Money & Microbes STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS INTERNATIONAL VACCINES TASK FORCE MAY 2018 viii MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS Money & Microbes STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS INTERNATIONAL VACCINES TASK FORCE Statements, recommendations, and opinions expressed are those of the International Vaccines Task Force (IVTF). The International Vaccines Task Force was supported by the World Bank Group and the Coalition for Epidemic Preparedness Innovations. The World Bank served as Secretariat for the IVTF. The World Bank team was led by Mukesh Chawla and included (in alphabetical order, by last name) Erika Hartingh, Consultant; Nicole Lurie, Consultant; Adrienne McManus, Consultant; Micaela Mussini, Consultant; Rocio Schmunis, Senior Operations Officer, Health, Nutrition and Population; and Gabrielle Williams, Consultant. The World Bank team was supported by several colleagues from the Coalition for Epidemic Preparedness Innovations (CEPI), including Joseph Simmonds-Issler, Chief of Staff; Rebeka Yasmin, Executive Assistant to the CEO; Rachel Grant, Director of Communications and Advocacy; and Shanni Dhoofer, Administrative Coordinator. © 2018 The World Bank 1818 H Street NW Washington DC 20433 Telephone: 202-473-1000 Internet: www.worldbank.org This work is a product of the staff of The World Bank with external contributions. The findings, interpretations, and conclusions expressed in this work do not necessarily reflect the views of The World Bank, its Board of Executive Directors, or the governments they represent. The World Bank does not guarantee the accuracy of the data included in this work. The boundaries, colors, denominations, and other information shown on any map in this work do not imply any judgment on the part of The World Bank concerning the legal status of any territory or the endorsement or acceptance of such boundaries. Rights and Permissions The material in this work is subject to copyright. Because the World Bank encourages dissemination of its knowledge, this work may be reproduced, in whole or in part, for noncommercial purposes as long as full attribution to this work is given. Any queries on rights and licenses, including subsidiary rights, should be addressed to World Bank Publications, The World Bank Group, 1818 H Street NW, Washington, DC 20433, USA; fax: 202-522-2625; e-mail: pubrights@worldbank.org. International Vaccines Task Force Members Marie-Paule Kieny, The Institut National de la Santé et de la Recherche (INSERM), Co-chair Richard Sezibera, Member, Senate of Rwanda, Co-chair Abraham Aseffa, Armauer Hansen Research Institute (AHRI) Nita Bhandari, Centre for Health Research & Development, Society for Applied Studies (CHRD, SAS) Tim Evans/Mukesh Chawla, World Bank Group (WBG) Mark Feinberg/Swati Gupta, International AIDS Vaccine Initiative (IAVI) Roger Glass/Peter Kilmarx, Fogarty International Center (FIC/NIH) Margaret Hamburg, National Academy of Medicine (NAM) Richard Hatchett/Cherry Kang/Melanie Saville, Coalition for Epidemic Preparedness Innovations (CEPI) Elizabeth Higgs/Cliff Lane, National Institutes of Health (NIH) Gerald Keusch, Boston University (BU) Claudio Lanata, Instituto de Investigación Nutricional (IIN) Nicole Lurie, Former United States Government (USG), Member-secretary Michael Makanga, European & Developing Countries Clinical Trials Partnership (EDCTP) Peter McIntyre, National Centre for Immunization Research and Surveillance, Australia (NCIRS) John Nkengasong, Africa Centres for Disease Control and Prevention (Africa CDC) Peter Salama/Ana Maria Henao-Restrepo, World Health Organization (WHO) Peter Smith, London School of Hygiene & Tropical Medicine (LSHTM) Moncef Slaoui, Galvani Bioelectronics Ed Whiting/Alycia Draper/Nancy Lee/Charlie Weller, Wellcome Trust INTERNATIONAL VACCINES TASK FORCE MEMBERS “Historically, we have had warriors who had spears to combat larger physical threats that could be easily seen (e.g., lions, snakes, tribal armies, etc.). We are now in an era where these threats cannot be seen with the naked eye or defended against with traditional weaponry. We are at war with things that we cannot see and we are losing many of the battles. In this era, it is the scientists who are the warriors and their weapons are micro- and nanoscopes. This change therefore demands that new policies and practices sufficiently fund these new warriors and equip them with the skills, knowledge, infrastructure and equipment to help address these serious health security hazards.” Prof John David Kabasa Makerere University College of Veterinary, Animal Resources and Biosecurity, Uganda Contents Foreword. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii Acronyms and Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1–Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 The International Vaccines Task Force. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Overview of the Report. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 2–Committing to Clinical Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Clinical Research Response during Outbreaks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Where to Start. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Accelerating R&D during Emergencies: The Nigerian Experience . . . . . . . . . . . . . . . . . . . . . 17 Investment Framework. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3–Enabling Clinical Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Legal Frameworks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Culture of Clinical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4–Assessing Clinical Research Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 5–Financing Clinical Research Capacity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Buy-downs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Regional Financing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Domestic Resource Mobilization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Coalition for Epidemic Preparedness Innovations (CEPI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Private Sector Contributions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 CONTENTS 6–Coordinating Investments in Clinical Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Mechanisms to Coordinate Investments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Trust Fund Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 National-Level Resource Tracking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 7–Monitoring Progress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 8–Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 vi MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS Foreword I n 2014, the world watched in horror as the Ebola Crisis unfolded in West Africa. This outbreak, of unprecedented proportions, devastated the countries of Guinea, Sierra Leone, and Liberia and presented tremendous challenges to the global public health and emergency response communi- ties. The inadequacy of the initial response demonstrated, if such demonstration were necessary, the world’s lack of preparedness to respond to such events. More than any other recent outbreak— and there have been many—the Ebola Crisis has stimulated concerted efforts, from the frontlines of country health systems to the back offices of UN bureaucracies, to improve our readiness for epidemic and pandemic threats. Despite many promising developments, not least the establish- ment of the World Bank’s Pandemic Emergency Financing Facility, there is still a long road ahead to achieving this goal. The development of effective vaccines and other medical countermeasures would greatly reduce the risks the world faces from emerging infectious diseases, but the efficacy of such products can be demonstrated definitively only during outbreaks. Having research capacity that can be mobilized quickly and effectively in the countries where outbreaks are most likely to occur will be a prereq- uisite for the rapid deployment and testing of candidate products. The lack of such capacity will result in tragic delays, as in West Africa, where investigational Ebola vaccines and therapeutics were deployed far too late to impact the outcome of the epidemic. The establishment in 2017 of the Coalition for Epidemic Preparedness Innovations (CEPI) and its subsequent investment in vaccines against high priority pathogens such as MERS, Lassa, and Nipah underscores the need to ensure that research capacity is in place during outbreaks. To advance this objective, the World Bank and CEPI supported the creation of an International Vaccines Task Force (IVTF) with the aim of producing actionable recommendations to secure essential national clinical research capacity in lower- and middle-income countries where such infrastructure is fragile or non-existent. Under the wise guidance of Co-chairs Marie-Paule Kieny and Richard Sezibera, the IVTF has, over the last 9 months, delved into this issue, consulting widely, deliberating deeply, and delivered the set of recommendations found in this report. We are extremely grateful to the co-Chairs and all of the IVTF members for their efforts in this regard. We are also grateful to the leadership of Dr. Nicole Lurie who together with the World Bank team led by Mukesh Chawla helped not only to meet tight timelines but also surpass our high expectations. There is no time to waste in implementing these recommendations. We look forward to doing our part, together with partners, to prepare for future outbreaks no matter where they may occur. Tim Evans Richard Hatchett Senior Director, Health, Nutrition and Chief Executive Officer, Coalition for Epidemic Population Global Practice, World Bank Group Preparedness Innovations (CEPI) FOREWORD vii viii MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS Preface L ack of capacity kills. Literally. Epidemics are happening with increasing severity and frequency. An ever-growing armory of new zoonotic infections descends on us each year. Older nemeses like Ebola and Lassa fever return more often and the outbreaks claim ever more lives. Clearly, the diseases are growing and adapting. Yet the approach to them has, in many important aspects, remained unchanged. Certainly, we have increased surveillance efforts, and are doing better at recognizing emerging epidemics earlier before the outbreak spreads so far that containing it becomes a Herculean task, demanding mind- boggling amounts of human, technical and financial resources that we can ill afford. We have also stepped up our response efforts, and are improving our efficacy and capabilities as we race in each new epidemic to prevent new infections and to treat the infected. These are admirable advances that we must strengthen even more as populations grow, live in ever closer contact with the zoonotic hosts, and the ability to travel far and quickly becomes a reality for more and more people—and pathogens as well. But at root our response to emerging epidemics remains just that: responsive. We remain in a seemingly unending game of “whack-a-mole”— the old carnival game in which players use a mallet to hit toy moles that pop up randomly from a “field” of holes before quickly disappearing again only to emerge from another hole over and over and over again. In short, we have been effectively giving these deadly enemies a pass, allowing them to con- trol the parameters of the playing field while we remain focused on response, on defense. It is time to stop giving these pathogens a pass. It is time to make a serious push to get ahead of them. It is time to find the pathogens before they find us and develop the tests, treatments and vac- cines we may need before we actually need them. Fortunately, people and institutions around the globe are already awakening to this challenge. Recent years have seen a wealth of new initiatives, new research and new funding efforts. For example, the World Health Organization (WHO) developed and is implementing a Research and Development (R&D) Blueprint for action to prevent epidemics by fast-tracking the availability of effective diagnostic tests, vaccines and medicines to save lives and avert large-scale crises. The Global Health Security Agenda (GHSA) is supporting an evaluation system to strengthen countries’ basic public health capacity and compliance with International Health Regulations for surveillance and reporting of outbreaks. And the Coalition for Epidemic Preparedness Innovations (CEPI), a novel global non-profit alliance that finances and coordinates partnerships for developing new vaccines to prevent and contain infectious disease epidemics is already funding vaccine development for three priority pathogens—Lassa, Nipah and MERS. Finally, the World Bank, with the support of Japan, Germany, WHO, and private sector partners, has developed the Pandemic Emergency Financing Facility (PEF), a quick-disbursing financing mechanism that provides a surge of funds to enable a rapid and effective response to a large-scale disease outbreak. PREFACE ix However, even as the battle has been joined, our ultimate goal remains out of reach. One important reason is that we haven’t fully equipped ourselves with all the tools we need to succeed. In addition to all the impressive research advances in leading laboratories in the developed world, we need a world where those research and clinical capabilities are just as strong in the lower- and middle- income countries where epidemics often strike. Without those capabilities, promising new interven- tions cannot advance as quickly as we need. Examples of this shortfall are sadly too easy to find. When the 2014-15 Ebola crisis first emerged, there were already candidate vaccines whose deployment could have been advanced by better preparedness. Lassa fever has been around for a long time, described first in 1969 from a case in the town of Lassa, in Borno State, Nigeria. Yet, our knowledge of its epidemiology and how to treat it has not evolved for decades. Identified by WHO as a likely cause of a future epidemic, Lassa virus has been listed for urgent R&D to develop new diagnostic tests, vaccines, and medicines. But the situation is not entirely grim. Times of crisis present opportunities to focus capabilities and energy on solving important problems. Research during outbreak response is critical to the genera- tion of new knowledge, especially for diseases like Ebola for which clinical trials must be conducted during outbreaks because the severity of illness and the frequency of fatal outcomes precludes using human experimental model infections for such studies. It is the only way to ensure that we don’t face future outbreaks with the same knowledge gaps over and over again. Research is so critical that WHO has now included research as a pillar in its incident management structure. Capabilities in low- and middle-income countries are also on the rise, with more robustly trained local researchers working in better equipped facilities, although their numbers remain far too limited. Moreover, during the recent epidemics of Ebola, plague, and Lassa fever, research groups from high-income countries have, with varying degrees of engagement of local partners, initiated important clinical research and trials in outbreak countries. Delays in implementing these efforts— well documented for the Ebola outbreak in West Africa by numerous reports, and continuing through the 2018 Lassa outbreak in Nigeria—have limited the potential to generate valuable information for clinical care on the one hand, and vaccine or drug treatment on the other. Yet, given the needs for country ownership and capacity-building, these and future outbreaks present important opportuni- ties for gaining experience by doing clinical research. The International Vaccines Task Force (IVTF) has been created to boost the national capacity of low- and middle-income countries to seize those opportunities and to create the clinical research capabilities necessary to surge activity during emergencies and sustain those efforts in times of calm. Founded by the World Bank and CEPI in October 2017, the goal of the Task Force is to produce a set of actionable recommendations that, when implemented, will ensure the existence of a minimal and sustainable clinical research capacity to enable low- and middle-income countries to collaborate and participate in late-stage clinical trials themselves or with regional or international partners in the event of an epidemic. The Task Force believes this goal can be reached through strengthening internal country capacity as well as by working with regional research networks. x MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS The key takeaway message is that what needs to be done can be done. There are many promising efforts already underway, and with sufficient commitment, focus, and coordination, we can develop the capabilities and find the solutions we need to take the lead away from our pathogenic foes. We must, and we can, outsmart epidemics. Marie-Paule Kieny Richard Sezibera Co-chair, International Vaccines Task Force Co-chair, International Vaccines Task Force PREFACE xi xii MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS Acknowledgements T he International Vaccines Task Force (IVTF) deeply appreciates and would like to thank the individuals, organizations and institutions who took the time to provide their knowledge, experience and advice to the Task Force. However, the Task Force takes full responsibility for all facts, opinions and recommendations contained in this report. We are deeply appreciative of the encouragement and advice from Tore Godal, Norway, who was instrumental in the establishment of the Task Force. We would not have come together—or worked as well—had it not been for his unwavering support. We are especially grateful to the sponsors of the Task Force, the World Bank and the Coalition for Epidemic Preparedness Innovations (CEPI), for their technical and financial support throughout the course of the work. We are also particularly appreciative of the support of the World Bank team who comprised the Secretariat of the Task Force. We owe special gratitude to the many health research leaders and experts who gave of their time and shared their experiences. We particularly thank Beyene Petros and Aster Tsegaye, Addis Ababa University; Afework Kassu, Ministry of Science and Technology, Ethiopia; Demissie Habte, Former Ethiopian Academy of Sciences; Taye Tolera, Armauer Hansen Research Institute; Alex Opio, Ministry of Health, Uganda; Cissy Kityo, Joint Clinical Research Center; Edward Mbidde, Former Uganda Virus Research Institute; John David Kabasa, College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University and One Health Centre and Eastern Africa Network; Agnes Kahundha, One Health Centre and Eastern Africa Network; Leslie Nielsen, International AIDS Vaccine Initiative; Pontiano Kaleebu, Uganda Virus Research Institute and Medical Research Council/Uganda Virus Research Institute Research Unit; Richard Brough, Infectious Disease Institute, Makerere University; Fernando Polack, Vanderbilt Vaccine Center, Argentina; Miguel O’Ryan, Biomedical Sciences Institute, University of Chile; Xavier Sáez Llorens, Hospital del Niño; José Renán Esquivel, Panama City, Panama; Felix Espinosa, Universidad Nacional Autonoma de Nicaragua; Nirmal Ganguly, Indian Council of Medical Research, India; and Pyatat Tatsanavivat, MedResNet, Thailand. We had several very insightful conversations with many key individuals knowledgeable about the health research environments. We gratefully acknowledge Ok Pannenborg, Council on Health Research for Development; Mike Ward and Abha Saxena, World Health Organization; Luis Gabriel Cuervo, Luis Alejandro Salicrup and Ian Stein, Pan American Health Organization; Mead Over and Jeremy Koyndyk, Center For Global Development; Keith McAdam, London School of Hygiene and Tropical Medicine; David Peters, John Hopkins Alliance for a Healthier World; Charles Holmes, Georgetown University; Simon Kay, Diogo Martins, Sophie Mathewson, and Alexis Gilbert, Wellcome Trust; Gail Carson and Peter Horby, University of Oxford; Ted Trimble and Doug Puricelli Perin, Center for Global Health, US National Cancer Institute; Jacques Demotes and Serena Battaglia, European Clinical Research Infrastructure Network; Øyvind Melien, Norwegian Directorate of Health, Norway; ACKNOWLEDGEMENTS xiii Murray Lumpkin, Peter Dull, Scott Dowell, and Thy Pham, Bill & Melinda Gates Foundation; Jimmy Kolker, Former United States Department of Health and Human Services; Paul Stoffels, Johnson & Johnson; Christian Bréchot, Global Virus Network; Nadia Khelef, Institut Pasteur; Mike Strange and Agbor Ako, GlaxoSmithKline; Patience Kuruneri, African Development Bank; Lawrence Gostin, O’Neill Institute for National and Global Health Law; Jean Lang, Sanofi Pasteur; Dalvir Gill, TransCelerate BioPharma Inc.; Flora Katz, Fogarty International Center, NIH; Christine Pierre, Society of Clinical Research Sites; Robert Mallett and Suzanne Oguntoye, Africare; Dominika Jajkowicz, The European and Developing Countries Clinical Trials Partnership; and colleagues from the World Bank, Enis Baris, John Paul Clark, Mickey Chopra, Francisco Marmolejo and Andreas Blom. We drew upon the related work of various organizations, and gratefully acknowledge their willing- ness to share their findings. These include Carel IJsselmuiden, Council on Health Research for Development; Martin Eigbike, Dalberg Associates (CARI/AAS initiative); Trudie Lang, The Global Health Network; and Michael Head, ResIn, University of Southampton, who allowed us benefit from the parallel work of their organizations. Attendees at the workshop on Sustainable Clinical Research Capacity: Architecture, Governance and Indicators, organized jointly with WHO and the National Institute of Allergy and Infectious Disease (NIAID) and held at WHO Headquarters Geneva, provided valuable comments and sugges- tions. We especially acknowledge Sven Trelle, University of Bern; Alex London, Carnegie Mellon University; Moses Massaquoi, Clinton Health Access Initiative, Liberia; Jane Carter, African Medical and Research Foundation; Martin Veller, University of Witwatersrand; Alash’le Abimiku, University of Maryland; Philip Onyebujoh, Africa CDC; Rosanna Lagos, Centro para Vacunas en Desarrollo, Chile; Mosoka Fallah, National Public Health Institute of Liberia; Milagritos Tapia, University of Maryland; Martin Eigbike, Dalberg Associates; and colleagues at the World Health Organization: Emer Cooke, Laragh Gollogly, Maria Van Kerkhove, Christian Lienhardt, Pascal Launois, Dermot Maher, Ahmed Mandil, Andreas Alois Reis, Martin Matthew Okechukwu Ota, and Abha Saxena. And finally, we thank Erika Hartingh for successfully organizing the launch event of the report, Anugraha Palan for coordinating the release of the report to the public, and Sheryl Silverman for supporting our online communication efforts. xiv MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS Acronyms and Abbreviations AAS African Academy of Sciences AfDB African Development Bank BMGF Bill & Melinda Gates Foundation CARI Coalition for African Research and Innovation CDC Centers for Disease Control and Prevention CEPI Coalition for Epidemic Preparedness Innovations COHRED Council on Health Research for Development CRO Clinical Research Organization DRC Democratic Republic of the Congo DRM Domestic Resource Mobilization ECOWAS Economic Community of West African States EDCTP The European and Developing Countries Clinical Trials Partnership ESSENCE Enhancing Support for Strengthening the Effectiveness of National Capacity Efforts FDA Food and Drug Administration FY Financial Year GCM Global Coordination Mechanism GDP Gross Domestic Product GFF Global Financing Facility GPMB Global Preparedness Monitoring Board GSK GlaxoSmithKline HIV/AIDS Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome IBRD International Bank for Reconstruction and Development IAVI International AIDS Vaccine Initiative ICTRP International Clinical Trials Registry Platform IDA International Development Association IDA18/19 18th/19th Replenishment of International Development Association Funding IDI Infectious Diseases Institute IFPMA International Federation of Pharmaceutical Manufacturers & Associations IHR (2005) International Health Regulations (2005) INSERM The Institut National de la Santé et de la Recherche Médicale IVTF International Vaccines Task Force IWG International Working Group on Financing Preparedness LMIC(s) Low- and Middle-Income Country(ies) ACRONYMS AND ABBREVIATIONS xv MENA Middle East and North Africa MERS-CoV Middle East Respiratory Syndrome-Coronavirus MTA Material Transfer Agreement MTR Mid-Term Review NASEM National Academies of Sciences, Engineering and Medicine NCD(s) Non-Communicable Disease(s) NCDC Nigeria Centre for Disease Control NHA National Health Accounts NIH National Institutes of Health ODA Overseas Development Assistance PAHO Pan American Health Organization PEF Pandemic Emergency Financing Facility PETS Public Expenditure Tracking System R&D Research and Development R&I Research and Innovation ResIn Research Investments in Global Health RFI Research Fairness Initiative RT Rwanda’s Resource Tracking Tool S&P Standard and Poor's SADC Southern African Development Community SARS Severe Acute Respiratory Syndrome SCRS Society of Clinical Research Sites SDR Special Drawing Right SICA Sistema de la Integracion Centroamericana TB Tuberculosis TDR Special Programme for Research and Training in Tropical Diseases TGHN The Global Health Network UK United Kingdom UN United Nations US United States of America USAID United States Agency for International Development WBG World Bank Group WHO World Health Organization xvi MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS Executive Summary I n the last 5 years alone, the world has been tested action to prevent epidemics. The Coalition for Epidemic with serious challenges from two viral diseases. The Preparedness Innovation (CEPI) has launched a US$1 Ebola outbreak that unfolded between 2014 and billion effort to shorten the time it takes to develop new 2016 devastated West Africa, and while its health and vaccines to protect