Why the IPTi Consortium was formed
From the results of the first trial of IPTi in Iafakara, Tanzania in 2001 (Schellenberg et al Lancet 2001) – over 50% protective efficacy against clinical malaria and anaemia - IPTi looked like a very interesting potential new tool to control malaria in infants. IPTi was particularly interesting because;
1. It did not hinder the development of anti-malarial immunity through the lack of exposure to parasites (so preventing the rebound of malaria morbidity), and in the Ifakara trial protection was extended into the second year of life (Schellenberg et al Lancet 2005);
2. It made use of a well established delivery system (the EPI) which would make the strategy feasible, sustainable and cheap;
3. It gave only 2 or 3 doses of the anti-malarial – unlike continuous chemoprophylaxis - reducing drug costs and eliminating the problem of compliance (which might lead to drug resistance) as IPTi was given under observation at the clinic;
4. The anti-malaria medicine used, sulphadoxine-pyrimethamine (SP), was cheap, safe, available and acceptable
However, despite the promising results from this trial, more scientific evidence was needed before WHO could recommend IPTi for the control of malaria. Evidence was needed on the efficacy of IPTi in more malaria transmission settings, and more safety data was needed as IPTi gives an anti-malarial drug to a healthy infant who does not have symptoms of clinical malaria.
The research team of the Ifakara trial received a number of informal enquires from several research collaborations, expressing an interest in the further evaluation of IPTi. An informal meeting of the various groups led to the development, with WHO and UNICEF, of a research agenda for the further evaluation of IPTi. This formed the basis of a proposal to the Bill and Melinda Gates Foundation to develop a consortium with a coordinated research and implementation agenda to rapidly resolve the outstanding scientific questions to move the intervention into policy and practice.
The IPTi Consortium received funding from the Bill and Melinda Gates Foundation in 2004 and was coordinated by a secretariat at the Barcelona Centre for International Health Research (CRESIB) in Spain. The Consortium with WHO developed a 5 year program of work to provide a robust evaulation of IPTi, plus experience on its feasibility for large scale implementation in Africa, in order to inform the policy making process.
This information focused on the efficacy of IPTi with SP and alternative anti-malarial drugs in different epidemiological settings, consolidated the evidence on the safety profile of IPTi, investigated the possibility of interactions between IPTi and the serological response to EPI vaccinations, investigated the effect drug resistance would have on the efficacy of IPTi and whether IPTi would drive drug resistance, investigated the cost effectiveness of IPTi, and its acceptability in the community. The Consortium also generated experience in large-scale implementation of IPTi so that if WHO were to recommend IPTi for the control of malaria, implementation experience already gained would facilitate rapid public health action following a policy decision. This was the first time a malaria control intervention underwent such a coordinated and rigorous evaluation in order to inform the policy making process.
Members of the IPTi Consortium
The Consortium was made of leading centres of malaria research in Africa, Europe, the United States, Papua New Guinea, Australia and two United Nations agencies:
01. Albert Schweitzer Hospital, Lambaréné, Gabon
02. Barcelona Centre for International Health Research, Barcelona, Spain
03. Case Western Reserve University, Cleveland, USA
04. Centers for Disease Control and Prevention, Atlanta, USA
05. Ifakara Health Research and Development Centre, Ifakara, Tanzania
06. Institut de Recherche pour le Développement, Dakar, Sénégal
07. Kenya Medical Research Institute, Kisumu, Kenya
08. Kilimanjaro Christian Medical Centre, Moshi, Tanzania
09. London School of Hygiene and Tropical Medicine, London, UK
10. Manhiça Health Research Centre, Manhiça, Mozambique
11. National Institute for Medical Research, Amani, Tanzania
12. PNG Institute of Medical Research, Goroka, Papua New Guinea
13. Swiss Tropical Institute, Basel, Switzerland
14. United Nations Children's Fund (UNICEF)
15. Université Cheikh Anta Diop de Dakar, Dakar, Sénégal
16. University of Copenhagen, Copenhagen, Denmark
17. University of Tübingen, Tübingen, Germany
18. Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Australia
19. World Health Organization (WHO)
Structure and Function of the IPTi Consortium
Interactions between the various components of the IPTi Consortium are represented schematically in the organogram below. The Consortium consisted of a number of key components, the most of which was the research projects conducted by autonomous collaborative research groups. These consisted of clinical trials in Tanzania, Kenya, Gabon and PNG, an effectiveness study in southern Tanzania, and implementation studies by UNICEF in 6 African countries (Ghana, Malawi, Madagascar, Benin, Mali and Senegal). Each research project proposal underwent review by the Gates Foundation appointed Technical Review Committee and received funding directly from the foundation.
