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Anna Nicholson, Rebecca A. English, Rita S. Guenther, and Anne B. Claiborne, Rapporteurs Forum on Drug Discovery, Development, and Translation Board on Health Sciences Policy

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THE NATIONAL ACADEMIES PRESS  500 Fifth Street, NW  Washington, DC 20001 NOTICE: The workshop that is the subject of this workshop summary was approved by the Governing Board of the National Research Council, whose mem- bers are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. This activity was supported by contracts between the National Academy of Sciences and Department of Health and Human Services (Contract Nos. N01-OD-4-2139 and HHSF223001003T), Abbott Pharmaceuticals, American Diabetes Association, American Society for Microbiology, Amgen Inc., Association of American Medical Colleges, Bristol-Myers Squibb, Burroughs Wellcome Fund, Celtic Therapeutics, LLLP, Critical Path Institute, Doris Duke Charitable Foundation, Eli Lilly and Com- pany, Eli Lilly & Co. Foundation, FasterCures, Foundation for the NIH, Friends of Cancer Research, GlaxoSmithKline, Janssen Research & Development, LLC, March of Dimes Foundation, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, and Pfizer Inc. The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for the activity. International Standard Book Number-13:  978-0-309-26595-9 International Standard Book Number-10:  0-309-26595-9 Additional copies of this workshop summary are available for sale from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2013 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2013. Developing and Strengthen- ing the Global Supply Chain for Second-Line Drugs for Multidrug-Resistant Tuber- culosis: Workshop Summary. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Acad- emy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Insti- tute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sci- ences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Coun- cil is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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PLANNING COMMITTEE FOR THE WORKSHOP ON GLOBAL DRUG SUPPLY CHAIN FOR SECOND- LINE ANTI-TUBERCULOSIS DRUGS1 BARRY R. BLOOM (Co-Chair), Harvard School of Public Health, Boston, MA GAIL H. CASSELL (Co-Chair), Harvard Medical School (Visiting), Carmel, IN RIFAT ATUN, Imperial College Business School, Imperial College London, England PETER CEGIELSKI, U.S. Centers for Disease Control and Prevention, Atlanta, GA LUCICA DITIU, Stop TB Partnership, World Health Organization, Geneva, Switzerland GARY L. FILERMAN, Atlas Health Foundation, McLean, VA HELLEN GELBAND, Center for Disease Dynamics, Economics & Policy, Inc., Washington, DC MARK J. GOLDBERGER, Abbott Pharmaceuticals, Rockville, MD DOUGLAS L. KEENE, Management Sciences for Health, Arlington, VA SALMAAN KESHAVJEE, Harvard Medical School, Boston, MA MONTSERRAT MEIRO-LORENZO, World Bank, Washington, DC ELIZABETH (BETSY) MYERS, Doris Duke Charitable Foundation, New York, NY PAUL P. NUNN,2 World Health Organization, Geneva, Switzerland ARIEL PABLOS-MÉNDEZ, United States Agency for International Development, Washington, DC TRACY J. SIMS, Eli Lilly & Co. Foundation, Indianapolis, IN BRENDA WANING, UNITAID, World Health Organization, Geneva, Switzerland PRASHANT YADAV, University of Michigan, Ann Arbor IOM Staff ANNE B. CLAIBORNE, Forum Director RITA S. GUENTHER, Program Officer REBECCA A. ENGLISH, Associate Program Officer ELIZABETH F. C. TYSON, Research Associate ANDREW M. POPE, Director, Board on Health Sciences Policy ROBIN GUYSE, Senior Program Assistant 1  Institute of Medicine planning committees are solely responsible for organizing the work- shop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. 2  Paul Nunn was with the World Health Organization during the planning of the workshop. v