against viruses that emerge sud- economic impacts beyond the continent were limited, denly as public health threats and has already targeted it sent a loud message to the rest of the world about Lassa fever, Middle East Respiratory Syndrome (MERS- how vulnerable it was to the next epidemic. This was CoV) and Nipah, three of the R&D Blueprint priority dis- followed by the Zika Virus outbreak that began in early eases. In 2017, the World Bank launched the Pandemic 2016, which also remained confined largely to Latin Emergency Financing Facility (PEF), a mechanism to America, and served to remind the rest of the world that ensure low-income countries can receive timely, predict- there was no room for complacency. Further warnings able and coordinated surge financing when affected by were not needed—but they nevertheless came in quick large-scale disease outbreaks (World Bank 2017a). succession. In May 2017, the Democratic Republic of the Congo notified international public health agencies Despite the progress, however, there is still a lot of a cluster of suspected cases of Ebola virus disease more that needs to be done. One area in which there in the Likati health zone of the province of Bas Uélé. In has been little progress relates to clinical research October 2017, Madagascar reported an outbreak of the response, especially to our ability to conduct clinical deadliest form of plague, pneumonic, which had hit its trials during an outbreak. The most striking example major cities and towns and was spreading fast. Around of the critical need for clinical research response the same time, a Marburg virus disease outbreak was was witnessed during the 2014-15 Ebola outbreak. A detected in the Kween district of eastern Uganda. And recent report by the National Academies of Sciences, a few months later, Nigeria begun experiencing what Medicine and Engineering (2017), which reviewed the would turn out to be its worst Lassa fever outbreak ever, response to the outbreak, concluded that it was “of recording more cases in January 2018 alone than during unprecedented magnitude in a setting of limited capac- all of 2017. ity, with political systems that were fragile after many years of civil war, plagued by violence, and the virus Stunned by the scale of human and economic suffering itself killed health care workers, further decimating the caused by these large-scale disease outbreaks, many indigenous capacity to care for patients and limit further international expert panels examined what went wrong dissemination of infection.” Although some promising with the way that countries and international agencies results emerged from the vaccine trials conducted dur- addressed these outbreaks, and made several recom- ing the 2014-15 Ebola outbreak, there was an overall mendations aimed at strengthening national public “thin scientific harvest” (Cohen and Enserink 2016). health systems, building resilience and enhancing Further, as noted by WHO, “the only way of obtaining global capabilities. Response has been strong, and in evidence on the safety and efficacy of any intervention many ways, we are better prepared now than we were in Ebola virus disease is during an outbreak” (WHO for previous pandemics. A large number of countries 2014). The NASEM report asserts that our ability to test have voluntarily opened their gates to external evalua- and develop life-saving vaccines during an outbreak tions of their state of preparedness. The World Health will depend on the progress we make in preparing dur- Organization (WHO) has rolled out its R&D Blueprint for ing the inter-epidemic period. EXECUTIVE SUMMARY 1 Framing Investments for Recognizing this challenge, the World Bank and CEPI established the International Vaccines Task Force on Clinical Research Strengthening Country Capacity for Vaccines Research and Development (Task Force) in October 2017 to develop a set of recommendations on strategic invest- ments that can strengthen clinical research and clini- Low- and middle-income countries are increasingly cal trial capacity in low- and middle-income countries. spending more on all research and development This report by the Task Force proposes ways in which (Figure 1). The limited data that are available on spend- national governments and development partners can ing on health R&D suggests that only a small fraction finance investments in clinical research capacity and of all R&D spending goes to health. At the same time, strengthen low- and middle-income countries capacity the investment case for clinical research is strong. A to conduct and participate in a late-stage vaccine trial research study estimating the economic returns gener- during an outbreak. ated by public and charitable investments in medical research in the UK, using musculoskeletal disease research as an exemplar, finds that every UK£1 invested Accelerating Commitment to in musculoskeletal, cancer, cardiovascular and mental health research delivers a return equivalent to around Clinical Research UK£0.25 every year in perpetuity.1 This suggests that investments in health research must be constrained by factors such as insufficient financing, lack of political The first step for countries seeking to strengthen clinical support for investing in activities that do not necessar- research capacity, especially surge capacity to conduct ily yield returns in the present time, complexity in terms clinical trials during an outbreak, is to make a politi- of implementation (that is, what to fund and how to cal and policy commitment to developing this capacity maintain the investments over time), and so on. These during the inter-epidemic period. In the broadest sense, challenges are further exacerbated in the context of political commitment is the decision of leaders—includ- resource-constrained economies, which use up all the ing political and government leaders, parliamentarians, scarce resources to take care of urgent needs today party leaders, civil and community leaders at all levels of instead of worrying about the imperatives of tomorrow. society, private sector and business leaders, and so on— to use their power, influence, and personal involvement Every investor needs an investment framework that to ensure that strengthening clinical research receives helps in improving decision-making outcomes. Likewise, the visibility, leadership, resources, and ongoing political countries seeking to invest scarce resources in clinical support that is required to support effective action to research would need to have clarity in understanding build capacity for clinical trials during an outbreak. the different types of capacities and capabilities that they must develop, different financing sources available RECOMMENDATION 1 to them, trade-offs associated with investing in clinical research at the expense of other proximate demands, By December 2018, in order to effectively respond and so on. A strong investment framework for clinical to disease outbreaks, reduce preventable deaths, research will help answer all these questions. strengthen productivity and improve quality of life, countries should commit to strengthening capacity to conduct or participate in clinical research to address their public health needs. 1 The research study was produced by the Policy Institute at Kings College London, RAND Europe, and the Health Economic Research Group at Brunel University London, with funding from the Academy of Medical Sciences, Arthritis Research UK, the National Institute for Health Research, Medical Research Council, and Wellcome Trust. Wellcome Trust (2018) has the details. 2 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS FIGURE 1: SPENDING ON R&D AS A PERCENTAGE OF GDP 3.0 2.5 2.0 1.5 1.0 0.5 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 High income Low & middle income Upper middle income World Source: World Bank 2018a Developing Legal Frameworks The World Bank, as part of its commitments under the 18th round of International Development Association for Clinical Research funding (IDA18),2 is helping at least 25 countries develop pandemic preparedness plans and strengthen their capacities to detect, prevent and respond to pandem- ics.3 The World Bank has begun working with many A comprehensive legal framework is essential for creat- countries to develop comprehensive pandemic pre- ing a strong clinical research environment. Enabling paredness plans and make available financial support legislation is needed in support of many areas related to for strengthening clinical research capacity. clinical research and clinical trial capacities in a country, such as the capacity to transport equipment and speci- RECOMMENDATION 2 mens across borders, protect intellectual property rights and ensure proper ethical and regulatory oversight. Recognizing the existing IDA18 commitment to While laws regarding clinical research, governance and strengthen preparedness in at least 25 countries, regulation of research have become commonplace the World Bank Group should include, as a part in Latin America over the past decade, they are less of its IDA Mid-Term (December 2018) Review common in Africa. Indeed, there is no comprehensive (MTR), an investment framework for national and repository or analysis of countries’ laws appropriate to regional clinical research capacities. the conduct of clinical research. Several organizations and partners have contributed to the development of the relevant health laws, and consolidating the laws and policies applicable to clinical research would enable countries to develop legislation more rapidly. 2 The 18th round of IDA covers the period July 1, 2017 to June 30, 2020. 3 These include Afghanistan, Bangladesh, Benin, Burkina Faso, Cambodia, Cape Verde, Democratic Republic of the Congo, Ethiopia, Ghana, Guyana, Haiti, Kenya, Lao PDR, Liberia, Mali, Myanmar, Nepal, Niger, Nigeria, Papua New Guinea, Senegal, Sierra Leone, Sudan, Tanzania, and Uganda. EXECUTIVE SUMMARY 3 RECOMMENDATION 3 RECOMMENDATION 4 By end 2019, WHO should develop and By 2019, Research Forums/Institutions and/or disseminate examples of broadly applicable Academies of Science in LMICs, drawing upon legislation and policies to support and enable their experience and that of others, should efficient conduct of clinical research. This should synthesize best practices and develop guidance include, at a minimum, model policies and for consideration by countries on how to build a laws that support the conduct of trials, enable supportive research climate/culture. timely ethics and regulatory review, address import/export of relevant commodities and Assessing Clinical Research bio-specimens, and address procurement and contracting systems. These policies should be Capacity a part of a broader governance architecture for clinical research. Figure 2 shows the number of clinical trials that have Creating a Culture of Clinical been conducted in different countries in recent years; however, since there is no widely accepted mea- Research sure of assessing country-level capacities for clinical research, it is challenging to determine the depth of expertise and capability in conducting clinical trials A supportive research culture is a sine qua non for in any particular country. There are some tools that strong clinical research capability, and there are several measure specific research competencies, such as the essential elements for such a supportive culture. First, TDR-TGHN Competency Wheel (TGHN 2018) that lists increasing visibility and political support for clinical all the competencies that should be demonstrated research, and ensuring that preparedness is a key by a research team to carry out a successful clinical foundation, is important. Second, support for careers study; the Mapping African Research Ethics Review in clinical research will motivate young investigators to and Medicines Regulatory Capacity initiative that maps pursue clinical research careers, and to choose to use health research oversight and regulatory activities in those skills in-country. Third, a coordination mechanism Africa; the Laboratory Network Scorecard that assesses that collects all funding and research proposals and national laboratory network functionality; the Research places them on one platform would help researchers in Fairness Initiative that creates a reporting system for low- and middle-income countries learn about the broad governments, business, organizations and funders array of available opportunities. And finally, opportuni- to describe the measures they take to create trust- ties for fair and mutually beneficial research partner- ing partnerships in research and innovation; the WHO ships within and between countries help in nurturing an Global Benchmarking Tool for Regulatory Capacities appropriate culture. that assesses and documents capacities of national regulatory agencies (PAHO 2017), including the capacity The Task Force believes that Academy of Sciences, to provide informed no-objection to clinical trials, post national research committees and other similar research marketing surveillance and oversight of research during centers, such as the Council on Health Research and outbreaks; and the Joint External Evaluation (JEE) that Development (COHRED), are strategically placed to assesses, inter alia, lab and surveillance preparedness communicate and prepare the necessary know-how (WHO 2016). for national governments on how to create an enabling environment and leverage existing initiatives. The Task Force believes that an assessment tool that is evidence-based and widely accepted would help coun- tries monitor and strengthen their research capacities and bring them up to international standards. It further believes that WHO is best placed to collate existing indi- cators and to take responsibility for creating a compre- hensive assessment of clinical research capacity. 4 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS FIGURE 2: NUMBER OF CLINICAL TRIALS PER COUNTRY OF RECRUITMENT Source: WHO ICTRP 2018 RECOMMENDATION 5 accepted that competing demands make preparedness investments somewhat unattractive for public budgets, By end 2018, WHO should consolidate a robust and that it is unlikely that significant resources will be set of indicators, to the extent possible building allocated in the absence of a clear and present danger. on indicators already used by countries, develop a The Task Force believes that in order to generate and tool for assessment of country-level capacities for sustain improvements in clinical research capacity, gov- clinical research, and propose a process to help ernments must commit the needed resources to finance countries rapidly conduct these assessments. the associated capital and recurrent costs. RECOMMENDATION 6 Committing Domestic By end 2019, governments in IDA-eligible Resources for Clinical countries should commit short- and medium- term resources to address their clinical research Research Capacity capacity goals. These resources could potentially come from their IDA portfolios. Despite numerous calls for higher domestic commit- Buying Down Loans for Clinical ments to general health and health research (Abuja Declaration 2001; Mexico Ministerial Summit on Health Research Capacity Research 2004; Bamako Call for Action on Research for Health 2008) and for more effective mobilization of domestic resources (Addis Tax Initiative 2015), there is no systematic thinking about financing gaps in capacity- Buy-downs, which essentially bundle IDA interest- building for clinical research. It is widely agreed by bearing loans and credits with donor-funded grants that most governments and donors that domestic resources are used to buy down the net present value of the loan should be deployed to fill the gaps. It is also widely or credit and reduce it to grant terms, are an innovative EXECUTIVE SUMMARY 5 financing mechanism that incentivize countries to bor- Second, suitable mechanisms must exist to finance row funds for investments in strengthening their clinical these partnerships. One such mechanism, offered by research capacity. Buy-downs represent a win-win-win the World Bank, is the Program for Regional Projects approach for countries, the World Bank and the donors. (“Regional Program”) initiated under IDA in 2003. Countries receive financing for a global public good if Financing provided by this program is added to funds they meet the agreed performance targets; the World already available in the regular country IDA allocation, Bank can leverage the technical expertise of other part- and so acts as a strong incentive to applying for funds ners; and the donors can leverage their funding. This from this program. As part of the 18th replenishment of mechanism has a lot of potential to support countries IDA’s resources—which resulted in a record replenish- wishing to invest in clinical research capacity. ment of US$75 billion to finance projects over the three- year period ending June 30, 2020—resources allocated RECOMMENDATION 7 to the Regional Program were increased more than two-fold, from SDR2.2 billion4 in IDA17 to SDR5 billion in By end 2018, the World Bank Group should IDA18 (World Bank 2017b). develop mechanisms to buy down IDA loans and convert them into grants for countries that have RECOMMENDATION 8 demonstrated development of research capacity based on agreed milestones. The World Bank Group should encourage IDA countries to establish or leverage existing regional partnerships for developing clinical research Leveraging Regional capacity, using the IDA Regional Window funds combined with domestic commitments. The Partnerships for Investments World Bank Group should highlight progress and showcase strategic development outcomes in Clinical Research Capacity of such regional partnerships in the IDA18 MTR (December 2018), and develop a robust case for inclusion of prioritized regional clinical research Infectious diseases do not respect national boundar- partnerships as a thematic area under IDA19 ies, and often the optimal response to an outbreak is (January 2020). one that comes from two or more adjoining countries and regional institutions. Two elements can greatly Incentivizing Domestic enhance the effectiveness of such a response. First, regional networks, if they exist, can greatly leverage the Resource Mobilization comparative advantages of the member partners, and facilitate sharing of critical infrastructure—such as labo- ratories—and distribute some of the fixed costs across the network partners. In inter-epidemic periods, regional As noted previously, countries stand to gain substan- networks can tackle health challenges common to part- tially if they increase public spending for strengthen- ners, such as malaria, tuberculosis or meningitis, thus ing clinical research, and use their domestic budgets creating and strengthening their independent and col- to ensure sustainable financing. However, inadequate lective research capacities. Many networks that support domestic resource mobilization is a huge challenge science and research in Africa already exist, including in many low-income countries. The World Bank works those supported by the African Academy of Sciences, closely with countries and development partners to the Bill & Melinda Gates Foundation, the European incentivize domestic resource mobilization. Examples of and Developing Countries Clinical Trials Partnership these engagements include the application of behav- (EDCTP), New Partnership for Africa’s Development ioral insights to improve tax compliance and increase (NEPAD), United States Health and Human Services (HSS), United States Department of Defense, Wellcome Trust, the World Bank, and other partners. Strong coordi- 4 SDRs (Special Drawing Rights) are an international reserve asset nation across these networks would be beneficial. created by the International Monetary Fund (IMF) in 1969 to supplement its member countries' official reserves. The value of the SDR is currently based on four major currencies: the US dollar, euro, Japanese yen and British pound. 6 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS the tax base, providing technical assistance to evaluate research capacity in order to address critical knowledge fiscal space for health, supporting efforts to increase gaps, such as better defining the epidemiology, reser- sector-specific revenues, etc. Another successful mech- voir and human host sites of viral persistence, and opti- anism is that of matching grants, which are funds from mizing clinical care and immune responses to infection. the granting organization that are matched with funds These initiatives provide an opportunity for CEPI and its from the beneficiary. Grant schemes generally stimulate partners to leverage other capacity-building efforts, e.g., new activities or induce particular processes, and usu- EDCTP- or NIH-funded networks, to strengthen research ally enhance beneficiaries’ economic activity. sites that enable researchers to be mentored in the con- duct of clinical trials during the inter-epidemic period. Both country and regional development partners have played a critical role in research capacity strengthen- RECOMMENDATION 10 ing, often through leveraging the domestic resource commitment. The African Development Bank (AfDB) By mid-2018, CEPI should commit resources includes research funding in each of its health system to strengthening clinical research capacities strengthening initiatives where feasible, re-affirming in LMICs where clinical trials for vaccines the recommendations of the WHO Consultative Expert against CEPI priority pathogens are likely to be Group on Research and Development.5 Like other conducted. funders, the World Bank has a long history of matching grants at the national level, having designed match- Leveraging the Private Sector ing grant schemes in the agricultural sector in several countries including Nicaragua, Peru, India, Ghana, and for Clinical Research Capacity Armenia (World Bank 2010). RECOMMENDATION 9 Development By end 2018, the World Bank Group should collaborate with development partners and Private sector activities, particularly those of pharma- other research funders to incentivize domestic ceutical, biotechnology and clinical research compa- resource mobilization in developing countries for nies, have led to the development of clinical research investment in clinical research capacity, including capacity across the globe simply through the conduct by such means as matching grants and other of clinical trials and in-country research. More recently, incentivizing mechanisms. there are examples of private companies engag- ing in direct capacity-building efforts in LMICs, such as the EDCTP-TDR Clinical Research Development Gaining Clinical Research Fellowships in which international product development organizations, including major pharmaceutical compa- Experience from CEPI nies are partnering with WHO and EDCTP to train their fellows to develop strong research capability in LMICs Investments (IFPMA 2018). One model that could potentially be scaled up CEPI finances and coordinates the development of to enhance capacity-building efforts in LMICs is new vaccines to prevent and contain infectious dis- TransCelerate, a non-profit organization in the bio- ease epidemics. Its three initial target diseases—Lassa, technology industry working to improve efficiencies Nipah and MERS-CoV—are endemic in Africa, Asia and and speed development in the clinical trial space. the Middle East respectively, which account for 59 TransCelerate facilitates information-sharing on relevant of the 75 countries currently eligible for IDA funds. In subject matters across its member companies to enable such resource-constrained settings, CEPI leverages its faster and more efficient identification and recruitment existing initiatives and works in-country to build clinical of qualified investigators. This could strengthen capacity in LMICs, which could benefit from the associated cross- 5 Kuruneri, Patience (AfDB) Personal communication, email dated site learning. April 16, 2018. EXECUTIVE SUMMARY 7 RECOMMENDATION 11 of investment in capacity development. The second initiative is the Global Coordination Mechanism (GCM) of By end 2019, the private sector pharmaceutical/ the R&D Blueprint at WHO, which focuses on coordi- biotech industry/clinical research organizations/ nating countries’ and partners’ research activities for other health sector businesses operating in LMICs priority diseases both during the inter-epidemic period should announce their commitment to maximize as part of research preparedness, and during outbreaks their contribution to clinical research capacity as part of the research response. Unlike ESSENCE, in LMICs. This includes transfer of skills and the R&D Blueprint GCM focuses on priority diseases expertise and/or allocating a percentage of their with outbreak potential, including the three pathogens spending to support the development of clinical that constitute CEPI’s initial vaccine focus. The GCM research capacity in LMICs that is aligned with has worked with Nigerian Authorities to bring together country public health needs and national research relevant stakeholders and establish a research plan agenda. to be executed during the 2018 Lassa fever outbreak. Together, the objectives of the ESSENCE program and the GCM are complementary to achieving the goals Coordinating Investments in of better coordination of funders for clinical research investments. ESSENCE draws on a decade of experi- Clinical Research Capacity ence and the R&D Blueprint focuses on ensuring that clinical research is part of the outbreak preparedness Building response research architecture. RECOMMENDATION 12 Coordinating the many funders that are engaged in clinical research capacity-building can be a challenge. By end 2019, ESSENCE, in collaboration with the Research Investments in Global Health (ResIn) maps Global Coordination Mechanism and reinforced global research investments in infectious disease with additional LMIC representation, should research awarded from public and philanthropic funders articulate a mechanism that permits a thorough in the G20 nations. ResIn (2018) has generated a data- review of current and planned investments in base of over 1,000 funders and approximately 80,000 research