Two members of each research project or one member of each working group of the Consortium made up a Consortium Committee that took part in annual update meetings to review results and discuss future research needs.
A small Executive Committee of decision makers guided the IPTi Consortium. The Executive Committee was made up of two standing members with institutional memory of the development of the Consortium, plus rotating members from each of the IPTi projects, plus the WHO, UNICEF and the Gates Foundation.
The core administration (the Consortium secretariat) was the central channel for communications and development of projects with the Consortium, and worked on cross-cutting Consortium-wide activities, and was responsible for the day to day management of the Consortium, and organised and held the Consortium meetings, and organised symposia on IPTi at international conferences. The core administration was based in Barcelona with a full-time coordinator; Dr. Andrea Egan.
All trials conducted by the Consortium were conducted to Good Clinical Practice (GCP) levels and underwent regular clinical monitoring, and had a data and safety monitoring board (DSMB), received ethical clearance, and were registered at www.clinicaltrials.gov
Consortium Safety Panel (CSP)
An independent safety panel provided an overview of the safety data generated under the umbrella of the Consortium and associate members. This was a major advantage of operating as a consortium as robust safety data was greatly valued in subsequent policy discussions. The CSP conducted a pooled analysis of all trials on IPTi with SP. The safety panel consisted of experts in pharmacovigilance, statistics, clinical medicine, epidemiology and ethics:
Chair: Sir Alasdair Breckenridge, Chairman of the UK Department of Health's Medicines and Healthcare Products Regulatory Agency (MHRA), London, UK
Dr. Julia Critchley, University of Newcastle, Newcastle, UK
Dr. Alexander Dodoo, Acting Director of the Centre for Tropical Clinical Pharmacology & Therapeutics, University of Ghana Medical School, Accra, Ghana
Prof. Zul Premji, Muhimbili University, Dar es Salaam, Tanzania
Dr. Esperanza Sevene, Coordinator of National Centre of Pharmacovigilance & Secretariat of the National Ethics Committee, Eduardo Mondlane University, Maputo, Mozambique
Dr. Rachida Soulaymani, Director of the National Pharmacovigilance Centre, Rabat, Morocco
Prof. Peter Winstanley, Director of the Wellcome Trust Tropical Centre, University of Liverpool, UK
WHO advisory committee on EPI serology
An expert panel convened by the WHO investigated whether there were any interactions between IPTi and the serological response to the Expanded Programme for Immunisation (EPI) vaccines.
Statistical working group (SWG)
Formed of the head statistician from each trial of IPTi with SP (including non-Consortium IPTi trials), they used an agreed upon an analytical plan to reanalyse results from the individuals trials using standardized methodologies and definitions to conduct a comparison of results, and pooled the results to conduct a meta-analysis.
Cost effectiveness working group (CEWG)
Each trial measured the costs and cost effectiveness of IPTi in the different settings using a standardised methodology.
Acceptability working group (AWG)
Each trial investigated the acceptability of IPTi to infants’ caregivers and clinic staff in the different settings using a standardised methodology.
Drug resistance working group (DRWG)
Each trial investigated the effect of IPTi on drug resistance. Each trial collected samples in cross-sectional surveys and from clinical malaria cases in trial participants. Molecular markers of resistance were used to assess the effect of IPTi on the selection of drug resistant parasites. Trials were conducted using standard WHO in vivo procedures in 6 to 59 month old children with symptomatic malaria and relate in vivo resistance levels to the efficacy of these drugs when used for IPTi. A large effectiveness study in southern Tanzania also investigated the effect of IPTi on the spread of resistance in all age groups in the community. Modelling techniques were used to estimate the effect that IPTi might have on driving drug resistance.
Applicability of IPTi working group
This group generated an overview of the age pattern of malaria disease and death in sub-Saharan Africa and developing mathematical models to link this information to IPTi efficacy study results in order to estimate the benefits of IPTi in specific countries and malaria transmission settings.
WHO Policy Platform
An important component of the Consortium was the WHO-based platform to facilitate policy discussions. The research findings on IPTi will need to be translated into policy decisions at national level. The key steps in this process include:
Obtaining the relevant evidence (the work of the IPTi Consortium)
Informing the key players likely to influence policy
Appraising the evidence (by a Technical Expert Group appointed by WHO)
Supporting and facilitating policy change
Facilitating the subsequent delivery and sustainability of the intervention UNICEF, having gained substantial experience in the large scale pilot implementation of IPTi in six African countries, would work side by side with the WHO to aid the implementation process for countries which decide to implement IPTi.