IMPLEMENTING RISK MANAGEMENT PLANS IN AFRICA: THE ASAQ Winthrop RISK MANAGEMENT PLAN. François Bompart Access to Medicines - Sanofi

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1 IMPLEMENTING RISK MANAGEMENT PLANS IN AFRICA: THE ASAQ Winthrop RISK MANAGEMENT PLAN François Bompart Access to Medicines - Sanofi

2 Artesunate Amodiaquine Winthrop (ASAQ Winthrop ) Infant (<8 kg) ASAQ Winthrop Artesunate-Amodiaquine Co-blister Arthemeter Lumefantrine AM PM Toddler (8-17 kg) 5-15 kg Child (17-35 kg) kg kg Adult (>35 kg) >35 kg

3 ASAQ Winthrop Risk Management Plan Rationale Counterfeits and substandard versions of ASAQ Winthrop will soon appear: safety issues, rumours, controversies Available data from clinical studies have limitations: Patients numbers Controlled conditions Single malaria episodes Limited pharmacovigilance systems in sub-saharan Africa Coartem Oct 1998 Aug 2008 > 200 million treatments 137 spontaneous reports, 60% from Africa* Virtually no pharmacovigilance data from industrialized countries for malaria drugs * Dec 3, 2008 FDA Advisory Commitee Meeting, Bethesda, MD

4 European Medicines Agency (EMA) Risk Management Plans Key sections 1. Safety Specifications Review of known safety profile of the drug, Potential risks, Populations not studied, Potential interactions, Etc. Classification into: - Identified risks - Potential risks - Missing information 2. Pharmacovigilance Plan - Routine pharmacovigilance - Additional pharmacovigilance and action plans 3. Risk Minimisation Plan

5 WHO Department of Medicines Policy and Standards ASAQ Winthrop Risk Management Plan Table of Contents (1) 1. Identified risks: to be minimized with specific information Intake during first trimester of pregnancy Allergy 2. Potential risks: to be quantified Hepatotoxicity Neutropenia / agranulocytosis Somnolence Audiometric dysfunction Extra-pyramidal symptoms Decreased efficacy (parasite resistance)

6 WHO Department of Medicines Policy and Standards ASAQ Winthrop Risk Management Plan Table of Contents (2) 3. Missing information: to be documented in new studies Safety of repeated administrations Specific populations (HIV/AIDS patients ) Second and third trimester of pregnancy Safety profile in non parasitaemic patients Drug interactions & Interactions with traditional drugs and remedies Efficacy in species other than P. falciparum

7 ASAQ Winthrop Risk Management Plan Objective : gather good quality safety and efficacy data in a variety of malaria transmission settings, in order to quantify potential risks and to document missing information Methods Randomized comparative clinical trials 9+ Randomized comparative cohorts 2 Field monitoring programs 2 Large-scale safety study 1 Expected database >>> 20,000 malaria episodes treated with ASAQ Winthrop

8 ASAQ Winthrop Risk Management Plan Methods Randomized clinical trials versus comparator Efficacy in various malaria transmission settings Clinical safety Biological safety, ECG data Data in specific populations (HIV+, pregnancy) Data in other parasites (P. vivax) Randomized cohort studies (multiple attacks) Efficacy / effectiveness and safety in Iterative administrations ECG and audiometric data Field monitoring study with Côte d Ivoire NMCP, MMV & DNDi Effectiveness Clinical safety in patients without parasites Pharmacovigilance education Large-scale pharmacovigilance program in Burkina Faso 3 passive monitoring sites, 3 active monitoring sites

9 Patients treated with ASAQ Winthrop in completed controlled trials (July 2011) 12 studies, 3622 patients, 6468 malaria attacks treated with ASAQ Winthrop Versus loose AS+AQ: Burkina Faso: 750 children < 5 years and > 5kg 375 ASAQ Kenya : 54 adults 26 ASAQ Versus AQ: India: 300 adults and children 202 ASAQ Versus AL: Liberia: 300 children < 5 years 150 ASAQ Liberia: 1000 patients > 5 years 498 ASAQ Senegal, Mali, Cameroon, Madagascar 941 adults + children >10 kg 628 ASAQ Benin: 225 children <10 years 90 ASAQ Senegal cohort study: 364 adults and children (213/429 attacks) 183 ASAQ Uganda cohort study : 413 children < 5 years (3129/ 6032 attacks) 208 ASAQ Colombia: 210 adults 105 ASAQ Versus AL & DHA-PQ: Burkina Faso, Gabon, Mozambique, Nigeria, Rwanda, Uganda and Zambia: 4114 children < 5 years 1002 ASAQ Versus AL, DHA-PQ,ASMQ FDC, ASMQ LDC Myanmar 155 ASAQ

10 ASAQ Winthrop clinical study sites in Africa

11 ASAQ Winthrop Risk Management Plan Selected Preliminary Outcomes Completed clinical cohort study: ASAQ vs AL repeated administrations over 2 years Uganda: 413 children, 6033 malaria episodes: Median number of episodes Extrapyramidal disorders 3 reports + Sanofi database + literature review + WHO VigiBase: ASAQ Winthrop labelling modified to include extrapyramidal disorders Resistance monitoring: with WorldWide Antimalarial Resistance Network (WWARN) - RMP: provide information on resistance development - WWARN: help identify issues to be investigated through RMPs

12 ASAQ Winthrop Risk Management Plan Key Features - Variety of study designs to address multiple safety issues and information gaps - Variety of study settings to address different malaria transmission patterns - 1st Risk Management Plan submitted to the WHO - 1st Risk Management Plan almost entirely set up in Africa - Complements and reinforces Routine pharmacovigilance activities, and contributes to capacity building in pharmacovigilance and drug resistance monitoring

13 ASAQ Winthrop Risk Management Plan Partners Sanofi National Malaria Control Programs (collaboration for all studies, information and education on malaria and appropriate use of ACTs) DNDi (Drugs for Neglected Diseases intitiative) MMV (Medicines for Malaria Venture): support of implementation program in Côte d Ivoire, anticipate RMP for new ACTs Academic teams WWARN (WorldWide Antimalarial Resistance Network): sharing ASAQ Winthrop efficacy data