capacity strengthening. This should discrete projects.6 However, the variety and number of be done in consultation with major external funders, while offering more diversified funding flows, funders of clinical research (including those can pose difficulties if funding is duplicated or con- involved in capacity strengthening of network, centrated in select areas, to the detriment of research laboratory, ethics, and regulatory capability). This initiatives needed to generate evidence to inform urgent collaborative mechanism should ensure synergy strategic policy questions. at country and regional levels, and streamline the administrative burden experienced by institutions Two initiatives have been established at WHO to dealing with multiple research funders. address these issues. The first is the ESSENCE program, an initiative that allows funders to identify synergies, Surging Clinical Research bring about coherence and increase the value of resources and actions for health research with a focus Financing through Trust Fund on LMICs (ESSENCE 2017). ESSENCE was created to respond to the sharp increase in uncoordinated and Mechanisms fragmented funding which has occurred over the past several decades. Its key areas of work include facilitat- ing policy dialogue between funders of research for health; development of best practices documents for Clinical research surge capacity during an outbreak harmonization; and monitoring and evaluation of indica- requires the ability to rapidly generate the funds tors to track input, process, outcomes and the impact required to support needed increases in researchers, mobile sites, medical and diagnostic equipment, and 6 Head, Michael (ResIn, University of Southampton). Personal associated support. Trust Fund mechanisms can offer communication, email dated April 11, 2018. stable and predictable pools of financing to support 8 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS Tracking National-Level individual countries and global public goods. The Trust Funds held by the World Bank complement IDA financ- Resources for Clinical ing and can act as a vehicle for supporting partnerships with other development actors. Of the many Trust Funds at the World Bank, two that Research Capacity could potentially support the research agenda emerg- ing from the WHO R&D Blueprint are the Pandemic Governments and development partners need to moni- Emergency Financing Facility (PEF) and CEPI Trust tor and track all funding that supports clinical research Funds. The PEF provides rapid surge financing in the capacity-building activities within the country, not only initial stages of a severe outbreak before it becomes a for planning purposes, but also for monitoring and pandemic. Financed through an insurance window that evaluation, and overseeing the performance of research will make available up to US$425 million for outbreaks partners. Of the many tools that are available for this of a group of diseases likely to cause major epidemics purpose, two that can be relatively easily adapted to and a US$61 million cash window, PEF funds can be track spending on clinical research are National Health used to finance the cost of response efforts during an Accounts (NHA) and the Public Expenditure Tracking outbreak, in line with what is described in the country system (PETS). NHA provides a systematic framework response plan (World Bank 2017c). To the extent that for mapping expenditures by ordering all flows in response-related research could be leveraged for sources-to-uses format, while PETS triangulates budget managing an outbreak, PEF funds may be used for and financial records from different sources on the strengthening research capacity and for improving the expenditure map and can uncover points of leakage in knowledge base to enable response to subsequent the expenditure chain. A widely available tool suitable outbreaks of the same pathogen. for tracking clinical research capacity in a variety of LMICs would go a long way towards improving coor- Likewise, the World Bank, which hosts CEPI funds for dination and strengthening oversight and targeting of development of vaccines, can leverage the efforts of national health research priorities. CEPI with its own initiatives to strengthen country-level preparedness. Drawing upon CEPI’s support for prepa- RECOMMENDATION 14 ratory actions needed to test the vaccines being devel- oped, such as helping to improve regulatory capacity in By June 2019, based on experience accumulated low-income countries and preparing countries and sites by countries, WHO and the World Bank Group to conduct clinical trials, the World Bank could comple- should develop a resource tracking tool enabling ment support through IDA as well as through the PEF. governments to monitor and track, at a national level, all funding that supports clinical research RECOMMENDATION 13 capacity-building activities within the country and accounts for the multiplicity of funders involved. By the end of 2018, the World Bank Group, working through the PEF and CEPI Trust Fund Monitoring Implementation on mechanisms, should establish a rapid financing vehicle to support the priority outbreak-related the Task Force Goals research agenda emerging from the WHO R&D Blueprint, and to strengthen in-country capacity, including the conduct of clinical research as part of outbreak response. The Task Force has made a series of recommendations addressing a diverse set of requirements for developing and strengthening clinical research capacity. Success will depend on a coordinated series of actions target- ing the entire spectrum of the clinical research ecosys- tem. Coordinating and tracking action in this complex space of pandemic preparedness will be challenging. The Task Force believes that a broad-based, scien- tifically qualified, and autonomous body, such as the EXECUTIVE SUMMARY 9 recently-announced Global Preparedness Monitoring ensure that that the next inevitable outbreak does not Board, would be appropriate to coordinate and review turn into an uncontrollable pandemic. We focused our progress on the implementation of the various recom- attention on one gap—that of getting clinical research mendations of the Task Force. capacity in low- and middle-income countries to a level at which they can conduct or support needed RECOMMENDATION 15 clinical trials at the time of an epidemic. We realized right away that this is by no means an easy task, for Reviewing progress on the implementation of it requires resource-challenged countries to have in these recommendations should inform the agenda place a strong, robust and functioning clinical research of the Global Preparedness Monitoring Board. capacity that could be rapidly called upon in the heat of an outbreak. We are encouraged by the large number of ongoing initiatives that are contributing directly and Conclusion indirectly to strengthening clinical research capac- ity in low-income countries. At the same time, we are sobered by the many challenges that governments and Infectious disease outbreaks are on the rise around development partners must overcome to be ready the the world. Severe Acute Respiratory Syndrome (SARS), next time the world gets hit. MERS, avian influenza, Ebola, Zika, Lassa—these dis- eases hitherto restricted to the vocabulary of epidemi- Our report outlines how low- and middle-income ologists and medical professionals have now almost countries could secure the political commitment, raise become household names. The number of new infec- necessary finances and leverage ongoing initiatives tious diseases affecting humans has increased fourfold of development partners to enhance research and in the past 60 years, and the number of outbreaks per development capacity and strengthen outbreak pre- year has more than tripled. Most are just a blip in the paredness. Our 15 recommendations define an inte- news; but once in a while one or two slip through our grated framework for action by countries, development containment defenses, and cause enormous harm. It is partners, research funders, research organizations and indeed only a matter of time before the next pandemic the private sector, and suggests clear timelines. We are hits us. confident that if countries and all stakeholders adopt the suggested framework, the world will see huge improve- The world is better prepared than before, of that ments in its ability, at the national level and globally, to there is no doubt. But knowing that it is not fully and build clinical research capacity and strengthen universal adequately prepared, we asked what must be done to health security. 10 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS References Addis Tax Initiative. 2015. ATI Monitoring Report 2015. Wellcome Trust. 2018. Medical Research: What’s it worth? A Accessed on April 26th, 2018 at 10:00hrs. URL: briefing on the economic benefits of musculoskeletal disease https://www.addistaxinitiative.net/documents/ research in the UK. Accessed on March 21st, 2018 at 11:00hrs. Addis-Tax-Initiative_Monitoring-Report_2015_EN.pdf URL: https://wellcome.ac.uk/sites/default/files/whats-it-worth- Cohen J, Enserink M. 2016. As Ebola epidemic draws to a close, a musculoskeletal-disease-research-januar-2018.pdf thin scientific harvest. Science 351(6268):12–13. World Bank. 2010. Designing and Implementing Agricultural ESSENCE. 2017. ESSENCE Flyer. Accessed on April 26th, 2018 at Innovation Funds. Lessons from Competitive Research and 20:00hrs. URL: http://www.who.int/tdr/partnerships/essence/ Matching Grant Projects. World Bank Publication. Accessed on Flyer_Essence_2017_web_version.pdf April 1st, 2018 at 12:00hrs. URL: http://documents.worldbank. org/curated/en/715661468163167577/pdf/548570ESW0P1220 Hartsfield D, Moulton A, McKie K. 2007. A Review of Model Public nnovationFunds100web.pdf Health Laws. American Journal of Public Health. April; 97 (Suppl 1): S56–S61. Accessed on April 5th, 2018 at 14:00hrs. World Bank. 2017a. Pandemic Emergency Financing Facility. World URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1854995/ Bank Website. Accessed on April 26th, 2018 at 17:00hrs. URL: http://www.worldbank.org/en/topic/pandemics/brief/ IFPMA. 2018. EDCTP-TDR Clinical Research Development pandemic-emergency-financing-facility Fellowships. Health Partnership Directory. IFPMA Website. Accessed on March 22nd, 2018 at 13:00hrs. World Bank. 2017b. Report from the Executive Directors of URL: http://partnerships.ifpma.org/partnership/ the International Development Association to the Board edctp-tdr-clinical-research-development-fellowships. of Governors: Additions to IDA Resources - Eighteenth Replenishment (English). Washington, D.C.: World Bank National Academies of Science, Engineering and Medicine Group. Accessed on March 31st, 2018 at 18:00hrs. URL: http:// (NASEM). 2017. Integrating Clinical Research into Epidemic documents.worldbank.org/curated/en/348661486654455091/ Response: The Ebola Experience. Accessed on March 19th, Report-from-the-Executive-Directors-of-the-International- 2018 at 21:00hrs. URL: https://www.nap.edu/catalog/24739/ Development-Association-to-the-Board-of-Governors- integrating-clinical-research-into-epidemic-response-the- Additions-to-IDA-Resources-Eighteenth-Replenishment ebola-experience World Bank. 2017c. Pandemic Emergency Financing Facility Pan American Health Organization (PAHO). 2008. The Bamako Call (PEF) Operational Brief for Eligible Countries December to Action on Research for Health. Strengthening research for 2017. Accessed on April 22nd, 2018 at 10:00hrs. URL: http:// health development and equity. From the Global Ministerial pubdocs.worldbank.org/en/168391509719305386/PEF- Forum on Research for Health. Bamako, Mali, Nov 17-18, Operations-Manual-September-13-2017.pdf 2008. Accessed on April 5th, 2018 at 13:00hrs. URL: http:// www1.paho.org/hq/dmdocuments/2008/BAMAKO_Call_for_ World Bank. 2018. Research and development expenditure (% Action_AMRO_Eng.pdf of GDP). World Development Indicators. World Bank Data. Accessed on April 26th, 2018 at 9:00hrs. URL: https://data. Pan American Health Organization (PAHO). 2010. PAHO’s Policy worldbank.org/indicator/GB.XPD.RSDV.GD.ZS?view=chart on Research for Health. Accessed on April 27th, 2018 at 11:00hrs. URL: http://www1.paho.org/hq/dmdocuments/2010/ World Health Organization (WHO). 2004. The Mexico Statement on RESEARCHpolicyBKLETeng_web.pdf Health Research. Knowledge for better health: strengthening health systems. From the Ministerial Summit on Health Pan American Health Organization (PAHO). 2017. Strengthening Research. Mexico City, Nov 16-20, 2004. Accessed on April national regulatory systems: the development of the 5th, 2018 at 13:00hrs. URL: http://www.who.int/rpc/summit/ Global Benchmarking Tool. Washington, DC, December agenda/en/mexico_statement_on_health_research.pdfhttp:// 15, 2017 (PAHO/WHO). PAHO Website. Accessed on May www.who.int/rpc/summit/agenda/en/mexico_statement_on_ 4th, 2018 at 12:00hrs. URL: http://www.paho.org/hq/index. health_research.pdf php?option=com_content&view=article&id=14030&Itemid=39 594&lang=fr World Health Organization (WHO). 2011. The Abuja Declaration: Ten Years On. Accessed on April 26th, 2018 at 9:00hrs. URL: The Global Health Network (TGHN). 2018. TDR-TGHN Competency http://www.who.int/healthsystems/publications/abuja_report_ Wheel. Global Health Trials. TGHN Website. Accessed on aug_2011.pdf?ua=1 March 23rd, 2018 at 14:00hrs. URL: https://globalhealthtrials. tghn.org/competencywheel/ EXECUTIVE SUMMARY 11 World Health Organization (WHO). 2014. Ethical issues related to study design for trials on therapeutics for Ebola virus disease. Geneva, Switzerland: WHO Ethics Working Group Meeting, October 20–21, 2014. Accessed on April 26th, 2018 at 17:00hrs. URL: http://apps.who.int/iris/ bitstream/10665/137509/1/WHO_HIS_KER_GHE_14.2_eng.pdf World Health Organization (WHO). 2016. Joint External Evaluation Tool. IHR (2005) Monitoring and Evaluation Framework. Accessed on May 4th, 2018 at 12:00hrs. URL: http://apps.who. int/iris/bitstream/handle/10665/204368/9789241510172_eng. pdf;jsessionid=F19EEAF19187ADC91E6E067235FFA048?sequ ence=1 World Health Organization (ICTRP). 2018. Welcome to the WHO ICTRP. Accessed on April 22nd, 2018 at 10:00hrs. URL: http:// www.who.int/ictrp/ 12 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS CHAPTER 1 Introduction Recent outbreaks and emergencies with health conse- However, even as countries and global institutions are quences, including the Ebola outbreak in West Africa, working on strengthening pandemic preparedness Zika in Latin America and the ongoing Lassa fever in and enhancing the speed and effectiveness of public Nigeria, shed light on the major gaps in health systems health response during outbreaks, the area of clinical throughout the world and the ever-present challenges research—and its connections with emergency outbreak to prevent, detect, and respond to health crises at coun- response—continues to be challenging. Noting that the try, regional and global levels. Recognizing the severe “mobilization of a rapid and robust research response health and economic costs of failing to adequately during the next epidemic will depend not just on what manage outbreaks and health emergencies, multiple happens during the epidemic, but on what happens international expert panels have recommended specific before or between epidemics”, the National Academies reforms related to strengthening national public health of Sciences, Engineering, and Medicine (NASEM) (2017) systems, enhancing global and regional coordination suggests that “careful inter-epidemic planning and and capabilities, and accelerating research and devel- execution through a well-coordinated and collaborative opment (R&D). effort from national, international, and local represen- tatives can help ensure that the global community is There has already been a significant response to these prepared to answer challenging questions through the recommendations. The World Health Organization conduct of research.” (WHO) has established a new program combining all aspects of events-based surveillance, infectious But this is by no means an easy exercise. First, it will disease expertise, response capacity, research and require resource-constrained countries to take con- development, and country capacity-building. The World scious decisions to move resources away from other Bank, through its 18th replenishment of International urgent and key areas and increase investments in Development Association (IDA18) funding, has priori- clinical research and development. Second, these tized country preparedness financing and established investments will have to be sustained over time, which the Pandemic Emergency Financing Facility (PEF) as an will require continuing budgetary allocations to clinical innovative mechanism to accelerate response financ- research and development. The implicit trade-offs in ing for outbreaks. Many other initiatives have been these allocations are bound to be difficult, and govern- developed at national, regional and global levels to ments would need to be convinced that investing in strengthen public health preparedness and response. clinical research and development is necessary despite Very importantly, the results are already being seen in the multitude of competing demands on their budgets. more timely detection and response to major outbreaks For some countries, development assistance may play around the world, such as the outbreak of Ebola in the an important role in financing clinical research—but the Democratic Republic of the Congo (DRC) in 2017 or same questions and trade-offs will need to be resolved pneumonic plague in Madagascar in 2017, and in the there as well. widespread efforts towards more objective assessment and achievement of International Health Regulations Recognizing this challenge, the committee convened (IHR) core capacities. by the National Academies of Sciences, Engineering, and Medicine to analyze the experience of clinical trials INTRODUCTION 13 that were conducted during the Ebola epidemic recom- countries at risk of emerging infectious disease mended that “national governments should strengthen outbreaks. and incorporate research systems into their emergency preparedness and response systems for epidemic infec- The Task Force held two face-to-face full member- tious diseases….multilateral institutions (WHO and The ship meetings and a series of theme-specific discus- World Bank), and regional and international develop- sions spread over seven months. Members used these ment agencies, and foundations working in global meetings to share ideas, examine data and evidence, health, should support national efforts by providing test hypotheses and form recommendations. The Task expertise and financing.” Operationalizing this recom- Force conducted literature reviews, key informant mendation in practical terms for countries, development interviews, site visits and case studies to inform its partners, research organizations, the private sector deliberations. It made use of additional work that other and others involved in funding or carrying out clinical organizations performed on its behalf or shared. This research is the focus of this report. includes, inter alia, a survey undertaken by The Global Health Network, a digital platform managed by Oxford University for facilitating collaboration and resource sharing on global health research (TGHN 2018a); a work- The International Vaccines shop convened jointly by the World Bank, WHO and the National Institute of Allergy and Infectious Disease Task Force (NIAID); analyses of global funders of infectious disease research provided by the University of Southampton; The International Vaccines Task Force on Strengthening inventory of clinical research and translation sites in Country Capacity for Vaccines Research and Africa, compiled by Dalberg Associates under an initia- Development (IVTF; henceforth referred to as the Task tive of African Academy of Sciences (AAS)/Coalition for Force) was established by the World Bank and the African Research and Innovation (CARI); and an ethics Coalition for Epidemic Preparedness Innovations (CEPI) review carried out by the Council of Health Research in October 2017 to develop a set of recommendations for Development (COHRED) for the Clinical Research on strategic investments that can strengthen clinical Initiative in Global Health (CRIGH). research and clinical trial capacity in low- and middle- income countries (LMICs). It comprises subject-matter Overview of the Report experts from around the globe, representing academia, development agencies, national governments and the private sector. In preparing its report and recommenda- tions, the Task Force has drawn upon recommendations The remainder of this report is organized as follows. from numerous reports, including the Harvard-London Chapter 2 makes a case for countries to commit to School of Hygiene and Tropical Medicine (LSHTM) clinical research. Chapter 3 describes the enabling Independent Panel on the Global Response to Ebola elements required for a strong clinical research environ- (2015), United Nations High-level Panel on the Global ment. Chapter 4 discusses the need for clinical research Response to Health Crises (2016), International capacity measures. Chapter 5 outlines various financing Working Group on Financing Preparedness (2017), options for clinical research capacity building. Chapter 6 and the National Academies of Sciences, Engineering outlines mechanisms to better coordinate investments in and Medicine report (2017), with the goal of identify- clinical research capacity. Chapter 7 proposes an option ing mechanisms for investments in healthcare, public for monitoring progress on the recommendations of the health, and health research capacity in resource-limited report. The report concludes in Chapter 8. 14 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS CHAPTER 2 Committing to Clinical Research conducting good quality clinical research during an epi- Clinical Research Response demic can reap even greater and more rapid dividends than many other investments. Often critical knowledge during Outbreaks related to how best to respond both at an individual clinical level and societal public health level can only be Clinical research, simply defined as “research in which generated by research conducted during an epidemic people, or data or samples of tissue from people, are (Lurie et al 2013). Assessing the key characteristics of a studied to understand health and disease” (National new infectious disease outbreak—such as clinical sever- Cancer Institute 2018), has played a fundamental role ity, presentation, the course of the illness, and associ- in advancing medicine and health. There are count- ated risk factors—is critical for decision-making (Williams less examples demonstrating that clinical research has et al 2013). helped prevent or mitigate the impact of infectious diseases while simultaneously strengthening national However, major epidemics are generally unpredictable health systems and changing clinical practices even and intermittent, and most often occur in settings with in low-resource settings. Oral rehydration therapy for the least capacity. The logistical, technical, and regula- diarrheal diseases was first developed and tested in tory requirements of clinical trials present a greater set clinical trials in India and Bangladesh and, in the past of hurdles when time is limited. It is clear that to develop three decades, has saved an estimated 50 million lives and be sustainable, clinical research and clinical trial worldwide, mainly of children who are most at risk systems must address routine health priorities of a coun- from fatal dehydrating diarrhea (The Lancet 2013). The try or region in the inter-epidemic period. To maximize International Center for Diarrheal Disease Research in the impact of these clinical research efforts, the core Bangladesh had its roots in early programs developed capabilities need to be just as strong in the lower- and to treat cholera and other diarrheal diseases. It has middle-income countries where epidemics strike most. grown over time to become a global research and train- ing center, branching out from its early work on chol- The desired outcome of the collective recommendations era to make breakthroughs in areas such as maternal of the Task Force is nationally-owned and/or regional mortality, family planning and health system redesign clinical research response capacity that conducts qual- (icddr,b 2018). HIV trials conducted in Africa have been ity research compliant with international standards on central to reducing maternal-to-child transmission of HIV national health priorities in the inter-epidemic period (NIH 2018) and to strengthening the clinical care system and can pivot to a robust urgent research response dur- for women and children. The vaccine developed under ing an outbreak. Achieving this requires a set of country the Meningitis A project in Africa, led by PATH and WHO commitments and activities, incentivized through financ- with Serum Institute of India and supported by the Bill ing and other arrangements by a range of development, & Melinda Gates Foundation, has had a dramatic effect research and private sector funders. on the incidence of suspected and confirmed meningitis cases (Trotter et al 2017). Following the Ebola epidemic in 2014-2015, the National Academies of Sciences, Engineering and Medicine “Surging” research during an outbreak is a critical but reviewed the clinical research response during the out- neglected part of the research architecture. Arguably, break, concluding that the capacity to conduct clinical COMMITTING TO CLINICAL RESEARCH 15 research was seriously lacking in a number of critical training, and do not have efficient electronic informa- areas in Guinea, Liberia and Sierra Leone (NASEM 2017). tion management systems to assist with their heavy and More specifically, it highlighted three critical shortcom- often complex workloads”. ings that impeded establishment of clinical research during the outbreak and the disappointing results from Where to Start research that was eventually conducted: i. The affected countries did not have the infrastruc- ture, human resources, or