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FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1 JEFFREY M. DRAZEN (Co-Chair), New England Journal of Medicine, Boston, MA STEVEN K. GALSON (Co-Chair), Amgen Inc., Thousand Oaks, CA MARGARET ANDERSON, FasterCures, Washington, DC HUGH AUCHINCLOSS, National Institute of Allergy and Infectious Diseases, Bethesda, MD CHRISTOPHER AUSTIN, National Center for Advancing Translational Sciences, Bethesda, MD LESLIE Z. BENET, University of California, San Francisco ANN BONHAM, Association of American Medical Colleges, Washington, DC LINDA BRADY, National Institute of Mental Health, Bethesda, MD ROBERT CALIFF, Duke University Medical Center, Durham, NC C. THOMAS CASKEY, Baylor College of Medicine, Houston, TX GAIL H. CASSELL, Harvard Medical School (Visiting), Carmel, IN PETER B. CORR, Celtic Therapeutics, LLLP, New York, NY ANDREW M. DAHLEM, Eli Lilly and Company, Indianapolis, IN TAMARA DARSOW, American Diabetes Association, Alexandria, VA JAMES H. DOROSHOW, National Cancer Institute, Bethesda, MD GARY L. FILERMAN, Atlas Health Foundation, McLean, VA GARRET A. FITZGERALD, University of Pennsylvania School of Medicine, Philadelphia MARK J. GOLDBERGER, Abbott Pharmaceuticals, Rockville, MD HARRY B. GREENBERG, Stanford University School of Medicine, CA STEPHEN GROFT, National Center for Advancing Translational Sciences, Bethesda, MD LYNN HUDSON, Critical Path Institute, Tucson, AZ MICHAEL KATZ, March of Dimes Foundation, White Plains, NY PETRA KAUFMANN, National Institute of Neurological Disorders and Stroke, Bethesda, MD JACK D. KEENE, Duke University Medical Center, Durham, NC RONALD L. KRALL, University of Pennsylvania Center for Bioethics, Steamboat Springs, CO FREDA LEWIS-HALL, Pfizer Inc., New York, NY MARK B. McCLELLAN, The Brookings Institution, Washington, DC CAROL MIMURA, University of California, Berkeley 1  Institute of Medicine forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. vii

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ELIZABETH (BETSY) MYERS, Doris Duke Charitable Foundation, New York, NY JOHN ORLOFF, Novartis Pharmaceuticals Corporation, East Hanover, NJ AMY PATTERSON, National Institutes of Health, Bethesda, MD MICHAEL ROSENBLATT, Merck & Co., Inc., Whitehouse Station, NJ JANET SHOEMAKER, American Society for Microbiology, Washington, DC ELLEN SIGAL, Friends of Cancer Research, Washington, DC ELLIOTT SIGAL, Bristol-Myers Squibb, Princeton, NJ ELLEN R. STRAHLMAN, GlaxoSmithKline, Research Triangle Park, NC NANCY SUNG, Burroughs Wellcome Fund, Research Triangle Park, NC JANET TOBIAS, Ikana Media and Mount Sinai School of Medicine, New York, NY JOANNE WALDSTREICHER, Janssen Research & Development, LLC, Raritan, NJ JANET WOODCOCK, Food and Drug Administration, White Oak, MD IOM Staff ANNE B. CLAIBORNE, Forum Director RITA S. GUENTHER, Program Officer REBECCA A. ENGLISH, Associate Program Officer ELIZABETH F. C. TYSON, Research Associate ANDREW M. POPE, Director, Board on Health Sciences Policy ROBIN GUYSE, Senior Program Assistant viii

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Reviewers This workshop summary has been reviewed in draft form by individu- als chosen for their diverse perspectives and technical expertise, in accor- dance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published workshop summary as sound as possible and to ensure that the workshop summary meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We wish to thank the following individuals for their review of this workshop summary: Colin Boyle, University of California, San Francisco, Global Health Sciences Jennifer Furin, Case Western Reserve University School of Medicine Robert Matiru, UNITAID Owen Robinson, Partners In Health Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the workshop summary before its release. The review of this workshop summary was overseen by Enriqueta C. Bond, QE Philanthropic Advisors. Appointed by the Institute of Medicine, she was responsible for making certain that an independent examination of this workshop summary was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this work- shop summary rests entirely with the rapporteurs and the institution. ix

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Contents ACRONYMS xv 1 INTRODUCTION 1 Background and History of the Current GLC Mechanism, 4 Principles of Drug Supply Chains, 12 Barriers, Challenges, and Needs, 18 2 LOGISTICS, SUPPLY, AND DEMAND 49 Quality Assurance, 49 Forecasting and Information Management, 56 Drug Shortages, 62 3 FINANCING OF MDR TB SLDs 67 Funding of the MDR TB Supply Chain, 67 Models for Financing and Supply, 76 4 INNOVATIVE SUGGESTIONS AND POTENTIAL SOLUTIONS 93 Mechanisms of Purchase and Supply, 93 Logistics, Supply, and Demand, 99 Innovative Financing, 103 Reflecting on the Way Forward, 106 REFERENCES 111 xi

