2009 Registered - Feb 13 Submitted Registered Jan 2012 Project Objectives Monitor SSG&PM safety Identify additional risks that have not been reported during clinical studies To determine if ADR are increased in specific groups of patients Monitor the treatment failure rate Monitor any evidence in regional variation in terms of effectiveness & safety 11
Project Design 12 Sites Ethiopia Sudan Kenya Uganda Prospective Open label Multicentre Observational Pharmacovigilance Effectiveness Country Study Coordinator KEMRI Data Centre / TCC 1. Data review and collection 2. SAE 3. Supplies 1. Data Management 2. Coding 3. Report preparation Steering Committee 1. Safety review 2. Periodic update report
13 Participating Sites in SSG&PM 6 5 3 1 2 4 10 9 11 Sudan 1. Kassab Hospital - IED 2. Prof El Hassan Centre for Tropical Disease, Doka 3. Tabarakallah - MSF 4. Um el Kehr MoH 5. Bazura MoH 6. Elhawata MOH Kenya 7. Kimalel - KEMRI 8. Kacheliba MSF, MoH/DNDi Ethiopia 9. Gondar University Hospital, 10. Abdurafi 11. Arba Minch Hospital Uganda 12. Amudat Hospital 12 8 7
Challenges to consider 15 Registration status required for implementation? EC and RA Approval Process Requirements for collecting additional data Clinical trial or not? Efficacy, safety or both? Special populations - young children, pregnant women etc. Patient registries eg pregnancy registry Feasibility of new treatments in resource limited setting? Revising & Implementing national treatment guidelines Status of National Pharmacovigilance program Collecting data in busy health centres / hospitals Training health care workers
ACKNOWLEDGEMENTS 16 All our patients East Africa India Site teams: Kassab Hospital and Prof El Hassan Centre for Tropical Disease, Doka, IED, Sudan; Tabarakallah MSF; Um el Kehr, Bazura, Elhawata, Ministry of Health, Sudan; Kimalel KEMRI; Kacheliba MSF, MoH/DNDi; Gondar University Hospital, Abdurafi, Arba Minch Hospital, Ethiopia; Amudat Hospital, Uganda; Team: Clelia Bardonneau,Robert Kimutai, Raymond Omollo, Godfrey Nyakaya, Peninah Menza, Michael Ochieng, Truphosa Omollo LEAP: Universities of Khartoum, Addis Ababa University, Gondar University, Makerere, Kenya Medical Research Institute; Ministries of Health of Kenya, Uganda, Ethiopia and Sudan, LSH&TM; MSF; I+ Solutions Donors: Médecins Sans Frontières/Doctors without Borders, International; Spanish Agency for International Development Cooperation (AECID), Spain; Swiss Agency for Development and Cooperation (SDC); Dutch Ministry of Foreign Affairs (DGIS), The Netherlands; Federal Ministry of Education & Research (BMBF) through KfW, Germany; Pro Victimis, Switzerland; Medicor Foundation, Liechenstein Site teams: Hajipur & Chhapra District Hospitals and Parsa, Marhaura, Dariyapur, Baniapur, Goraul, Mahnar, Mahua, Raghopur & Vaishalli PHCs Team: Nathalie Strub, Vishal Goyal, Abhijit Sharma, Pankaj Kumar, Muhammad Akram, Raj Kishore Rai, Anurag Singh Partners: Bihar State Health Society, MSF, Rajendra Memorial Research Institute, OWH/ PATH, WHO-TDR Donors: Bill & Melinda Gates Foundation; Department for International Development (DFID), UK; Médecins Sans Frontières/Doctors without Borders; Spanish Agency for International Development Cooperation (AECID); Swiss Agency for Development and Cooperation (SDC); Starr International Foundation, Switzerland; Other private foundations & private individual donors