experience to deal with While the field of clinical research is broad—encompass- the public health and health care demands of the ing epidemiologic, observational, cost effectiveness, epidemic, let alone to facilitate research; operational and implementation research, and clinical trials (US FDA 2018)—this Task Force focuses primarily ii. Ethics review boards and regulatory authorities on clinical research capacities for epidemic response, in the affected countries lacked the resources, including those ultimately needed to conduct clinical experience, training, and information management trials. In doing so, it recognizes that clinical research systems that were needed to evaluate a sudden capacity is often built in a stepwise fashion and must onslaught of clinical research proposals; and encompass fundamental capacities required for surveil- lance, epidemiologic analysis, and reporting under IHR iii. The affected countries did not have experience and 2005 (WHO 2008). expertise in completing the various and complex legal and bureaucratic steps in clinical trial conduct, The core capacities for conducting clinical trials are e.g., issues around data and sample-sharing. enabled by a national legal framework that permits and facilitates the conduct of this research, and includes Such capacity gaps are not unique to these three an experienced clinical trial team, appropriate space countries. One recent study examining the situation in which to conduct clinical trials and maintain records, across the Economic Community of the West African a capable laboratory system, biobanking, capacity for States (ECOWAS) reported that just half of West reliable data management, a functioning ethical review African countries had established directorates for system, a capable regulatory authority, the capacity to health research with defined terms of reference; that fulfill responsibilities as a trusted institution, including the existing funding mechanisms were inadequate to through execution of administrative functions, such as support the research structures within and outside the contracting or accounting for funds, and the capacity ministries or to improve the capacity of researchers; to engage communities. Achieving these capacities and that networking and monitoring activities were requires not only physical infrastructure, but a human weak. Most countries had not even established national infrastructure consisting of a trained, capable, multi- research priorities (Sombié et al 2013). A follow up disciplinary work force. In addition, the system must survey reported that there was evidence of increased be sufficiently flexible to move from a fixed space for regional investment and some progress, but “high staff clinical research and trials during inter-epidemic periods turnover, weak institutional capacities, and ineffective to emergency units set up to provide care and isolation collaboration” remained significant challenges (Aidam of subjects with an epidemic infectious disease, such as and Sombié 2016). At a broader level, a mapping study the Ebola Treatment Units set up during the outbreak in of research ethics committees conducted by COHRED West Africa during 2014-2015. identified over 165 committees operating in 34 African countries, but concluded that there was great variability To this end, in-country researchers will be best prepared in skills, membership, capacity, and efficiency (Kasule to lead the response to an emerging infectious disease et al 2016). Despite efforts to train many in research threat if they have broad capabilities, including epidemi- ethics and help promote the establishment of functional ology/surveillance, effective community connections, mechanisms for ethics review of clinical research, the translational research capacity, clinical research lack of structural and institutional support continues to capabilities, relevant laboratory capacity, international hamper the establishment of meaningful capacity in eth- research partnerships, and so on. All these capacities ics as evidenced by the findings from Kasule et al (2016): need to be fostered in the right enabling environment. “Many [ethics committee] administrators may not have Research sites and researchers are at the heart of the defined roles and responsibilities, may lack adequate research architecture, but they will not survive without 16 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS arteries to the government institutions (awareness and Center at the National Institutes of Health (NIH) has support) and to communities (empowerment and trust). dubbed the investigators who lead such efforts These pathways must be created and maintained by ‘research entrepreneurs’, highlighting many of them in strong research governance (Box 2.1). their publications (Fogarty International Center, NIH 2009, 2012, 2017). BOX 2.1 BOX 2.2 BUILDING TRUST IN UGANDA FOGARTY RESEARCHERS DIVERSIFYING FOCUS IN A CRISIS Institutions such as the Infectious Diseases Institute (IDI) in Uganda, have gone to great As more and more babies in Brazil were born lengths to establish policies and mechanisms with microcephaly in 2015, Fogarty-supported that showcase their commitment to transparency, scientists rapidly changed gears on work they'd high standards, fiscal management, measurable been doing for years on Chagas disease and results, and zero tolerance for corruption and dengue, and shifted their focus to the Zika virus, mismanagement of funds. This commitment, which was suspected of causing the spate of combined with efforts in community outreach, birth defects. By the time researchers had con- education and hiring has been central to building firmed the link between Zika and microcephaly in population-level trust as well. While sometimes infants, scientists in Brazil who had been trained uncomfortable, balancing a zero-tolerance policy with Fogarty support were using the resources in with community engagement, including the place for Chagas disease brain research to better willingness to take fair but definitive action in the understand Zika, and collaborating with other face of inappropriate behavior, has led to broad groups to advance knowledge of the disease, sustained community engagement and trust. said Dr. Jamary Oliveira-Filho of Brazil's Federal IDI leadership has also been clear that building University of Bahia. Meanwhile, in Mexico, two this kind of capacity does not happen overnight; Fogarty-supported Ph.D. candidates who were indeed, achieving this status has been a decade- researching different aspects of preventing and long effort, marked by major challenges. controlling dengue—transmitted by the same Source: Potter, Christopher and Brough, Richard (IDI). Personal Aedes Aegypti mosquito as Zika—refocused their communication, email dated April 13, 2018 work on Zika. Source: Fogarty International Center, NIH (2017) Simultaneously, research institutions need to be dynamic and be ready to diversify their research agenda to increase their likelihood of funding sustainability. Most research institutions in LMICs developed from a Accelerating R&D during single disease focus, and as a result, their funding can be at risk when the disease becomes controlled (e.g., Emergencies: The Nigerian polio, H5N1 avian influenza) or when research funders change their research emphasis. Even in developed Experience countries, estimates indicate that over half of clinical trial sites fail to become sustainable because of their inability At the time of this writing, Nigeria is experiencing the to attract a second trial.7 While the impetus to diversity worst Lassa fever outbreak on record, with the number can come from the country government, it also comes of confirmed cases in January and February 2018 alone when investigators themselves recognize additional exceeding the total number reported in the whole of health challenges in their environment and garner 2017. Between January 1 and April 22, 2018, a total of resources to address them. The Fogarty International 1,865 cases (416 confirmed) have been reported from 20 states in Nigeria. Since the onset of the 2018 outbreak, 7 Society for Clinical Research Sites (SCRS). Personal communication, there have been 105 deaths in confirmed cases, a Case email dated May 3, 2018. Fatality Ratio in confirmed cases of 25.2 percent. Recent COMMITTING TO CLINICAL RESEARCH 17 weeks have seen a decline in the growth rate of new ●● Strengthening oversight by the Nigerian ethics and cases, but “We should interpret the recent declining regulatory review bodies to evaluate a possible blitz trend in new cases with caution. The Lassa fever season of research protocols applications; and is not yet over.”8 ●● Mapping and coordination of the offers of support along the lines of the identified research priorities to What has been remarkable about the response this time develop a national research plan that addresses the is the speed and the quality of research that has been Nigerian priorities. launched to better understand the nature of the out- break and obtain crucial insights which will help mitigate Researchers at the Irrua Specialist Teaching Hospital—in future Lassa fever outbreaks. At the onset of the current collaboration with NCDC, the Bernhard-Nocht Institute Lassa outbreak, the Nigeria Centre for Disease Control for Tropical Medicine, Germany, WHO, and others—have (NCDC), working with WHO and other partners, promptly conducted genome sequencing of the Lassa virus. As developed a list of research priorities aimed at improv- Dr Wondimagegnehu Alemu, WHO Representative to ing the ability of the response team to prevent, detect Nigeria, notes, “by conducting research as the Lassa and control an outbreak in the future and to establish fever outbreak unfolds, Nigeria is a pioneering a new a national long-term capacity to conduct Lassa-related approach. Until now research in Africa has taken research, building on existing capacity. The research place much later in the response cycle. This is a new priorities and actions, which were initiated in record time approach which opens the way to much more effective as part of the Nigerian research plan, address: control of emerging and dangerous pathogens.”9 ●● Harmonization of core clinical data variables and documentation of patterns of care for Lassa fever Not only has Nigeria responded quickly and adequately patients to improve support of care, aid interpre- to the Lassa fever epidemic, it has also seized upon tation of results from future studies on immune the opportunity provided by the outbreak to establish response to Lassa infection, and put in place an and initiate action on research priorities in parallel to infrastructure for multi-site evaluations of therapeu- managing the response. Despite a plethora of chal- tics and vaccines; lenges—including lack of career paths, lack of aware- ness of research in their communities and instability in ●● Testing of diagnostic assays to distinguish between contracts/funding—this experience demonstrates that acute illness, repeat or chronic infections, and researchers and research institutions, in low-income response to vaccination that will permit improved countries, have the potential to produce life-saving inno- management of cases and clinical research on vations and improve quality of life for many. This leads promising Lassa fever treatments and vaccines; us to our first recommendation, that governments com- ●● Strengthening of Lassa surveillance and laboratory mit to strengthening capacity to conduct or participate in capacity to enhance the understanding of disease clinical research to address their public health needs. incidence, prepare to respond to outbreaks and facilitate future vaccine trials; RECOMMENDATION 1 ●● Strengthening infrastructure of critical health facili- By December 2018, in order to effectively respond ties, alongside supply-chain of essential medicines to disease outbreaks, reduce preventable deaths, and equipment; strengthen productivity and improve quality of ●● Training of health and research workers on basic life, countries should commit to strengthening infection prevention and control measures and good capacity to conduct or participate in clinical clinical practices; research to address their public health needs. ●● Planning critical translational research to inform community engagement strategies and to further document risk factors for transmission of Lassa virus; 8 Dr Wondimagegnehu Alemu, WHO Representative to Nigeria, speaking on the Lassa fever outbreak in Nigeria, March 26th, 2018, Abuja, Nigeria. Accessed on April 26th, 2018 at 17:00 hrs. URL: http://www.afro.who.int/news/ who-nigerias-lassa-fever-outbreak-slowing-remains-concer 9 Ibid 18 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS FIGURE 1: SPENDING ON R&D AS A PERCENTAGE OF GDP 3.0 2.5 2.0 1.5 1.0 0.5 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 High income Low & middle income Upper middle income World Source: World Bank 2018a Investment Framework that South Korea spent 0.21 percent of GDP on health R&D, which was under 5 percent of all R&D spending (UNESCO 2018). Likewise, Singapore and Netherlands What clinical research capacities and capabilities spent 0.4 and 0.34 percent respectively of GDP on must countries develop? What financing sources must health R&D in 2014, equivalent to 18 and 17 percent of all countries tap, especially those that are already very R&D spending in these countries (WHO 2017). stretched in terms of unmet demands? In an environ- ment of constrained resources, what strategies must The mix of arguments to be used to make the case for countries employ to prioritize investments in a subset investing in clinical research will vary from country to of interventions? What strategies must countries put in country, depending on the scale of additional invest- place to sustain these investments over time? These are ment required and the broader socio-political and the kinds of questions that a strong investment frame- economic context. But one thing is certain: investing in work for clinical research must help answer. health science research and research capacity yields positive economic benefits, and evidence suggests that The world invested US$1.67 trillion in all R&D, including the aggregate economic returns are large. The Fogarty health-specific R&D, in 2015, the latest year for which International Centre, NIH (2017), the Wellcome Trust data are available, equivalent to 2.23 percent of global (2018), and the Global Health Technologies Coalition GDP (World Bank 2018a). The proportions varied con- (2017) have all documented the economic returns of siderably across countries, with high-income countries investing in health research. While estimates vary many spending 2.56 percent of their gross domestic product fold, and are more often based on higher income coun- (GDP) on all R&D in 2015, followed by upper-middle- tries experience, they demonstrate that every dollar income countries (1.66 percent) and low- and middle- invested in health research, or research more generally, income countries (1.49 percent). Between 2000 and returns far more than a dollar in return. 2015, global spending on all R&D as a percentage of GDP increased by only 0.56 percent annually on aver- ●● The Fogarty International Center, NIH reports that age. Encouragingly, R&D spending in low- and middle- each US$1.00 increase in public basic research income countries increased at an annual average rate of stimulated an additional $8.38 of industry R&D 8.8 percent during this period (Figure 1). investment after 8 years, and each US$1.00 increase in public clinical research stimulated an additional Comparable data on spending on health R&D is not US$2.35 of industry R&D investment after 3 years readily available. The limited data available shows (Toole 2007). In FY2017, US$26.1 billion in NIH grants COMMITTING TO CLINICAL RESEARCH 19 led to US$68.8 billion in economic activity nation- Government Bonds. In short, publicly funded R&I is a wide. NIH grant funding in FY2017 created over good investment” (Science Business 2017). 400,000 jobs in the United States. In California, the largest recipient of federal research funds, about Although the investment case for clinical research is US$3.9 billion in NIH grants and contracts supported strong, mobilizing the necessary resources is con- more than 62,000 jobs in the state in 2017. Another strained by a variety of factors, including insufficient state receiving substantial NIH funds is New York, financing, lack of political support for investing in activi- with US$2.4 billion supporting more than 29,000 life ties that do not necessarily yield returns in the present sciences jobs in 2017 (United for Medical Research time, and complexity in terms of implementation (that 2018). NIH research also helps to foster the creation is, what to fund and how to maintain the investments of new biotechnology companies: one study by over time). These challenges are further exacerbated in Kolympiris et al (2014) found that every US$1 million the context of resource-constrained economies, which in public R&D funding to universities over a 5-year use up all the scarce resources to take care of urgent period generated a 5.9 percent increase in the needs today instead of worrying about the imperatives creation of location biotechnology firms in the of tomorrow. nearby metropolitan area. Maryland, for example, contains 50 research-intensive federal institutes and The World Bank is strategically placed to help countries centers that have helped foster about 500 biosci- develop investment frameworks for clinical research ence companies. for low-income countries through its International Development Association (IDA) lending arm (Box 2.3). ●● A research study produced by the Policy Institute As part of commitments under IDA18, the World Bank at Kings College London, RAND Europe, and Group is committed to helping at least 25 countries the Health Economic Research Group at Brunel develop pandemic preparedness plans and strengthen University London,10 and reported by Wellcome their capacities to detect, prevent and respond to dis- Trust (2018) shows that for musculoskeletal, cancer, ease outbreaks. The World Bank Group has tentatively cardiovascular and mental health research, every identified these countries and has begun working with UK£1 invested in medical research delivers a return them to develop, update, and/or review comprehensive equivalent to around UK£0.25 every year in perpe- pandemic preparedness plans. Strengthening clinical tuity. It finds that research funding stimulates or research capacity is an integral element of country pre- ‘crowds in’ private investment, resulting in a boost to paredness for disease outbreaks, and the World Bank economic activity through industry commercializing Group, through its IDA lending arm as well as its IDA18 new products or investing in further research. commitments, can extend financial support to coun- ●● Global Health Technologies Coalition (2017) esti- tries willing to invest in clinical research development. mates that the US$26 million invested in polio Although the commitments in the last round of IDA of vaccine R&D resulted in treatment cost savings developing preparedness plans are for 25 countries,11 of US$180 billion since the 1950s, and the US$50 all IDA eligible countries have the potential to be sup- million that it cost to develop meningitis A vaccine ported under future commitments. is expected to have saved US$9 billion in treatment costs by 2020. The World Bank Group carries out a detailed review of progress in all sectors midway through the IDA cycle. Science Business (2017) puts these estimates in The review not only examines achievements and con- perspective. It notes that “the many economic mea- straints within the IDA cycle under consideration, it also surements of returns on investment to publicly funded provides a strategic platform to explore new and innova- research and innovation (R&I) vary wildly in range, but tive approaches that could potentially enhance IDA’s seem to cluster at around a 20 percent annual return ability to respond to sustainable development goals on investment. This can be compared to 6.8 percent (World Bank 2015a). The mid-term review of the ongoing for the past 10 years of the US stock market (S&P 500) IDA18 cycle is scheduled for December 2018. This would or the 3.1 percent for 10-year Euro Area (19 countries) 11 These include Afghanistan, Bangladesh, Benin, Burkina Faso, Cambodia, Cape Verde, Democratic Republic of the Congo, Ethiopia, 10 Funding for this research was provided by the Academy of Medical Ghana, Guyana, Haiti, Kenya, Lao PDR, Liberia, Mali, Myanmar, Nepal, Sciences, Arthritis Research UK, the National Institute for Health Niger, Nigeria, Papua New Guinea, Senegal, Sierra Leone, Sudan, Research, and the UK Medical Research Council. Tanzania, and Uganda. 20 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS BOX 2.3 INTERNATIONAL DEVELOPMENT ASSOCIATION (IDA) The International Development Association (IDA) is the part of the World Bank that helps the world’s poor- est countries. Overseen by 173 shareholder nations, IDA aims to reduce poverty by providing loans (called “credits”) and grants for programs that boost economic growth, reduce inequalities, and improve people’s living conditions. IDA complements the World Bank’s original lending arm—the International Bank for Reconstruction and Development (IBRD). IBRD was established to function as a self-sustaining business and provides loans and advice to middle-income and credit-worthy poor countries. IBRD and IDA share the same staff and headquarters and evaluate projects with the same rigorous standards. IDA is one of the largest sources of assistance for the world’s 75 poorest countries, 39 of which are in Africa, and is the single largest source of donor funds for basic social services in these countries. IDA lends money on concessional terms. This means that IDA credits have a zero or very low interest charge and repayments are stretched over 25 to 40 years, including a 5- to 10-year grace period. IDA also provides grants to countries at risk of debt distress. In addition to concessional loans and grants, IDA provides significant levels of debt relief through the Heavily Indebted Poor Countries (HIPC) Initiative and the Multilateral Debt Relief Initiative (MDRI). In the fiscal year ending June 30, 2017, IDA commitments totaled US$19.5 billion, of which 17 percent was provided on grant terms. New commitments in FY17 comprised 261 new operations. Since 1960, IDA has provided US$345 billion for investments in 113 countries. Annual commitments have increased steadily and averaged about US$18 billion over the last three years. Source: World Bank (2018b) provide a good opportunity to consider which innova- RECOMMENDATION 2 tions implemented in IDA18 are ready to be scaled- up—and look ahead to what sort of next-generation Recognizing the existing IDA18 commitment to innovations IDA can support going forward (World Bank strengthen preparedness in at least 25 countries, 2015b). It thus provides a forum for proposing prioritiza- the World Bank Group should include, as a part tion of a set of tailored investment frameworks for LMICs of its IDA Mid-Term (December 2018) Review to develop clinical research capacity in the scope of (MTR), an investment framework for national and the 19th replenishment of International Development regional clinical research capacities. Association funding (IDA19) commitments. COMMITTING TO CLINICAL RESEARCH 21 CHAPTER 3 Enabling Clinical Research The capacity to conduct clinical research, including Legal and policy frameworks in other areas have been clinical trials, does not exist in a vacuum. Indeed, the helpful in addressing these shortcomings to advance capacity requires more than a few investigators to policy solutions. For example, a review of material trans- conduct a trial. Building capacity begins with a national fer agreements (MTAs) of various countries was used commitment, which includes creating a comprehensive by WHO to support efforts to develop and make a MTA legal framework and nurturing a culture of conducting template available for countries to use; these agree- high-quality clinical research are essential elements for ments set forth the conditions for sample sharing and a more sustained capacity-building program. specimen sharing outside of the country of origin. This analysis is being used by the Government of Nigeria to promote clinical research related to its Lassa outbreak. Legal Frameworks Many countries, ranging from Singapore to Senegal have found that a governmental entity, such as a A legal framework and research governance system that national health research institute, is key to working with supports and enables the conduct of clinical research its research institutions (both public and private). In a and clinical trials is a prerequisite for building capacity. virtuous cycle, research conducted in national research Laws are critical for authorizing a national entity to over- institutions in turn provides evidence to strengthen see a national research plan and priorities; a national country policies regarding not only health, but other sec- regulatory and ethics review system; import, export and tors including education, animal and agriculture, science customs regulations related to research; and mecha- and technology, industrial/economic, and security. nisms for dispersing funds to support researchers and research institutions. Laws are also necessary to protect The Pan American Health Organization (PAHO) has intellectual property rights. played a key role in promoting relevant laws in Latin America through its Policy on Research for Health While legislative frameworks and laws enabling a (PAHO 2010), but a comprehensive repository or analy- national health research system, clinical research and sis of countries’ laws appropriate to the conduct of clini- clinical trials are critical, the Task Force notes that there cal research appears to be non-existent. A synthesis of is uneven adoption of such laws. To illustrate, laws existing, broadly applicable laws and policies regarding regarding clinical research, governance and regula- clinical research would enable countries to