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xii CONTENTS APPENDIXES A WORKSHOP AGENDA 115 B PARTICIPANT BIOGRAPHIES 129 C REGISTERED WORKSHOP ATTENDEES 149

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Table, Figures, and Boxes TABLE 1-1 SLD Supply Chain Stakeholders: Responsibilities, Interests, and Barriers, 26 FIGURES 1-1 Number of GLC pilot projects implemented around the world between 2000 and 2009, 10 1-2 Creation of a centralized node of control for the GLC-approved SLD supply chain, 11 1-3 Existing supply chain for SLDs, 14 1-4 A “buffer” supply of SLDs smoothens the lumpiness of demand, 16 1-5 Shifting the push-pull boundary in the SLD supply chain, 17 1-6 The current structure of supply and demand works against the goals of affordable and sustainable access, 19 1-7 Key barriers to improving SLD access: high prices and limited availability of QA MDR TB drugs, 20 1-8 The GLC initiative flow through cycle, 21 1-9 Of the estimated 5 million MDR TB cases that occurred between 2000 and 2009, only 0.2–0.5 percent were treated in GLC- approved programs, 23 1-10 Push and pull mechanisms for adopting innovations for MDR TB, 29 xiii

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xiv TABLE, FIGURES, AND BOXES 1-11 Regulatory steps from drug development to delivery, 32 1-12 GDF procurement cycle, 34 2-1 WHO PQ second-line medicines as of the July 2012, IOM workshop, 51 3-1 Global TB drug pipeline, as of June 18, 2012, 73 3-2 Global Fund product classification framework proposed by Results for Development Institute (R4D), 83 3-3 Price benefits of splitting tenders, 86 3-4 SLDAII vision and goals, 88 3-5 Owner/participant teams for the top five MDR TB Innovation Summit ideas, 91 BOXES 1-1 Key Drug Supply Chain Themes from Previous IOM Forum Publications, 4 1-2 Statement of Task for the Workshop, 6 1-3 Cycloserine Case Study, 18 1-4 Country Approaches to the MDR TB SLD Supply Chain, 43 1-5 Suggested Ways Forward, 46 2-1 Considering Two Key Priorities in the Donor-Funded MDR TB Market: QA and Treatment Access, 58 3-1 Related Efforts in SLD Supply Chain and Access, 88 4-1 Suggestions and Low-Hanging Fruit, 109

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Acronyms ACT artemisinin-combination therapy AIDS acquired immune deficiency syndrome AMC advance market commitment AMFm Affordable Medicines Facility-malaria AMRH African Medicines Regulatory Harmonization APC advance purchase commitment API active pharmaceutical ingredient ARV antiretroviral BMGF Bill & Melinda Gates Foundation BRICS Brazil, Russia, India, China, and South Africa CDC U.S. Centers for Disease Control and Prevention CHAI Clinton Health Access Initiative DOT directly observed treatment DOTS Directly Observed Treatment-Short course DR TB drug-resistant tuberculosis DST drug susceptibility testing EMA European Medicines Agency EMR electronic medical record FDA U.S. Food and Drug Administration FLD first-line anti-TB drug xv

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xvi ACRONYMS FPP finished pharmaceutical product GDF Global Drug Facility GHC Global Health Committee GLC Green Light Committee HCP health care professional HIV human immunodeficiency virus ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IFFIm International Finance Facility for Immunization IOM Institute of Medicine IQA internationally quality-assured MDR TB multidrug-resistant tuberculosis MSF Médecins Sans Frontières MSH Management Sciences for Health M.tb. Mycobacterium tuberculosis NGO nongovernmental organization NRA national regulatory authority NTP national TB control programme OpenMRS Open Medical Record System PAS 4-aminosalicylic acid PEPFAR U.S. President’s Emergency Plan for AIDS Relief PMDT programmatic management of drug-resistant tuberculosis PQ prequalified (by WHO) PRI Program-Related Investment QA quality-assured/quality assurance QC quality control SCM supply chain management SCMS Supply Chain Management System (PEPFAR/USAID) SLD second-line anti-TB drug SLDAII Second-Line Drug Access Improvement Initiative SMS short message service SRA stringent regulatory authority

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ACRONYMS xvii TB tuberculosis UNICEF United Nations Children’s Fund USAID United States Agency for International Development USP U.S. Pharmacopeial Convention WHO World Health Organization WHO PQ WHO prequalification WHO PQP WHO Prequalification of Medicines Programme XDR TB extensively drug-resistant tuberculosis

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