more rapidly tion of research have become commonplace in Latin develop legislation, if needed, and assess whether their America over the past decade (for example, Peru, existing legal framework was sufficient to their needs. Argentina, Mexico, Ecuador, Paraguay, Brazil) (Motti 2008), but they are far less common on the African continent. ENABLING CLINICAL RESEARCH 23 RECOMMENDATION 3 Second, an environment that supports, promotes and publicizes careers in clinical research and role models By end 2019, WHO should develop and for young investigators is a necessary element to sup- disseminate examples of broadly applicable port and motivate scientists to pursue clinical research legislation and policies to support and enable careers, and to choose to use those skills in-country. efficient conduct of clinical research. This should While actions that a country might take to create such include, at a minimum, model policies and a culture may be clear to scientists themselves (e.g., laws that support the conduct of trials, enable adequate salaries, a career ladder) public understanding timely ethics and regulatory review, address and appreciation, including that of government officials import/export of relevant commodities and is usually limited. bio-specimens, and address procurement and contracting systems. These policies should be Third, while well-resourced, research-intensive insti- a part of a broader governance architecture for tutions have an infrastructure to compile and ‘push’ clinical research. funding announcements to researchers, there does not appear to be any one-stop shop for researchers in LMICs to learn about a broader array of funding oppor- tunities. One suggestion has been that Academies of Culture of Clinical Research Sciences fulfill such a role, although that may result in duplication of effort. The Council on Health Research Numerous interviews conducted for this Task Force, for Development (COHRED) initiated a platform, Health as well as a study of barriers and enablers to develop- Research Web (HRWeb), with the intent of gathering a ing clinical research capacity conducted by Franzen et range of research and management information, includ- al (2017), identified the need for a supportive research ing funding opportunities, but funding to support it has culture if clinical research capability is to develop and not been maintained. It may be prudent for COHRED thrive. The literature and the Task Force identified sev- and others and global research funders to examine dif- eral elements that can create such a supportive culture. ferent models to support such a platform. Some of these are highlighted below. Finally, it is necessary to maximize opportunities for fair First, increasing visibility and political support for clini- and mutually beneficial research partnerships within and cal research is important. Ensuring there are national across countries. COHRED has published guidelines on research plans and priorities, with preparedness as a the Fair Research Contracting Program (COHRED 2013). key element, is central to that effort. Even in the face Additionally, ensuring speedy ethical review is crucial to of such plans, in many countries, the general public, the conduct of trials in-country. RHInnO Ethics, an online students considering future careers, and government review platform for research ethics committees, seeks to officials could benefit from increased information about facilitate an efficient ethical review clearance of clinical nationally produced research and the role it can play research involving human subjects. In 2015, RHInnO in improving population health and economic develop- Ethics was used by 25 research ethics committees in 8 ment. At a recent workshop on strengthening clinical African countries (Mokgatla et al 2017). These existing research in LMICs (organized by the UK Academy of initiatives are just a few that can be supported and lev- Medical Sciences and the InterAcademy Partnership eraged nationally to create an enabling environment. for Health), representatives of 25 LMICs reiterated the need for increased public interest, and noted that In some industrialized countries, Academies of countries could benefit from increased awareness of Sciences or other research institutes (e.g., the National what it takes to develop a research culture and that “the Academies of Sciences in the US, or highly respected engagement of scientists with governments in order to institutions such as the Royal Society and the Academy raise awareness and advocate for policies supporting of Medical Sciences in the UK) are influential in-country, clinical research is a key step to addressing many of the and often global health and research policy. In Africa, issues faced by the [research] community” (Academy of the African Academy of Sciences (AAS) is now playing Medical Sciences 2017). a key role in coordinating clinical research develop- ment and funding in the creation of the Coalition for 24 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS African Research and Innovation (CARI), and is poised to governments on the best way to strengthen enabling become a catalyst and coordinator for clinical research elements, culture and sustainability of clinical research. activity. Similarly, in South Africa, the South African Medical Research Council is influential in research policy RECOMMENDATION 4 direction for the country. The Task Force found that such Academies, by nature of their stature, leadership, inde- By 2019, Research Forums/Institutions and/or pendence and growing influence, are well positioned Academies of Science in LMICs, drawing upon to take charge over the immense knowledge transfer their experience and that of others, should required between the decision-makers in govern- synthesize best practices and develop guidance ments, research capacity development experts, and the for consideration by countries on how to build a researchers themselves. As a pivotal group in this, the supportive research climate/culture. Academy of Sciences should be engaged by national ENABLING CLINICAL RESEARCH 25 CHAPTER 4 Assessing Clinical Research Capacity There are no widely-accepted measures of assess- Some indicators that measure research competency at ing country-level capacities for clinical research, which various levels are in use. These include: makes it challenging to determine whether a country has the capability to participate in or conduct a clinical ●● Global Health Observatory on Health R&D, which trial, including whether it has in place adequate regula- monitors the number of researchers in health and tory and ethics frameworks necessary for the conduct medical sciences, by country (WHO 2018a); of clinical research. It is also difficult to determine the ●● The TDR-TGHN Competency Wheel (TGHN 2018), extent of community engagement and the level of trust developed by the TDR (Special Programme for that would facilitate voluntary participation in random- Research and Training in Tropical Diseases) at WHO ized controlled trials. An evidence-based tool for assess- in partnership with The Global Health Network ing clinical research capacity would help governments which lists all the competencies that should be identify the gaps and the needed investments to bring demonstrated by a research team to carry out a their research capacities up to international standards. successful clinical study; ●● The Mapping African Research Ethics Review and Existing approaches that track clinical trials in countries Medicines Regulatory Capacity (MARC) initiative, are indicative of the gaps in country capacities. WHO, established by COHRED in partnership with the for instance, maintains an International Clinical Trials South African Research Ethics Training Initiative Registry Platform (ICTRP),12 which provides handy data (SARETI) to map health research oversight and on registered clinical trials in countries. According to this regulatory activities in Africa, which has collected registry, 96 countries have registered vaccine trials in information on over 150 African research ethics the last twenty years. Fifty-six out of these 96 countries committees (COHRED 2018); have registered between 1 and 10 trials, followed by 13 countries that have registered between 10 and 20 trials, ●● The Laboratory Network Scorecard (LABNET) devel- 3 between 20 and 30, 5 between 30 and 40, 4 between oped by the African Society for Laboratory Medicine 40 and 50, and 11 countries over 50 trials. An additional (ASLM) and the Association of Public Health 100 countries have registered non-vaccine related trials. Laboratories for the assessment of national labora- Figures 2 and 3 show the world-wide spread.13 tory network functionality (Ondoa et al 2016); ●● The Research Fairness Initiative (RFI), developed by 12 The figures are made using ongoing and completed vaccine trials that were registered since 1999 regardless of recruitment status. COHRED and currently adopted by many countries Country of recruitment refers to the country "from which participants and organizations, including the TDR at WHO, “to will be, are intended to be, or have been recruited at the time of create a reporting system that encourages govern- registration". A trial may be counted more if participants are recruited from more than one country. Figure 2 data is as of April 6th, 2018; ments, business, organizations and funders to figure 3 data is as of April 4th, 2018. Source: International Clinical describe how they take measures to create trusting, Trials Registry Platform (ICTRP). Available at: http://www.who.int/ ictrp/search/en/ Note: The ICTRP compiles trial records form 17 data lasting, transparent and effective partnerships in providers, including ClinicalTrials.gov and EU Clinical Trials Register research and innovation” (RFI 2018). (EU-CTR). More information can be found at: http://www.who.int/ictrp/ search/data_providers/en/. ●● The WHO Global Benchmarking Tool for Regulatory 13 In the absence of detailed information on who and how these trials were conducted, it is difficult to make a determination about the Capacities, which assesses and documents country’s capacity and expertise to carry out clinical trials. capacities of national regulatory agencies (PAHO ASSESSING CLINICAL RESEARCH CAPACITY 27 FIGURE 2: NUMBER OF CLINICAL TRIALS PER COUNTRY OF RECRUITMENT Source: WHO ICTRP 2018 2017), including the capacity to provide informed during crises; and standard operating procedures for no-objection to clinical trials, post marketing operationalizing during different types of crises. It also surveillance and oversight of research during requires the existence of an enabling environment outbreaks; and with the necessary legal framework, professionally generated guidelines, and an atmosphere of trust and ●● The Joint External evaluation (JEE) that, inter alia, support, data management capacity and community assesses laboratory and surveillance preparedness participation. These elements, which comprise a multidi- (WHO 2016). mensional construct, have not yet been combined into a useful index, or developed into a standard that can be A critical but neglected part of the response archi- readily used at the country level. tecture in the context of an outbreak is the ability to “surge” research to take advantage of the brief window Building upon the various existing indicators and ongo- of opportunity to better understand the nature of the ing work in this area, and developing a robust set of outbreak and test new diagnostics, therapeutics and indicators to systematically assess country capacity for vaccines. This depends on the existence of a clini- clinical research is a huge but necessary task. As a spe- cal research system and its agility and ability to shift cialized agency of the United Nations, WHO is strategi- priorities. Key constituent parts of this research system cally and best placed to consolidate measures already include appropriately trained researchers, including epi- in use and develop a tool for assessing clinical research demiologists, anthropologists and clinical trialists; appro- capacity at the country level.14 priate institutional conditions ( jobs, salary, hardship supplements, personal protection precautions, etc.) to sustain researchers in the inter-epidemic period as well as during outbreaks; support for researchers to under- 14 This point was reinforced at a workshop co-organized by WHO, the take research; ethics review boards (rapid but thorough); National Institute of Allergy and Infectious Disease, and the World Bank in March 2018, and attended by low- and middle-income regulatory capacity for new diagnostics, treatments country representatives as well as the concerned international and vaccines; state-of-the-art methods for research agencies. 28 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS FIGURE 3: NUMBER OF VACCINE TRIALS PER COUNTRY OF RECRUITMENT Source: WHO ICTRP 2018 Given the urgent need to be better prepared to address RECOMMENDATION 5 outbreaks, countries need not wait for such a measure to be finalized before conducting their own assess- By end 2018, WHO should consolidate a robust ment of research gaps. Key informant interviews as set of indicators, to the extent possible building well as qualitative results from a TGHN survey of 5,000 on indicators already used by countries, develop a individuals suggest that researchers are readily able to tool for assessment of country-level capacities for identify key capacity gaps. One interim suggestion is clinical research, and propose a process to help that governments encourage researchers, in both public countries rapidly conduct these assessments. and private institutions across their countries, to partici- pate in a rapid assessment process, followed if needed by a more formal inventory of capacity gaps. COHRED typifies the organization that could facilitate these assessments, and has a track record of doing so. Such assessments could be facilitated by development of a relevant scenario-driven exercise to assess what would be required and is in place to participate in or conduct a relevant vaccine or therapeutics trial. ASSESSING CLINICAL RESEARCH CAPACITY 29 CHAPTER 5 Financing Clinical Research Capacity We believe that countries seeking to step up invest- challenging for most low-income countries. One issue is ments in clinical research should raise and spend their that domestic resource mobilization for clinical research own funds to provide for their people. We believe that in health must compete with other country priorities, “domestic resource mobilization not only provides such as building roads and bridges. When investments governments with the funds needed to alleviate poverty are likely to generate an immediate revenue stream, and deliver public services, but is also a critical step on such as through power generation, the decision to fund the path out of aid dependence” (USAID 2018). At the is often easier. And, in part because the link between same time, we realize that despite recognition of the epidemic preparedness and clinical research is not well need for country investment and ownership, mobilizing appreciated by policy-makers, it is neither widely known, domestic resources to support clinical research will be nor clearly understood, that countries could choose to BOX 5.1 DOMESTIC VS. INTERNATIONAL FUNDING: BASIC PRINCIPLES As a fundamental principle, countries should aim to increase their domestic spend on development and specifi- cally health, including preparedness, to maximize country ownership and self-reliance over time. This idea has been articulated in many settings: for example, the commitment of African Union countries to allocate at least 15 percent of their national budgets to improve the health sector (Abuja declaration 2001), and the partnership for improved domestic research mobilization (Addis Tax Initiative 2015). Whenever international development assistance is deployed, it should focus on “catalytic” activities or activi- ties that have high global externalities and low domestic demand. Catalytic activities allow a step change in a country’s level of preparedness. These are expected to be mostly one-off costs—but can also be recurring costs, if these are critical to establish capacities in the countries, or if executing certain functions at a centralized level enables scale efficiencies. Activities with high global externalities and low domestic return are those that prom- ise high impacts for global risk mitigation but may be deprioritized in countries without international support. Regional entities and neighboring countries can play an important role in providing technical and financial support for preparedness activities in cases where they can add value through coordination (e.g., the establish- ment of the Mekong Basin Disease Surveillance Network and Africa CDC); economies of scale (e.g., joint drug procurement in Central America by SICA); or sharing expertise. The private sector should also be included across the entire preparedness planning process, and its expertise should be leveraged in carrying out planning activities. Source: IWG (2017); Phommasack et al (2013) FINANCING CLINICAL RESEARCH CAPACITY 31 commit resources, such as those from their IDA alloca- loans and credits to finance what they see as more tions, to support clinical research capacity-building. immediate needs. Financing mechanisms that offer soft terms may tilt the scales in favor of borrowing funds to Costs incurred for clinical research capacity-building, as strengthen their clinical research capacity. One such with other initiatives, include start-up costs, fixed costs mechanism is the buy-down. and recurrent costs, all of which must be provisioned for in the development or expansion of clinical research Buy-downs capacities. Some of the enabling elements for strength- ening a clinical research system, including establishing a legal framework, and country and institutional system for regulatory and ethics review, could be considered One innovative solution used in some cases by the start-up costs. These costs would need to be funded World Bank is ‘buy-downs’, which essentially bundle IDA early in the process. Further, countries setting up clinical interest-bearing loans and credits with donor-funded research capabilities will face several fixed and recur- grants that are used to buy down the net present rent costs. Fixed costs are typically large and lumpy value of the loan or credit and reduce it to grant terms. capital costs, such as those that may be incurred in This provides an attractive motivation to achieve the such areas as building a clinical trial facility, purchasing intended outcome, in that countries are incentivized laboratory equipment, regional biobank/specimen stor- to incur debt to undertake an activity that they might age, and establishing a data management infrastructure. otherwise not have done, and to work toward successful Recurrent costs, on the other hand, must be borne on completion of pre-defined targets so as to have the loan a regular basis year after year, and include salaries and reduced to a grant (World Bank 2010a). Experience with wages, consumables, travel, training, and so on. Ethics pilot buy-downs suggests that they can help govern- and regulatory review systems, and running a laboratory ments achieve purely national targets, creating internal or biobank may also generate considerable recurrent incentives for improved monitoring and evaluation and costs because of the human resource needs required more clearly defined accountability (World Bank 2010a), for effective approval and oversight of clinical research. or they can be used to support regional activities that are considered global public goods. The most problematic of all these costs are often recur- rent costs, in that countries need to mobilize domestic One example of the successful use of buy-downs resources and make specific budgetary allocations to relates to financing of intensified polio-eradication pay salaries and wages, buy consumables, pay trainers, activities in Pakistan in 2003. Developed in partner- etc. While start-up costs may be borne from one-time ship with the Bill & Melinda Gates Foundation (BMGF), grants from development partners, recurrent costs are Rotary International (RI) and the UN Foundation, the incurred every year and must be provided for in every World Bank set up a multi-donor Polio Eradication Trust budget cycle. In contrast, financing for capital invest- Fund, which was used to pay the service fee for the IDA ments can be sourced by loans and credits, such as Credit to Pakistan15 during the implementation, and to those from the World Bank Group’s IDA. buy down the Net Present Value of the IDA Credit and reduce it to grant terms upon successful completion of RECOMMENDATION 6 the project.16 This effectively translated the IDA Credit to Pakistan to a grant for polio eradication. The external By end 2019, governments in IDA-eligible partners bought the credit at the Net Present Value, countries should commit short- and medium- term resources to address their clinical research 15 Other countries that benefited from this Trust Fund and buy-down capacity goals. These resources could potentially were Afghanistan, Pakistan and India in South Asia and Nigeria and come from their IDA portfolios. Angola in the Africa Region. 16 Two indicators were used to measure project performance: (i) Timely arrival of the Oral Polio Vaccine at the central stores of Committing domestic resources for epidemic prepared- Pakistan’s Expanded Program on Immunization (EPI) at least five ness, and the clinical research needed to support it, weeks before each of the planned Supplemental Immunization Activities (SIAs); and (ii) SIA coverage of 80 percent achieved in the can be a huge challenge for resource-constrained remaining endemic provinces during 2005. The timely arrival of the economies that struggle to meet more proximate and vaccine was measured through the EPI’s vaccine arrival reports. SIA coverage was measured through a cluster sampling survey immediate demands. Countries also hesitate to borrow according to a WHO approved methodology. Achievement of these for investments in these areas, preferring to use external indicators constituted the trigger for the IDA buy-down. 32 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS which enabled them to leverage their funds for financ- collaboration can facilitate the organization and leader- ing polio eradication in Pakistan with about a third of ship of a coordinated research response in the region the funds they would otherwise have needed to finance in the event of an outbreak. In inter-epidemic periods, the same goods and services. This partnership enabled regional networks can tackle health challenges common the external partners to access the rigor of the World to partners such as malaria, tuberculosis, or meningi- Bank’s project preparation and supervision in support tis, thus creating and strengthening their independent of their efforts for polio eradication. As of 2017, the Bill and collective research capacity. National support for & Melinda Gates Foundation continues to support polio regional collaboration facilitates translation of research eradication in Pakistan through this mechanism. results into policy as well. Buy-downs represent a win-win-win approach for Many networks have emerged in recent years to sup- countries, the World Bank and the donors. Countries port science and research in Africa. These include receive financing for a global public good if they meet the Joint West Africa Research Group (JWARG), sup- the agreed performance targets; the World Bank can ported by the US Department of Defense, and the East leverage the technical expertise of other partners; and African Consortium for Clinical Research-2 (EACCR2), the donors can leverage their funding (World Bank supported by EDCTP. EDCTP has recently funded the 2017a). This mechanism has a lot of potential to support African coaLition for Epidemic Research, Response countries wishing to invest in clinical research capacity, and Training (ALERRT) and the Pan-African Network for particularly when it also supports the global public good Rapid Research, Response, Relief, and Preparedness value of preparedness. for Infectious Diseases Epidemics (PANDORA-ID-NET), anchored by European institutions, to develop outbreak RECOMMENDATION 7 response capability. Building on prior investments from the World Bank (e.g., African Centers of Excellence (ACE)) By end 2018, the World Bank Group should and the Wellcome Trust (e.g., Developing Excellence in develop mechanisms to buy down IDA loans and Leadership, Training and Science Initiative (DELTAS) and convert them into grants for countries that have Accelerating Excellence in Science in Africa (AESA)), the demonstrated development of research capacity Wellcome Trust, the Bill & Melinda Gates Foundation, based on agreed milestones. NIH, NEPAD, and the African Academy of Sciences (AAS) are organizing CARI (the Coalition for African Research and Innovation) to serve as a hub for African-led Regional Financing research institutions. The West African Clinical Research Consortium (WAC) is a collaboration of researchers across Liberia, Sierra Leone, Guinea and Mali. Box 5.2 Infectious diseases know no borders, and move eas- illustrates a regional network in Africa that began with ily with travelers and trade. With porous boundaries, a focus on HIV-AIDS and has continued to expand to countries and regions need a borderless response. address other diseases of regional significance. During the Ebola outbreak research groups in Liberia, Sierra Leone and Guinea began to organize into a Networks have their own challenges, however. research network to collaborate on Ebola research. If Financing arrangements among partners can be com- such a network were in place in early 2014 it is prob- plicated, as can ensuring that the developed country able that clinical trials of Ebola diagnostics, therapeutics partner is focused on capacity-building, supporting and vaccines would have been successfully completed ‘learning by doing’ and successively transferring respon- sooner. Networks leverage the comparative advan- sibility, including fiscal and administrative arrangements tages of the member partners, often with one goal that and clinical trial execution, to network partners. Often a center of excellence serves as an organizational and such networks have overlapping agendas and pose a administrative anchor as well as a source of training challenge to national authorities in terms of coordina- and mentoring. Networks can facilitate sharing of critical tion or ensuring that nationally-relevant research is infrastructure, such as high-level laboratory support, conducted. Ensuring financial sustainability over time is biobanking, gene sequencing and other resources, also challenging. The networks usually have earmarked thereby distributing some of the fixed costs across the resources with a medium-term outlook, and are often network partners. Critically important to preparedness led by researchers from outside, which poses chal- and response, regional networks with government lenges for capacity-building and research leadership. FINANCING CLINICAL RESEARCH CAPACITY 33 BOX 5.2 LEVERAGING AND SUSTAINING CLINICAL RESEARCH CAPACITY IN LMICS: THE IAVI-AFRICA CLINICAL RESEARCH NETWORK Sustaining clinical research capacity is rooted in partnerships with in-country scientists, community leaders, governments, and policy-makers—stakeholders whose contributions are essential to developing effective and acceptable products, ensuring country ownership and enabling access to new biomedical innovations. In 1998, IAVI (the International AIDS Vaccine Initiative) established a clinical network in Kenya to provide IAVI and its scientific partners access to local populations for clinical trials of promising vaccine candidates. Since then, the network has grown to eight research centers in five countries in Eastern and Southern Africa that can recruit and retain study volunteers in both the general population and at-risk groups. The network includes sites in: ●● Kenya: Kenya AIDS Vaccine Initiative-Institute for Clinical Research and the Kenya Medical Research Institute (KEMRI)/Wellcome Trust Centre for Geographic Medicine Research) ●● Uganda: Medical Research Council/UVRI Uganda Research Unit on AIDS and the UVRI-IAVI HIV Vaccine Program ●● South Africa: HIV Pathogenesis Program at the University of KwaZulu-Natal and the Aurum Institute ●● Zambia: Zambia Emory HIV Research Project ●● Rwanda: Projet San Francisco (PSF) More than 100 clinical studies in vaccines, epidemiology, mucosal immunology, opportunistic infections and antiretroviral treatment have provided critical insights into global health challenges. Notably, the IAVI-Africa Clinical Research Network maintains (or exceeds) the clinical standards of networks in high income countries as evidenced by a 97 percent participant retention rate in HIV vaccine clinical trials. In a long-standing partnership with the US Agency for International Development (USAID) now in its 17th year of financial and strategic support, IAVI has invested heavily in human and technical capacity-building for the network and has trained thousands of African healthcare workers, scientists, technicians, community advisory boards, regulatory agencies and other stakeholders in Good Clinical Practice (GCP), Good Clinical Laboratory Practice (GCLP) or Good Participatory Practice (GPP). Support for investigator-initiated research has nurtured the next generation of African scientists. These scientists have gone on to publish findings in peer reviewed jour- nals, lead clinical trials and epidemiology protocols, generate additional funding for their research and become influential scientific leaders in their communities. Scientists in the network meet routinely to share progress, best practices and lessons learned. In addition, physical infrastructure improvements have included clinical space, immunological laboratories, intake facilities for participant recruitment, testing and counseling centers and administrative offices. These investments have enabled interventional trials for HIV, malaria and Ebola, influ- enced development of national and regional health policy guidelines, and facilitated plans for domestic financing for health R&D among policy-makers. Source: Feinberg, Mark (IAVI). Personal communication, email dated April 13, 2018 Buy-down arrangements might help, as could ensuring will help avoid lengthy legal review and facilitate funding that network partners communicate and collaborate flows when they are needed. While this may present a on an ongoing basis, and work on day-to-day projects challenge to countries, having research agreements in in the inter-epidemic period. If the networks are to be place is certainly preferable to having a lengthy delay in used in emergencies, pre-existing written agreements an outbreak. 34 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS BOX 5.3 ACCESSING IDA REGIONAL FUNDS To be eligible for support under IDA’s Regional Program, initiatives must (World Bank 2013): i. Involve three or more countries, all of which need to participate for the project’s objectives to be achievable and at least one of which is an IDA country. The required minimum number of countries is reduced from three to two if at least one IDA Fragile and Conflict-affected State (FCS) participates in the regional project; ii. Have benefits that spill over country boundaries (e.g., generate positive externalities or mitigate negative ones across countries); iii. Have clear evidence of country or regional ownership (e.g., by ECOWAS or SADC) which demonstrates commitment of the majority of participating countries; and iv. Provide a platform for a high level of policy harmonization between countries and be part of a well-devel- oped and broadly-supported regional strategy. In addition to the regional project eligibility criteria described above, two additional criteria are applied to priori- tize projects, including (World Bank 2013): v. Regional projects should avoid funding primarily national-level investments with regional resources. The specific investments proposed within a regional project should have clear externalities, not just the regional concept itself; and vi. Given the high demand for IDA regional project financing, IDA funding should be considered only once other options have been ruled out. Leveraging other resources and working with development partners are strongly encouraged. IDA’s Regional Program requires participating countries to contribute a third of the cost of their participation in regional projects from their IDA allocation. The co-financing ratio, however, depends on project design and resource availability. IDA18 introduced the following enhancements to the Regional Program: (i) the credit/grant distribution of Regional IDA financing will match that of concessional Core Financing for all beneficiary countries; (ii) the threshold for triggering the 20 percent cap under the Regional Program will be based on the definition of small states—i.e., countries with a population of 1.5 million or less;18 and (iii) the establishment of an SDR1.4 billion refugee sub-window under the regional program to finance projects benefitting refugees and their host commu- nities (World Bank 2017b). Source: World Bank (2013; 2017b) IDA’S PROGRAM FOR REGIONAL PROJECTS period ending June 30, 2020, IDA resources allocated to the Regional Program were significantly increased The Program for Regional Projects (“Regional Program”) from SDR2.2 billion17 in IDA17 to SDR5 billion in IDA18 was initiated by IDA in 2003 in response to the increas- (World Bank 2017b). Box 5.3 outlines the primary ing interest to establish regional cooperation and the eligibility criteria for IDA’s Regional Program. acknowledgement that many development issues call for neighboring countries to work together. Through 17 SDRs (Special Drawing Rights) are an international reserve asset this program, countries may access extra financing created by the International Monetary Fund (IMF) in 1969 to above their regular IDA allocation for participation supplement its member countries' official reserves. The value of the SDR is currently based on four major currencies: the US dollar, euro, in a regional program (World Bank 2013). As part of Japanese yen and British pound. the most recent replenishment of IDA’s resources 18 Given that regional integration is particularly important for countries with small allocations to overcome diseconomies of scale, for IDA- (IDA18)—which resulted in a record replenishment of eligible small states, their contribution to a regional project is capped US$75 billion to finance projects over the three-year at 20 percent of their annual allocation. FINANCING CLINICAL RESEARCH CAPACITY 35 BOX 5.4 EAST AFRICA PUBLIC HEALTH LABORATORY NETWORKING PROJECT The World Bank has a track record of financing regional capacity-building initiatives in health. In 2010, the World Bank made financing available for the East Africa Public Health Laboratory Networking Project (EAPHLNP), with the goal of establishing a network of public health laboratories to enhance the diagnosis and surveillance of tuberculosis (TB) and other communicable diseases in the region. The US$63.66 million project provides sup- port to 25 satellite laboratories located in border areas of East Africa, specifically in Kenya, Rwanda, Tanzania, Uganda, and Burundi, with large numbers of vulnerable populations and high risk of disease outbreaks. Implementation is carried out by the EAC Partner States in collaboration with the East African Community Secretariat, the East Central and Southern Africa Health Community, the US Centers for Disease Prevention and Control and the World Health Organization. The project includes three mutually reinforcing components, aimed at boosting the regional diagnostic and surveillance capacity through the development and operationalization of a regional diagnostic network among the project countries; supporting training and capacity-building for laboratory personnel to increase the pool of experts in the sub-region and to improve the effectiveness of public health laboratories; and financing of opera- tional research and knowledge-sharing activities that aim to evaluate the impact of the new TB diagnostic tech- nologies, assess drug-resistance patterns for endemic diseases, and ascertain feasibility of using mobile phone technologies for surveillance reporting; and support regional coordination and program management functions. The project has already achieved multiple positive outcomes, including, inter alia, the introduction of a unique and cost-effective peer-review mechanism for cross country laboratory’s performance assessment, the attain- ment of substantial gains in laboratory quality improvements and accreditation, the development of a regional framework for cross-border surveillance, the financing of the construction and equipment of state of the art laboratories in cross border areas, and expanding the pool of qualified personnel by providing training to over 7,000 professionals. Source: World Bank (2015c) Regional financing can leverage existing networks, such (December 2018), and develop a robust case for as IAVI or the many networks established by EDCTP, or inclusion of prioritized regional clinical research develop new networks, such as a regional Lassa fever partnerships as a thematic area under IDA19 research network in West Africa; Middle East Respiratory (January 2020). Syndrome (MERS) network in MENA; and Nipah network in South Asia. The World Bank also has a track record of Domestic Resource financing regional capacity-building initiatives in health. Box 5.4 provides an example of one such initiative. RECOMMENDATION 8 Mobilization The World Bank Group should encourage IDA The importance of country ownership of its clinical countries to establish or leverage existing regional research infrastructure has been highlighted throughout partnerships for developing clinical research this work. Domestic Resource Mobilization (DRM)— capacity, using the IDA Regional Window funds increasing the flow of taxes and other income into combined with domestic commitments. The government treasuries—is key to achieving the ambi- World Bank Group should highlight progress tious Sustainable Development Goals (SDGs) (World and showcase strategic development outcomes Bank 2016). To map their own futures and fund essential of such regional partnerships in the IDA18 MTR services such as healthcare, countries need to generate 36 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS additional fiscal space in ways that increase public spending in the desired areas of attention without jeop- BOX 5.5 ardizing the government’s long-term financial sustainabil- MATCHING GRANTS ity. For most countries, the optimal source of finance for healthcare, including for strengthening clinical research, Matching grants are funds from the granting is the domestic budget, which is the best way to ensure organization that are matched with funds from the sustainable financing and to facilitate seamless integra- beneficiary. Grant schemes generally stimulate new tion across the multiple initiatives. However, in many activities or induce particular processes, so they low-income countries, the challenge will be inadequate should give higher priority to investing in know-how domestic resource mobilization (World Bank 2017). rather than equipment (favoring expenditures on technical assistance, capacity-building, services, and The World Bank is strategically placed to engage with studies, rather than on salaries, inputs, equipment’s countries to strengthen their tax systems, improve the and infrastructure). These grants are more commonly equity dimension of their overall fiscal systems, allocate used for demand-driven services and development a greater share to health, and promote public goods subprojects (such as community-driven projects) such as better public health, preparedness, and clini- or for enhancing private economic activity. For this cal research (World Bank 2016). Lending and advisory reason, they often target select groups and indus- services for DRM are provided by the World Bank across tries and are expected to increase their incomes or the world. Examples include the application of behav- profitability, improve their competitiveness, facilitate ioral insights to improve tax compliance and increase their access to finance, and strengthen collaboration the tax base in Guatemala; fiscal technical assistance in and the development of partnerships. China; tax incentives in Sri Lanka; equity aspects of tax reform in Colombia; and prevention of illegal transfer When should they be used? pricing in Kenya (World Bank 2016). The rationale for providing grants is often associated with the public good nature of the investment; promo- The Global Financing Facility (GFF) for women, chil- tion of innovation, learning, or partnerships; or the dren and adolescents’ health and nutrition, launched reversal of market failures. Matching grants for enter- in 2015, has supported multiple successful efforts to prise development often take the form of a one-time strengthen DRM. GFF support has focused on three subsidy for a concrete additional investment activity. mechanisms: (1) providing technical assistance to evalu- Grants are generally considered justifiable, although ate fiscal space for health in beneficiary countries (e.g., not without further scrutiny, for particular innovation- Cameroon and DRC) and to support more effective related activities: dialogue between the ministries of health and ministries of finance; (2) prioritizing health in the budget through ●● Skills training, technology development, country investment cases and health financing strate- innovation, technical assistance, partnerships, gies, identifying high-impact interventions and efficient interactive learning processes, and access to service modalities (e.g., Mozambique, Tanzania, Kenya, information (with an emphasis on know-how Guatemala, DRC, Senegal, Liberia); and (3) supporting over equipment). efforts to increase sector-specific revenues by pro- ●● Starting a business or facilitating private invest- viding technical assistance to design and/or imple- ment in local infrastructure or networks. ment these taxes, particularly sin taxes (e.g., alcohol in Liberia, tobacco in Mozambique, Sierra Leone and ●● Subproject preparation and participation in trade Senegal) (World Bank 2018c). fairs. ●● Lumpy capital investments with externalities. Other efforts of the GFF evaluate the feasibility of ●● Investments of a public good nature (for exam- earmarking taxes for health (e.g., Uganda, DRC), and ple, investments that are expected to confer provide technical assistance to develop or strengthen environmental and social benefits). an equitable social health insurance scheme (e.g., ●● Collective action for mutual benefit, with spill- Sierra Leone, DRC, Burkina Faso). The GFF is also over effects. exploring ways to leverage the capacity of the World Bank units that work directly with ministries of finance Source: World Bank (2010b) to strengthen overall domestic resource mobilization FINANCING CLINICAL RESEARCH CAPACITY 37 and public financial management in health to improve on Research and Development.19 Like other funders, the budget preparation, monitoring, and execution, and World Bank has a long history of matching grants at the thus strengthen the argument for increasing domestic national level (Box 5.5), having designed matching grant resources for health (World Bank 2018c). schemes in the agricultural sector in several countries including Nicaragua, Peru, India, Ghana, and Armenia Both country and regional development partners have (World Bank 2010b). played a critical role in research capacity strengthening, often leveraging the domestic resource commitment or The World Bank has the ability to convene development through some type of matching mechanism. Regional partners seeking to stimulate and assist government development banks can also play a role; for example, ownership in prioritizing health research and clinical the African Development Bank (AfDB) has included research as part of its national agenda, and to facilitate research funding in each of its recent health system strengthening initiatives as feasible, re-affirming the rec- 19 Kuruneri, Patience (AfDB). Personal communication, email dated ommendations of the WHO Consultative Expert Group April 16, 2018. BOX 5.6 INNOVATE IN INDIA FOR INCLUSIVENESS While India is recognized as a leading global manufacturer of high-quality generic drugs, industry gaps and market failures constrain its innovation capabilities, limiting its competitiveness and ability to address its disease burden. The Government of India has recognized, through initiatives such as the Make in India program, the need for strong innovation policies particularly in support of the biopharmaceutical sector that allow the country to successfully transition towards world-class innovation in biopharmaceuticals and medical devices. The Innovate in India for Inclusiveness, a World Bank financed US$250 million project supports the Government of India in transforming the biopharmaceutical and medical devices industries in India and unlocking the coun- try’s potential for increased innovation. Drawing from global best practices adapted to the strategic and insti- tutional context of India, the project focuses on select sections of the biotechnology value chain where critical gaps impede the development of the industry. The project is implemented through two main components. The first component targets critical gaps in infra- structure, human capital, and technology transfer with the objective of strengthening the pilot-to-market innova- tion ecosystem. Grant funding is provided to support the creation of centers of excellence for validation, early stage bio-manufacturing, clinical development, training, and technology transfer. Grant recipients under this component are primarily private and autonomous public entities, selected through open and competitive calls for proposal with transparent selection criteria. Grantees are selected among top institutions from both the pub- lic and private sectors that already have a successful track record in the biotechnology space but lack specific capabilities required to enable faster, lower-cost validation, clinical development, and early stage manufacturing. The second component aims at accelerating the pilot-to-market process for specific products. It provides grant funding to consortia of cutting-edge private, public, and academic institutions to accelerate the development of low-cost, select vaccines, biopharmaceuticals, diagnostics and medical devices that address public health priorities in India. By extending financing to consortia, the project seeks to foster a more collaborative R&D environment and supports the opportunity to link micro, small and medium enterprises in the field with larger companies. This funding covers the cost of critical aspects of the product development process, such as acquisi- tion or licensing of proprietary technologies, equipment and specialized services as well conducting clinical trials and meeting other regulatory requirements. Source: World Bank (2017c) 38 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS FIGURE 4: COUNTRIES WITH MORE THAN 5 REPORTED CASES OF WHO BLUEPRINT PRIORITY DISEASES Source: WHO Personal Communication20 Coalition for Epidemic and recommend matching funds in a way that best provides appropriate country incentives for investment. Preparedness Innovations The “Innovate in India for Inclusiveness” is an example of one such engagement. Box 5.6 has the details. RECOMMENDATION 9 (CEPI) By end 2018, the World Bank Group should The task of increasing clinical trial capacity in-country collaborate with development partners and does not fall only on development partners. There other research funders to incentivize domestic are other important ongoing and new initiatives by resource mobilization in developing countries for non-profits and private sector entities to contribute investment in clinical research capacity, including to capacity-building. Large research and research- by such means as matching grants and other funding institutions with an international presence— incentivizing mechanisms. such as NIH, Wellcome Trust, the Bill & Melinda Gates Foundation (BMGF), Institut Pasteur, INSERM, Medical Research Council UK, Swiss Development Corporation, and USAID—have a long history of supporting clini- cal research platforms in LMICs, including those that address country needs. CEPI, a co-sponsor of this Task Force, was specifically established in 2017 to “finance and coordinate the development of new vaccines to prevent and contain infectious disease epidemics…[and] ensure that the vac- cines…. are available to populations with the most need” 20 Henao-Restrepo, Ana Maria (WHO). Personal communication, email (CEPI 2018). Together with other public and private dated May 4, 2018 sector vaccine R&D entities, and drawing upon the WHO FINANCING CLINICAL RESEARCH CAPACITY 39 Private Sector Contributions R&D Blueprint’s list of priority pathogens (see Figure 4 for countries affected by the priority pathogens), CEPI has selected priority emerging epidemic diseases in LMICs in Africa (Lassa fever virus), Asia (Nipah virus) The private sector, particularly the biopharma industry, and countries in the Middle East (MERS-CoV virus) as has played an important role in building research capacity its initial vaccine development priorities, and intends to in low- and middle-income countries. One of the ways stimulate and coordinate activities from the discovery in which the private sector can develop this capacity stage up to licensed vaccines to be stockpiled, allocated is through investments in research and development and distributed in the event they are needed. relating to infectious diseases. Drawing upon data on R&D funding flows for neglected diseases collected by However, as the previous Ebola and current Lassa the Policy Cures Research G-FINDER, the WHO Global experiences have highlighted, there are important gaps Health Observatory on Health R&D shows that private in knowledge that must be addressed on the critical sector investments in neglected diseases increased by path to vaccine development in addition to the essential 32 percent between 2012 and 2016, from US$377.2 mil- capacities necessary to conduct clinical trials. These lion to US$496.5 million. In 2016, 44 percent of private include better defining the epidemiology, reservoir sector investments in R&D for neglected diseases went and human host sites of viral persistence, and optimal into vaccines R&D. In the same year, most private sector clinical care and immune responses to infection, all of investments in R&D for neglected diseases was spent on which require clinical research. Given the importance of malaria (US$137.3 million), tuberculosis (US$96.6 million) ‘learning by doing’, CEPI and its partners intend to use and HIV/AIDS (US$84.1 million) (WHO 2018b).21 the vaccine development process to help build clini- cal research capacity through addressing such critical In addition to investing directly in R&D, private funding knowledge gaps. Further, CEPI and partners can lever- has been instrumental in establishing sustainable inde- age other capacity-building efforts, e.g., EDCTP-funded pendent research capacity. For example, the Infectious networks, to strengthen research sites that enable Diseases Institute (IDI) in Uganda was developed by the researchers to be mentored in the conduct of clinical Academic Alliance for AIDS Care and Prevention (now trials during the inter-epidemic period. Accordia Global Health Foundation), an initiative of uni- versity-based Ugandan and North American physicians, The Nigerian Lassa outbreak, which occurred before with the financial support from Pfizer Inc. in the form CEPI had signed its first vaccine development contract, of unrestricted seed funding of US$10 million over ten has highlighted additional opportunities to simultane- years. Support and mentoring from academic research- ously build clinical research capacity and speed vaccine ers at leading North American universities was also development through supporting local researchers, with critical. Pfizer provided funding for building construction, mentorship as needed to develop essential critical path start-up costs and for systems development that was knowledge. This may involve epidemiologic investiga- integral to its evolution to a ‘trusted institution’. When tion, gene sequencing, development of immunologic Pfizer discontinued funding as planned in 2012, IDI had assays, or other clinical trial protocols. CEPI has already already established other sources of funding, including taken steps to support such work as part of the Lassa from competitive research grants and sponsored trials. outbreak response and has plans to work with partners This is attributable to multiple factors, including the to strengthen clinical trial capacity to conduct Phase 1 systems that had been put in place, the collaborations and 2 vaccine trials for its candidate vaccines. fostered, the deliberate diversification of their research scope to address country needs, and the demonstration RECOMMENDATION 10 that IDI could conduct high quality clinical research.22 By mid-2018, CEPI should commit resources to strengthening clinical research capacities in LMICs where clinical trials for vaccines against CEPI 21 For 2016, funding data were collected from 187 private, public and priority pathogens are likely to be conducted. philanthropic organizations, on all types of product-related R&D and basic research and platform technology investments covering 33 neglected diseases. Data are reported in US$ 2016 22 Brough, Richard (IDI). Personal communication, email dated April 13, 2018 40 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS Pharma and biotech companies have initiated and returning home, the fellows are expected to become sustained several significant capacity-building programs, valuable resources for institutional capacity develop- returning benefits to countries, to researchers and ment to undertake and manage clinical research in research institutions and to science. accordance with international regulatory requirements and standards (IFPMA 2018). ●● GlaxoSmithKline, through the GSK Africa NCD Open Lab, is investing up to UK£25million in developing Good clinical research capacity in LMICs may also attract research capacity in 8 sub-Saharan African countries more research funding and clinical trial activity from these through funding investigator-initiated studies in non- companies. If done with appropriate balance and ongoing communicable diseases (NCDs). In addition to these attention to country health needs, clinical research capac- funds, GSK is leveraging its wider R&D expertise ity can provide opportunities to sustain existing research to provide scientific collaboration to strengthen platforms and increase the likelihood that they will be projects and build capacity through skills and available when needed, for clinical trials of products such knowledge transfer.23 In partnership with EDCTP, as vaccines, therapeutics, and diagnostics for epidemic GSK NCD Open Lab supports capacity development infectious diseases. For this goal to be realized, it is critical of potential African research leaders using the train- that countries have a functional enabling infrastructure, the-trainer model (EDCTP 2018). legal system and regulatory and ethics review system. ●● Hilleman Laboratories, a joint-venture partnership Indeed, companies continue to cite factors such as lengthy between Merck and Wellcome Trust, based in New processing times for ethics committees, legal and regula- Delhi, India, supports the development of high tory agency review, and delays in getting material and impact, affordable vaccines for people in develop- equipment through a country customs process, as reasons ing countries in a sustainable manner. It has built why they do not move more clinical trial business to LMICs. translational research capacity in India to address important issues around vaccine delivery, including Country and investigator ownership of the research thermostability, ease of use, and low-cost goods agenda, which this Task Force has identified as central through core expertise and innovative partnership to building and sustaining clinical research capacity, may models with biotech companies, academia, and encourage product development and subsequent trials pharmaceutical manufacturers. germane to country health needs. While the GSK Open Lab is still relatively new, it provides a strong example of ●● Pharmaceutical companies such as Astellas, Bayer, private sector funded research that is aligned with coun- GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, tries’ national health needs. Box 5.7 has the details. and Sanofi have partnered with the BMGF, EDCTP, and WHO to develop strong research capability in In addition to the capacity-strengthening associated with LMICs. This partnership seeks to train researchers bringing clinical trial business to LMICs and more direct from LMICs involved in clinical research projects to capacity-building partnerships, there may be opportu- acquire experience and develop skills for conducting nities for private sector companies, working alone or clinical trials outside of an academic or public-sector together, to facilitate clinical research capacity devel- setting. Between 2008 and 2014, the WHO-TDR opment modeled on existing work. One model which program has trained 32 fellows, and this number is carries significant potential for working to enhance set to increase in coming years. These fellows have synergies between private and public actors in LMICs is come from 19 African countries (Benin, Burkina Faso, TransCelerate, which is a member-based initiative of the Botswana, Cameroon, the Democratic Republic of biopharma industry collaborating around shared learn- the Congo, Ethiopia, Gabon, Ghana, Guinea, Kenya, ings and best practices related to processes critical to The Gambia, Madagascar, Mali, Nigeria, Senegal, product development and clinical trials. TransCelerate’s Swaziland, Tanzania, Uganda and Zimbabwe) and membership includes employees embedded in 19 large from China, Colombia, Peru and Vietnam. The host pharma and biotech companies where they work glob- organizations trained fellows to develop special- ally to adapt and implement integrated solutions for the ist product development skills not readily taught in conduct of clinical trials (TransCelerate 2017). Member academic centers or public research institutions. On companies can pool data from consenting investigators 23 Strange, Mike and Ako, Agbor (GSK). Personal communication, email into a centralized, cloud-based resource to enable faster dated April 17, 2018 and more efficient identification, and prevent duplication FINANCING CLINICAL RESEARCH CAPACITY 41 BOX 5.7 GSK OPEN LABS Building on its Open Lab model in Tres Cantos, Spain, GlaxoSmithKline started the Africa NCD Open Lab in 2014. The impetus for this initiative was the recognition of the need for in-country scientists to address the burgeon- ing challenge of non-communicable disease on the African continent. Its aim is to stimulate scientific research to address NCDs in Africa, to identify ‘what is unique about NCDs in Africa,’ and to build a cadre of African scientists enabled to advocate for increased attention to these problems. This includes collecting data to better understand the scope and magnitude of the problems, and to elucidate the unique attributes of NCDs in the region such as disease etiology, clinical manifestations, complications and determinants of response to treatment, GSK began this initiative with a planned initial investment of UK£25 million, and established a small team of GSK scientists based in the UK to collaborate with African researchers, providing them access to experts across GSK R&D. Through a landscape analysis, GSK identified where science infrastructure was already in place, ‘building on the infectious disease heritage.’ They convened a scientific advisory board composed of leading African researchers to identify critical problems, and have subsequently funded and are collaborating on 11 projects with African research- ers/institutions led from 4 mains countries: Uganda, Nigeria, Malawi and South Africa. However, many of these proj- ects involve collaboration between institutions from multiple African countries and these include Cameroon, Kenya and Mozambique. Projects focus on asthma, diabetes, hypertension, chronic renal disease, cardiovascular disease and cancers as well as the relationship between locally-prevalent infectious diseases and NCDs. Subsequently, a critical gap was identified where early career researchers lacked mentoring, support and funds to undertake research that would enable them to transition into more established researchers whilst generat- ing valuable preliminary data to compete for major funding. Through an open call for proposals, GSK has further identified 10 early career researchers from Tanzania, Nigeria, Kenya, Ethiopia, Uganda, and Malawi with projects covering the NCDs of focus. After completing due diligence, these researchers will be provided full funding and scientific support to undertake and successfully deliver their projects. Through an extensive multi-stakeholder engagement process, including an external scientific advisory board, GSK ensures that funded projects are aligned with the national health plan and priorities in the country in which the principal investigator is located, and that the bulk of the funding stays in the country to build expertise, rather than being used to sub-contract out research components (e.g., outsourcing advanced technologies such as gene sequencing) to developed countries. GSK views this and other investments in human research capacity are in the ‘pre-competitive space’ and anticipates that engagement with other stakeholders will provide a coordi- nated structure and additional support for ongoing NCD clinical research that can be sustained and translated into improved outcomes for the African patient. Source: Strange, Mike and Ako, Agbor (GSK). Personal communication, email dated April 17, 2018 of site-qualification activities. For LMICs, the model and/or support clinical trials in some LMICs. For exam- could reduce administrative and record-keeping burden ple, ClinWin, a medium sized contract research organi- on research sites, and provide important opportunities zation based in Kenya “provides clinical development for cross-site learning and rapid initiation of clinical trials services for poverty-related diseases. It has partnered during public health emergencies. with industry, not-for-profits and academic sponsors to provide a suite of trial and site management, and In addition to private research institutions and pharma sponsor oversight services to local clinical research companies, both for-profit and not-for-profit clinical programs. These services include: training, trial monitor- research organizations (CROs) continuously conduct ing, quality assurance, ethical and regulatory expertise; 42 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS contract negotiation and trial coordination among RECOMMENDATION 11 others. Leveraging its indigenous knowledge of the clinical trial landscape in the region, it has developed By end 2019, the private sector pharmaceutical/ a database of potential and current local investigators biotech industry/clinical research organizations/ capable of conducting registration trials. The lessons other health sector businesses operating in LMICs learnt in each project are documented and shared with should announce their commitment to maximize investigator staff at new sites” (Onyango 2016). In gen- their contribution to clinical research capacity eral, CROs can play a key role in strengthening capacity- in LMICs. This includes transfer of skills and building and provide opportunities to local research expertise and/or allocating a percentage of their staff by hiring and training them, offering fellowships, spending to support the development of clinical and by partnering with them to provide operational and research capacity in LMICs that is aligned with logistical support to investigators and sites lacking those country public health needs and research agenda. capabilities. FINANCING CLINICAL RESEARCH CAPACITY 43 44 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS CHAPTER 6 Coordinating Investments in Clinical Research Mechanisms to Coordinate to prevent and respond to epidemics. Its intent is to bring together major stakeholders of research on the Investments Blueprint priority pathogens in order to better plan research initiatives during an outbreak and avoid many of the problems that affected the ability to launch clinical The magnitude of resources and the volume of initia- trials during the 2014-2015 West Africa Ebola outbreak. tives, networks and funders involved in research capac- One helpful activity undertaken under the aegis of the ity-building, especially in Africa, is dizzying, and pose Blueprint is a mapping of funders and research groups their own unique opportunities and challenges. Key involved with the priority pathogens. This not only has benefits of having many initiatives is that they generate the potential to set the stage for greater collaboration, large amounts of funding for clinical research and help but also for enhancing speed during response. The develop core research capacities. A major challenge is research response coordination mechanism of the GCM that the scope and distribution of funding is often not was used during the 2018 Nigeria Lassa outbreak. The well coordinated. Key informant interviews conducted GCM Secretariat at WHO worked with the Government by the Task Force show that large funders are often of Nigeria to identify priorities for research, and commu- unaware of one another’s efforts and plans, and there- nicated them to the community of research funders. fore miss opportunities to realize potential synergies. The interviews also show that recipients often receive These two mechanisms are well-suited to facilitate funding from multiple funders for related efforts. enhanced coordination of capacity-strengthening activities during inter-epidemic periods and more rapid Two existing mechanisms housed at WHO offer the planning and implementation of research during an potential to better coordinate donor and funder capac- outbreak. Bringing together the partners that focus on ity-building activities. The first is the ESSENCE program capacity-building more broadly through ESSENCE, with housed within TDR, which brings together funders for the R&D-focused coordinating function of the GCM, information-sharing and to increase coordination related offers promise for acting with urgency when new events to investments. One of its stated goals is to promote are detected and identified. Together with ESSENCE, it harmonization and optimization of resources (ESSENCE could serve as a powerful forum for information-sharing 2017). Organizationally, it is well placed, not only to and coordination, including about research and capac- share best practices, but to address the types of admin- ity-building for addressing outbreak pathogens. istrative issues and needs for harmonization raised by the research community. Two interesting models supporting better coordination are the Strategic Coherence of ODA-funded Research The second mechanism is the Global Coordination (SCOR) Board, launched by the UK “to better coordi- Mechanism of the R&D Blueprint, which was estab- nate government operations, eliminate duplication, lished in 2017 to improve coordination and to foster an and prevent waste” (Devex 2017); and the Research enabling environment for research and development Investments in Global Health (ResIn) study, housed COORDINATING INVESTMENTS IN CLINICAL RESEARCH 45 at the University of Southampton. Since 2015 ResIn As a distinctive aid vehicle, they add value by providing researchers report that their database currently includes coordinated financing and grant resources for individual over 1,000 funders and approximately 80,000 discrete countries, targeting development issues and providing projects. Staggeringly, the bulk of this research funding, global public goods (World Bank 2011). Two Trust Fund roughly 85 percent, is generated by approximately 10 mechanisms at the World Bank that are aligned with the funders, with the US NIH providing roughly half of the goals of strengthening clinical research capacity in low resources.24 income countries are the PEF and the CEPI. These are discussed below. RECOMMENDATION 12 By end 2019, ESSENCE, in collaboration with the PEF TRUST FUND Global Coordination Mechanism and reinforced with additional LMIC representation, should The Pandemic Emergency Financing Facility (PEF) articulate a mechanism that permits a thorough provides rapid surge financing in the initial stages of a review of current and planned investments in severe outbreak before it becomes a pandemic. The research capacity strengthening. This should funds are paid out through two windows: insurance and be done in consultation with major external cash. For the next three years, the insurance window will funders of clinical research (including those make available up to US$425 million for outbreaks of a involved in capacity strengthening of network, group of diseases likely to cause major epidemics. And laboratory, ethics, and regulatory capability). This it will pay out quickly, within days of the outbreak reach- collaborative mechanism should ensure synergy ing a defined level of severity, to the eligible-countries at country and regional levels, and streamline the and/or designated responding agency. Insurance premi- administrative burden experienced by institutions ums have already been paid for the next three years by dealing with multiple research funders. donor contributions, including by Japan and Germany. The PEF also has a US$61 million cash window it can Trust Fund Mechanisms use to make resources available for outbreaks that have not or will not meet the criteria of the insurance window. This window will be operational and available A Trust Fund is a financing arrangement established to countries in 2018, and can be used to finance the with contributions from one or more external devel- cost of response efforts during an outbreak, in line with opment partner(s), including multinational agencies, what is described in the country response plan (World non-governmental organizations, foundations, and Bank 2017e). With some forethought, the opportunity other private organizations, and in some cases, from the exists to consider how response-related research could World Bank, to support development-related activities. be ‘surged’ with the triple aim of managing an outbreak, The World Bank uses Trust Funds as a complement to strengthening research capacity, and ensuring that the IDA and IBRD financing to mobilize and direct conces- knowledge base for responding to subsequent out- sional resources to its strategic development priorities, breaks of the same pathogen is better. and as a vehicle for supporting partnerships with other development actors. Trust Funds may be country- specific, regional, or global in their geographical scope, CEPI TRUST FUND and can finance recipient activities (i.e., of governmen- tal, non-governmental or other external entities), World In hosting CEPI funds for development of vaccines and Bank activities, partnership activities, or a combination ensuring that vaccine candidates are advanced past the of these. Trust Funds play a pivotal role in strengthening Phase 2 stage of clinical development, the World Bank institutional and knowledge capabilities in previously is ideally positioned to coordinate its own initiatives with under-addressed areas like gender, climate change, and CEPI’s to strengthen country-level preparedness. The fragility, etc., and help expand the scope and scale of World Bank’s emergency response and lending instru- annual flagship funding programs (World Bank 2017d). ments strategically complement vaccine development and deployment objectives, and provide opportunities 24 Head, Michael (ResIn, University of Southampton). Personal for robust, sustainable, and effective action at all levels communication; email dated April 11, 2018. of development, deployment, and response. 46 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS The opportunity of accelerating vaccine development opportunities for other countries to utilize a resource against pathogens with pandemic potential is a criti- tracking tool. In addition to a custom tool—as chosen cal part of pandemic risk management, and actually by Rwanda—there are several tools and instruments conducting a pivotal, regulatory trial in an outbreak is that countries and development partners use to track part of that, as it enables a safe and effective vaccine expenditures and any of them can be readily adapted to be deployed as soon as is feasible. CEPI’s support to track flow of funds that support clinical research. for preparatory actions needed to test the vaccines it Two tools that deserve mention are National Health is developing, such as collaborating with others to help Accounts (NHA) and the Public Expenditure Tracking improve regulatory capacity in low-income countries system (PETS). and prepare countries and sites to conduct clinical trials could complement support provided through IDA as National Health Accounts provides a systematic frame- well as the PEF. Ultimately, the intent is that vaccines work for mapping expenditure levels in a country’s developed through CEPI support could help to ensure health system both for decision-making and account- that low-income countries rapidly and effectively have ability. It identifies all goods and services that relate to access to life-saving vaccines. health care and organizes the flow of funds to finance these goods and services in a sources-to-uses frame- RECOMMENDATION 13 work. Organized in ways compatible with the national income and product accounts, the NHA method orders By the end of 2018, the World Bank Group, health expenditures and use of funds in a format that working through the PEF and CEPI Trust Fund provides an analytical base for accountability and policy mechanisms, should establish a rapid financing development, and is flexible enough to adapt to the vehicle to support the priority outbreak-related evolving features of health systems. WHO has provided research agenda emerging from the WHO R&D expertise and technical advice to a very large number Blueprint, and to strengthen in-country capacity, of countries that have developed and institutionalized including the conduct of clinical research as part NHAs over time. of outbreak response. Public Expenditure Tracking Surveys (PETS) is a set of tools developed in 1996 to uncover points of leakage in the expenditure chain for particular programs or line National-Level Resource items. While PETS has become an umbrella term for wider budget tracking, traditional PETS involves the Tracking triangulation of budget and financial records from dif- ferent sources on the expenditure map. Implementing It is important that governments and development part- a PETS search tracks the flow of resources through the ners monitor and track all funding that supports clinical various layers of government bureaucracy, down to the research capacity-building activities within the country. service facilities to determine how much of the originally This essential element of housekeeping is important, allocated resources reach each level, and how long they not only for planning purposes, but also for regular, take to get there. It can help identify the location and systematic monitoring and evaluation. It further assists extent of impediments to resource flows (financial, staff, in accounting for the multiplicity of funders involved and equipment), and therefore evaluate the mechanisms in oversight of their performance of research and its and incentives responsible for leakages, capture and outcomes. deployment impediments. PETS became a popular tool for the World Bank and other international and multilat- The case of Rwanda, elaborated in Box 6.1, shows that eral organizations, due in part to its potential to identify it is not easy for governments to have ready access to hard-to-uncover problems with spending. It is axiomatic information and be fully aware of the range of research that funding allocated but not delivered cannot accom- or capacity-building funds that flow into their country. plish what it has been provided to do. This makes it challenging for countries to own the research and focus on country-specific priorities. Finally, The University of Southampton and the EDGE program are working with partner countries includ- Although the case of Rwanda is related to overall health ing the Philippines, Sri Lanka, Indonesia, Ethiopia spending flows, it depicts the characteristic issues and and Jamaica, and with the Asian eHealth Information COORDINATING INVESTMENTS IN CLINICAL RESEARCH 47 BOX 6.1 RWANDA’S EXPERIENCE WITH HEALTH RESOURCE TRACKING It is vital for effective policy-making that decision-makers have access to essential information on health expen- diture in a timely manner. Such information includes the share of health expenditure within an economy, the financial burden of health spending on households, the magnitude of external financing in health expenditure, and the share of spending on primary care. From these patterns of spending the policy-makers and funders are able to determine coverage and equity and the breadth and scope of services covered. They are normally two ways of determining such metrics either through routing and continuous resource tracking or through ad hoc periodic surveys, the most prevalent method in LMICs. By 2009, the Rwanda Health Sector was conducting seven separate periodic data collection surveys. These activities were placing an enormous burden on health care providers. Additionally, results from such surveys are retrospective and too late for planning cycles. They can also be full of errors in terms of misclassification, recall bias and completeness. The Ministry of Health teamed up with the Clinton Health Access Initiative to institutionalize data collection through the Resource Tracking Tool (RT) that harmonizes and standardizes data collection, making it routine, timely, complete and comprehensive. Because the RT was being populated annually and alongside implementa- tion, data became available and in sync with the annual planning cycle. The RT produced many benefits: including reducing costs, making information available on a timely basis, iden- tifying significant gaps in per capita spending between regions and discovering misalignment of resources with national priorities. The RT also allowed the government to develop three critical policies: Human Resources for Health Plan; District Health Strengthening System; and Division of Labor. Source: Sezibera, Richard. Personal communication, email dated April 3, 2018 Network (AeHIN), Canadian and Belgian Health to RECOMMENDATION 14 develop a resource tracking tool, with the goal of being able to monitor and capture all external funding, By June 2019, based on experience accumulated including private sector sponsored research or training. by countries, WHO and the World Bank Group However, a widely available tool suitable for use in a should develop a resource tracking tool enabling variety of LMICs would go a long way towards improving governments to monitor and track, at a national coordination and strengthening oversight and targeting level, all funding that supports clinical research of national health research priorities. capacity-building activities within the country and accounts for the multiplicity of funders involved. 48 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS CHAPTER 7 Monitoring Progress Development and strengthening of clinical research implementation of an “independent mechanism for capacity will depend on a coordinated series of actions reporting on the status of the world’s preparedness targeting the entire spectrum of the clinical research through (i) monitoring system-wide progress towards ecosystem. The recommendations in this report address increased health crises preparedness and response; a diverse set of requirements for a successful outcome, (ii) helping to ensure political visibility and account- including country ownership and strategic alignment ability for efforts at country, regional and global levels; of the research infrastructure and country health goals; and (iii) providing an alert to the Secretary-General and a climate and culture in which clinical research can other key stakeholders if the system is not functioning thrive; shared investment in the clinical research system adequately.” Located at WHO Headquarters in Geneva, between countries themselves and development part- GPMB is an independent, comprehensive, and inclusive ners, research funders and the private sector; a value of global mechanism that will monitor systems-wide prog- public-private partnerships; and coordination between ress towards increased preparedness and response funders, and between research institutions themselves. capacity for health crises, including outbreaks and emergencies with health consequences. Comprised Governance and coordination of the complex space of of political leaders, agency principals and world-class pandemic preparedness, including research, is chal- experts (in the process of being identified), the GPMB lenging. Therefore, the Task Force believes that a will play a critical role in ensuring system-wide account- broad-based, scientifically qualified, and autonomous ability for preparedness efforts at community, country, body is necessary to monitor and evaluate the imple- regional and global levels. It will provide an annual mentation of the recommendations contained in this overview of the state of the world’s preparedness, report. The Global Preparedness Monitoring Board and report on the adequacy of financing, monitor the (GPMB), announced at the 2018 IMF-World Bank Spring progress of relevant research and development, make Meetings, is emerging as the platform of choice for specific recommendations, and engage in communica- coordinating and reviewing progress on the implemen- tions and advocacy, as required. tation of various aspects of preparedness, including of the recommendations of this Task Force. RECOMMENDATION 15 The GPMB is a new initiative co-convened by WHO and Reviewing progress on the implementation of the World Bank Group in follow-up to the UN Secretary these recommendations should inform the agenda General’s Global Health Crises Task Force (2017), which of the Global Preparedness Monitoring Board. recommended in its final report the development and MONITORING PROGRESS 49 CHAPTER 8 Conclusion Infectious disease outbreaks are on the rise around countries to have in place a strong, robust and function- the world. Severe Acute Respiratory Syndrome (SARS), ing clinical research capacity that could be rapidly called MERS, avian influenza, Ebola, Zika, Lassa—these dis- upon in the heat of an outbreak. We are encouraged by eases hitherto restricted to the vocabulary of epidemi- the large number of ongoing initiatives that are con- ologists and medical professionals have now almost tributing directly and indirectly to strengthening clinical become household names. The number of new infec- research capacity in low-income countries. At the same tious diseases affecting humans has increased fourfold time, we are sobered by the many challenges that gov- in the past 60 years, and the number of outbreaks per ernments and development partners must overcome to year has more than tripled. Most are just a blip in the be ready the next time the world gets hit. news; but once in a while one or two slip through our containment defenses, and cause enormous harm. It is Our report outlines how low- and middle-income indeed only a matter of time before the next pandemic countries could secure the political commitment, raise hits us. necessary finances and leverage ongoing initiatives of development partners to enhance research and The world is better prepared than before, of that there is development capacity and strengthen outbreak pre- no doubt. But knowing that it is not fully and adequately paredness. Our 15 recommendations define an inte- prepared, we asked what must be done to ensure that grated framework for action by countries, development that the next inevitable outbreak does not turn into an partners, research funders, research organizations and uncontrollable pandemic. We focused our attention on the private sector, and suggests clear timelines. We are one gap—that of getting clinical research capacity in confident that if countries and all stakeholders adopt the low- and middle-income countries to a level at which they suggested framework, the world will see huge improve- can conduct or support needed clinical trials at the time ments in its ability, at the national level and globally, to of an epidemic. We realized right away that this is by no build clinical research capacity and strengthen universal means an easy task, for it requires resource-challenged health security. CONCLUSION 51 References Academy of Medical Sciences, UK. 2017. Strengthening clinical research capacity in low- and middle income. Accessed on April 1st, 2018 at 13:00hrs. URL: https://acmedsci.ac.uk/publications Addis Tax Initiative. 2015. ATI Monitoring Report 2015. Accessed on April 26th, 2018 at 10:00hrs. URL: https://www. addistaxinitiative.net/documents/Addis-Tax-Initiative_Monitoring-Report_2015_EN.pdf Aidam J, Sombié I. 2016. The West African Health Organization’s experience in improving the health research environment in the ECOWAS region. Health Res Policy Syst. 2016; 14: 30. Published online 2016 Apr 20. doi:10.1186/ s12961-016-0102-7 Coalition for Epidemic Preparedness Innovations (CEPI). 2018. CEPI’s Mission. CEPI’s Website. Accessed on May 1st, 2018 at 17:00hrs. URL: http://cepi.net/mission Council on Health Research for Development (COHRED). 2013. Where there is no lawyer: Guidance for fairer contract negotiation in collaborative research partnerships. Accessed on April 22nd, 2018 at 10:00hrs. URL: http://www. cohred.org/wp-content/uploads/2012/04/COHRED-guidancebookletv-web-ISBN.pdf Council on Health Research for Development (COHRED). 2018. Mapping of ethics review capacity in Sub-Saharan Africa (MARC). March 23rd, 2018 at 15:00hrs. URL: http://www.cohred.org/marc/ Devex. 2017. UK launches coordinating body for aid funded cross-government research. 26th September 2017. Devex Website. Accessed on March 23rd, 2018 at 11:00hrs. URL: https://www.devex.com/news/ uk-launches-coordinating-body-for-aid-funded-cross-government-research-91128 EDCTP. 2018. EDCTP-GSK Senior Fellowships for co-morbidities between poverty-related diseases (PRDs) and non- communicable diseases (NCDs)—Joint Call with GlaxoSmithKline (GSK). EDCTP Website. Accessed on April 22nd, 2018 at 10:00hrs. URL: http://www.edctp.org/call/edctp-gsk-senior-fellowships-co-morbidities-poverty-related- diseases-prds-non-communicable-diseases-ncds-joint-call-glaxosmithkline-gsk/ ESSENCE. 2017. ESSENCE Flyer. Accessed on April 26th, 2018 at 20:00hrs. URL: http://www.who.int/tdr/partnerships/ essence/Flyer_Essence_2017_web_version.pdf Fogarty International Center, NIH. 2009. Question and Answer with Dr. Jean William (Bill) Pape. Accessed on March 23rd, 2018 at 14:00hrs. URL: https://www.fic.nih.gov/News/GlobalHealthMatters/Pages/0409_haiti-pape.aspx Fogarty International Center, NIH. 2012. Celebrating 25 years of research training to combat HIV/AIDS. Accessed on March 23rd, 2018 at 13:00hrs. URL: https://www.fic.nih.gov/News/GlobalHealthMatters/july-august-2012/Pages/hiv- aids-aitrp-program-anniversary.aspx Fogarty International Center, NIH. 2017. Fogarty-supported Chagas, dengue researchers redirect efforts to tackle Zika virus. Global Health Matters Newsletter, May / June 2017 | Volume 16, Issue 3. Accessed on March 22nd, 2018 at 11:00hrs. URL: https://www.fic.nih.gov/News/GlobalHealthMatters/may-june-2017/Pages/chagas-dengue- researchers-help-tackle-zika.aspx Franzen SRP, Chandler C, Siribaddana S, Atashili J, Angus B, Lang T. 2017. Strategies for developing sustainable health research capacity in low and middle-income countries: a prospective, qualitative study investigating the barriers and enablers to locally led clinical trial conduct in Ethiopia, Cameroon and Sri Lanka. BMJ Open 2017;7: e017246. doi: 10.1136/bmjopen-2017-017246 52 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS Global Health Technologies Coalition. 2017. R&D Facts. GHTC Website. Accessed on March 21st, 2018 at 11:00hrs. URL: http://www.ghtcoalition.org/pdf/GHTC-RD-Facts-Dec-2017.pdf Hartsfield D, Moulton A, McKie K. 2007. A Review of Model Public Health Laws. American Journal of Public Health. April; 97(Suppl 1): S56–S61. Accessed on April 5th, 2018 at 14:00hrs. URL: https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC1854995/ Harvard Global Health Initiative-London School of Hygiene and Tropical Medicine. 2015. Will Ebola change the game? Ten essential reforms before the next pandemic. The report of the Harvard-LSHTM Independent Panel on the Global Response to Ebola. The Lancet. Accessed on March 20th, 2018 at 12:00hrs. URL: http://dx.doi.org/10.1016/ S0140-6736(15)00946-0 Henao-Restrepo AM, Camacho A, Longini I, Watson C, Edmunds J, Egger M, Carroll M, Dean N, Diatta I, Doumbia M, Draguez B, Duraffour S, Enwere G, Grais R, Gunther S, Gsell PS, Hossmann S, Watle SV, Kondé MK, Kéïta S, Kone S, Kuisma E, Levine M, Mandal S, Mauget T, Norheim G, Riveros X, Soumah A, Trelle S, Vicari A, Røttingen JA, Kieny MP. 2017. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: Final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!). The Lancet. Volume 389, No. 10068, p505–518, 4 February 2017. Accessed on May 1st, 2018 at 15:00hrs. URL: https://www.thelancet.com/ journals/lancet/article/PIIS0140-6736(16)32621-6/abstract?code=lancet-site icddr,b. 2018. Achievements. About Us Webpage. iccdr,b Website. Accessed on April 5th, 2018 at 13:00hrs. URL: http:// www.icddrb.org/about-us/achievements IFPMA. 2018. EDCTP-TDR Clinical Research Development Fellowships. Health Partnership Directory. Sanofi Website. Accessed on March 22nd, 2018 at 13:00hrs. URL: http://partnerships.ifpma.org/partnership/ edctp-tdr-clinical-research-development-fellowships. International Working Group on Financing Preparedness (IWG). 2017. From Panic and Neglect to Investing in Health Security. Financing Pandemic Preparedness at the National Level. World Bank Publication. Accessed on March 21st, 2018 at 13:00hrs. URL: http://documents.worldbank.org/curated/en/979591495652724770/ From-panic-and-neglect-to-investing-in-health-security-financing-pandemic-preparedness-at-a-national-level Kasule M, Wassenaar D, IJsselmuiden C, Mokgatla B. 2016. Silent voices: Current and future roles of African Research Ethics Committee administrators. IRB: Ethics & Human Research 38(1):13–19. Kolympiris C, Kalaitzandonakes N, Miller D. 2014. Public funds and local biotechnology firm creation. Research Policy. Volume 34, Issue 1, February 2014, Pages 121-137. Accessed on May 2nd, 2018 at 14:00hrs. URL: https://www. sciencedirect.com/science/article/pii/S0048733313001285 Lurie N, Manolio T, Patterson A, Collins F, Frieden T. 2013. Research as a Part of Public Health Emergency Response. March 28th, 2013. New England Journal of Medicine. 2013; 368:1251-1255. doi: 10.1056/NEJMsb1209510. Accessed on April 26th, 2018 at 9:00hrs. URL: http://www.nejm.org/doi/full/10.1056/NEJMsb1209510 Mokgatla B, Bahati P, IJsselmuiden C. 2017. Enhancing the Efficiency and Quality of African Research Ethics Review Process—Through an Automated Review Process. Journal of Aids and Clinical Research. Mokgatla et al., J AIDS Clin Res 2017, 8:2. doi: 10.4172/2155-6113.1000658 Motti E. 2008. Doing Clinical Research in South America. The Monitor. 63-67. Accessed on May 1st, 2018 at 18:00hrs. URL: https://www.researchgate.net/publication/256375404_Doing_Clinical_Research_in_South_America National Academies of Science, Engineering and Medicine (NASEM). 2017. Integrating Clinical Research into Epidemic Response: The Ebola Experience. Accessed on March 19th, 2018 at 21:00hrs. URL: https://www.nap.edu/ catalog/24739/integrating-clinical-research-into-epidemic-response-the-ebola-experience National Cancer Institute. 2017. NCI Dictionary of Cancer Terms. NCI Website. Accessed on March 20th, 2018 at 10:00hrs. URL: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/clinical-research National Institute of Health (NIH). 2018. Clinical Trials.gov. National Library of Medicine. Accessed on March 20th, 2018 at 15:00hrs. URL: https://clinicaltrials.gov/ct2/results?term=Mother-to child+transmission+OR+MTCT&cond=Hiv REFERENCES 53 Ondoa P, Datema T, Keita-Sow MS, Ndihokubwayo JB, Isadore J, Oskam L, Nkengasong J, Lewis K. 2016. A new matrix for scoring the functionality of national laboratory networks in Africa: introducing the LABNET scorecard. African Journal of Laboratory Medicine. Vol 5, No. 3. Accessed on April 5th, 2018 at 14:00hrs. URL: https://ajlmonline.org/ index.php/ajlm/article/view/498/712 Onyango P. 2016. The Role of Local Contract Research Organisations in Building GCP-Compliant Clinical Research in Poverty-related Diseases in Africa: a Case of ClinWin Research Services. BMJ Global Health. Accessed on April 22nd, 2018 at 10:00hrs. URL: http://gh.bmj.com/content/2/Suppl_2/A52.2 Pan American Health Organization (PAHO). 2010. PAHO’s Policy on Research for Health. Accessed on April 27th, 2018 at 11:00hrs. URL: http://www1.paho.org/hq/dmdocuments/2010/RESEARCHpolicyBKLETeng_web.pdf Pan American Health Organization (PAHO). 2017. Strengthening national regulatory systems: the development of the Global Benchmarking Tool. Washington, DC, December 15, 2017 (PAHO/WHO). PAHO Website. Accessed on May 4th, 2018 at 12:00hrs. URL: http://www.paho.org/hq/index.php?option=com_content&view=article&id=14030&Item id=39594&lang=fr Phommasack B, Jiraphongsa C, Ko Oo M, Bond K, Phaholyothin N, Suphanchaimat R, Ungchusak K, Macfarlane S. 2013. Mekong Basin Disease Surveillance (MBDS): A Trust-Based Network. Emerging Health Threats Journal. 2013; 6:10.3402/ehtj.v6i0.19944. doi:10.3402/ehtj. v6i0.19944. Accessed on April 27th, 2018 at 13:00hrs. URL: https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC3557908/ Research Fairness Initiative. 2018. Origin of the RFI. COHRED Website. Accessed on March 23rd, 2018 at 13:00hrs. URL: http://rfi.cohred.org/origin-of-the-rfi/ Science Business. 2017. Why fund research? A guide to why EU-funded research and innovation matters. Published by Science Business. Accessed on March 23rd, 2018 at 13:00hrs. URL: https://sciencebusiness.net/system/files/ reports/Why-fund-research_.pdf Sombié I, Aidam J, Konaté B, Somé T, Kambou SS. 2013. The state of the research for health environment in the ministries of health of the Economic Community of the West African States (ECOWAS). Health Research Policy and Systems 11(1):35. The Global Health Network (TGHN). 2018a. About This Site. TGHN Website. Accessed on March 22nd, 2018 at 11:00hrs. URL: https://tghn.org/about/ The Global Health Network (TGHN). 2018b. TDR-TGHN Competency Wheel. Global Health Trials. TGHN Website. Accessed on March 23rd, 2018 at 14:00hrs. URL: https://globalhealthtrials.tghn.org/competencywheel/ The Lancet. 2013. Profile: The icddr,b—saving lives in Bangladesh and beyond. World Report. The Lancet, Vol 381. Accessed on March 20th, 2018 at 11:00hrs. URL: http://www.thelancet.com/pdfs/journals/lancet/PIIS0140- 6736(13)60870-3.pdf Toole A. 2007. Does Public Scientific Research Complement Private Investment in Research and Development in the Pharmaceutical Industry? The Journal of Law and Economics. Volume 50, Number 1, February 2007. Accessed on May 2nd, 2018 at 14:000hrs. URL: https://www.journals.uchicago.edu/doi/full/10.1086/508314 TransCelerate. 2017. TransCelerate BioPharma Grows Industry Collaboration. Business Wire, September 14, 2017. Accessed on April 27th, 2018, at 12:00hrs. URL: https://www.businesswire.com/news/home/20170914005409/en Trotter C, Lingani C, Fernandez K, Cooper L, Bita A, Tevi-Benissan C, Ronveaux O, Préziosi M-P, Stuart J. 2017. Impact of MenAfriVac in nine countries of the African meningitis belt, 2010-2015: An analysis of surveillance data. The Lancet, Infectious Disease. Volume 17. No. 8, p867-782, August 2017. Accessed on May 3rd, 2018 at 11:00hrs. URL: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30301-8/fulltext?code=lancet-site UNESCO Institute for Statistics. 2018. UIS Statistical Database. Accessed on April 26th, 2018 at 9:00hrs. URL: http:// data/uis.unesco.org/ 54 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS United for Medical Research. 2018. NIH’s Role in Sustaining the U.S. Economy. 2018 Update. Accessed on May 2nd, 2018 at 13:00hrs. URL: http://www.unitedformedicalresearch.com/wp-content/uploads/2018/02/NIHs-Role-in- Sustaining-the-U.S.-Economy-2018-Update-FINAL.pdf United Nations High-level Panel on the Global Response to Health Crises. 2016. Protecting Humanity from Future Health Crises. Advanced Unedited Copy, January 2016. Accessed on March 20th, 2018 at 12:00hrs. URL: http:// www.un.org/News/dh/infocus/HLP/2016-02-05_Final_Report_Global_Response_to_Health_Crises.pdf US Food and Drug Administration (FDA). 2018. What Are the Different Types of Clinical Research? FDA Website. Accessed on March 21st, 2018 at 10:00hrs. URL: https://www.fda.gov/ForPatients/ClinicalTrials/Types/default.htm USAID. 2018. Domestic Resource Mobilization. Economic Policy and Analysis. USAID Website. Accessed on April 26th, 2018 at 9:00hrs. URL: https://www.usaid.gov/what-we-do/economic-growth-and-trade/ domestic-resource-mobilization Wellcome Trust. 2018. Medical Research: What’s it worth? A briefing on the economic benefits of musculoskeletal disease research in the UK. Accessed on March 21st, 2018 at 11:00hrs. URL: https://wellcome.ac.uk/sites/default/ files/whats-it-worth-musculoskeletal-disease-research-januar-2018.pdf Williams S, Fitzner J, Merianos A, Mounts A. 2013. The challenges of global case reporting during pandemic A(H1N1) 2009. Bulletin of the World Health Organization. Accessed on April 26th, 2018 at 9:00hrs. URL: http://www.who.int/ bulletin/volumes/92/1/12-116723/en/ World Bank. 2010a. Innovative Finance for Development Solutions. Initiatives of the World Bank Group. Accessed on March 31st, 2018 at 18:00hrs. URL: http://siteresources.worldbank.org/CFPEXT/Resources/IF-for-Development- Solutions.pdf World Bank. 2010b. Designing and Implementing Agricultural Innovation Funds. Lessons from Competitive Research and Matching Grant Projects. World Bank Publication. Accessed on April 1st, 2018 at 12:00hrs. URL: http:// documents.worldbank.org/curated/en/715661468163167577/pdf/548570ESW0P1220nnovationFunds100web.pdf World Bank. 2011. The Effectiveness of Trust Fund Support for Development. Independent Evaluation Group (IEG) Report. Accessed on April 22nd, 2018 at 10:00hrs. URL: http://ieg.worldbankgroup.org/sites/default/files/Data/ reports/chapters/tf_chap3.pdf World Bank. 2013. Strengthening Support for Regional Projects Background Note. Washington, D.C. World Bank Group. Accessed on March 31st, 2018 at 18:00hrs. URL: http://documents.worldbank.org/curated/ en/833511468158982661/pdf/818030BR0Box370official0use0only090.pdf World Bank. 2015a. IDA17 mid-term review: enhancing IDA's financial support in IDA17 - proposal for scale-up facility (English). IDA17 mid-term review. Washington, D.C: World Bank Group. Accessed on March 31st, 2018 at 17:00hrs. URL: http://documents.worldbank.org/curated/en/703621467999376919/ IDA17-mid-term-review-enhancing-IDAs-financial-support-in-IDA17-proposal-for-scale-up-facility World Bank. 2015b. IDA17 Mid-Term Review: Opening Session. World Bank Website. Accessed on March 31st, 2018 at 11:00hrs. URL: http://www.worldbank.org/en/news/speech/2015/11/18/ida17-mid-term-review-opening-session World Bank. 2015c. Africa - East Africa Public Health Laboratory Networking project: additional financing (English). Washington, D.C.: World Bank Group. Accessed on April 27th, 2018 at 17:00hrs. URL: http://documents.worldbank.org/curated/en/282291467991024300/ Africa-East-Africa-Public-Health-Laboratory-Networking- project-additional-financing World Bank. 2016. Domestic Resource Mobilization Brief. World Bank Website. Accessed on March 31st, 2018 at 12:00hrs. URL: http://www.worldbank.org/en/topic/governance/brief/domestic-resource-mobilization World Bank. 2017a. Financing the ‘last mile’ in global polio eradication. World Bank Blogs. Accessed on April 1st, 2018 at 16:00hrs. URL: https://blogs.worldbank.org/health/financing-last-mile-global-polio-eradication REFERENCES 55 World Bank. 2017b. Report from the Executive Directors of the International Development Association to the Board of Governors: Additions to IDA Resources - Eighteenth Replenishment (English). Washington, D.C.: World Bank Group. Accessed on March 31st, 2018 at 18:00hrs. URL: http://documents.worldbank.org/curated/ en/348661486654455091/Report-from-the-Executive-Directors-of-the-International-Development-Association-to- the-Board-of-Governors-Additions-to-IDA-Resources-Eighteenth-Replenishment World Bank. 2017c. Appraisal Project Information Document-Integrated Safeguards Data Sheet - Innovate in India for Inclusiveness - P156241 (English). Washington, D.C.: World Bank Group. Accessed on April 27th, 2018 at 17:00hrs. URL: http://documents.worldbank.org/curated/en/118461489415805544/Appraisal-Project-Information-Document- Integrated-Safeguards-Data-Sheet-Innovate-in-India-for-Inclusiveness-P156241 World Bank. 2017d. Trust Fund Annual Report. Accessed on April 22nd, 2018. URL: https://siteresources.worldbank.org/ CFPEXT/Resources/299947-1274110249410/CFP_TFAR_AR13_High.pdf World Bank 2017e. Pandemic Emergency Financing Facility (PEF) Operational Brief for Eligible Countries December 2017. Accessed on April 22nd, 2018 at 10:00hrs. URL: http://pubdocs.worldbank.org/en/168391509719305386/PEF- Operations-Manual-September-13-2017.pdf World Bank. 2018a. Research and development expenditure (% of GDP). World Development Indicators. World Bank Data. Accessed on April 26th, 2018 at 9:00hrs. URL: https://data.worldbank.org/indicator/GB.XPD.RSDV. GD.ZS?view=chart World Bank. 2018b. What is IDA? World Bank Website. Accessed on April 5th, 2018 at 14:00hrs. URL: http://ida. worldbank.org/about/what-ida World Bank. 2018c. GFF’s Contribution to Domestic Resource Mobilization for Health and Nutrition. Fact Sheet. Global Financing Facility Website. Accessed on March 31st, 2018 at 12:00hrs. URL: https://www.globalfinancingfacility.org/ sites/gff_new/files/documents/DRM_EN_Web.pdf World Health Organization (WHO). 2008. International Health Regulations (2005), Second Edition. WHO Publication. Accessed on March 21st, 2018 at 10:00hrs. URL: http://apps.who.int/iris/bitstream/10665/43883/1/9789241580410_ eng.pdf World Health Organization (WHO). 2011. The Abuja Declaration: Ten Years On. Accessed on April 26th, 2018 at 9:00hrs. URL: http://www.who.int/healthsystems/publications/abuja_report_aug_2011.pdf?ua=1 World Health Organization (WHO). 2016. Joint External Evaluation Tool. IHR (2005) Monitoring and Evaluation Framework. Accessed on May 4th, 2018 at 12:00hrs. URL: http://apps.who.int/iris/bitstream/ handle/10665/204368/9789241510172_eng.pdf;jsessionid=F19EEAF19187ADC91E6E067235FFA048?sequence=1 World Health Organization (WHO). 2017. Gross domestic R&D expenditure on health (health GERD) as a % of gross domestic product (GDP). Global Observatory on Health R&D. Accessed on April 26th, 2018 at 9:00hrs. URL: http:// www.who.int/research-observatory/indicators/gerd_gdp/en/ World Health Organization (WHO). 2018a. WHO Global Observatory on Health R&D. WHO Website. Accessed on May 3rd, 2018 at 16:00hrs. URL: http://www.who.int/research-observatory/en/ World Health Organization (WHO). 2018b. Distribution of R&D funding flows for neglected diseases (G-FINDER), by country, funder, and recipient organizations. WHO Global Observatory on Health R&D. Accessed on May 4th, 2018 at 20:00hrs. URL: http://www.who.int/research-observatory/monitoring/inputs/neglected_diseases_country/en/ World Health Organization (WHO ICTRP). 2018. Welcome to the WHO ICTRP. Accessed on April 22nd, 2018 at 10:00hrs. URL: http://www.who.int/ictrp/en/ 56 MONEY & MICROBES: STRENGTHENING CLINICAL RESEARCH CAPACITY TO PREVENT EPIDEMICS INTERNATIONAL VACCINES TASK FORCE 27231