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Committee on Understanding the Global Public Health Implications of Substandard, Falsified, and Counterfeit Medical Products Board on Global Health Gillian J. Buckley and Lawrence O. Gostin, Editors
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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Govern- ing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineer- ing, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropri- ate balance. This study was supported by Contract No. HHSF22301024T, TO #25 between the National Academy of Sciences and the U.S. Food and Drug Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-26939-1 International Standard Book Number-10: 0-309-26939-3 Additional copies of this report are available 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 ad- opted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Cover image from 1900 calendar produced by the Antikamnia (“Opposed to Pain”) Chemical Company of St. Louis, Missouri (http://unitproj.library.ucla.edu/biomed/ his/antikamnia/antikamnia.html). Suggested citation: IOM (Institute of Medicine). 2013. Countering the problem of falsified and substandard drugs. 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 engi neers. 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 Council 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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COMMITTEE ON UNDERSTANDING THE GLOBAL PUBLIC HEALTH IMPLICATIONS OF SUBSTANDARD, FALSIFIED, AND COUNTERFEIT MEDICAL PRODUCTS LAWRENCE O. GOSTIN (Chair), the Linda and Timothy O’Neill Professor of Global Health Law; Director, WHO Collaborating Center on Public Health Law and Human Rights, Georgetown University Law Center, Washington, DC DANIEL CARPENTER, Allie S. Freed Professor of Government, Harvard University, Cambridge, MA HANS HOGERZEIL, Professor of Global Health, Groningen University, The Netherlands; Former Director, Essential Medicines and Pharmaceutical Policies, World Health Organization, Geneva, Switzerland THOMAS P. LAYLOFF, Senior Quality Assurance Director, Supply Chain Management System, Arlington, VA ANN MARIE KIMBALL, Senior Program Officer of Epidemiology and Surveillance, Bill & Melinda Gates Foundation, Seattle, WA PATRICK LUKULAY, Director, Promoting the Quality of Medicines Program, U.S. Pharmacopeia, Rockville, MD MARGARETH NDOMONDO-SIGONDA, Pharmaceutical Coordinator, New Partnership for Africa’s Development, Pretoria, South Africa ARTI K. RAI, Elvin R. Latty Professor, Duke University School of Law, Durham, NC MARCO ANTONIO STEPHANO, Professor, University of São Paulo, School of Pharmaceutical Sciences, Brazil JOHN THERIAULT, Former Vice President of Security, Apple Inc., Cupertino, CA; Former Vice President of Security, Pfizer, Inc., New York, NY MARY E. WILSON, Adjunct Associate Professor of Global Health and Population, Harvard University School of Public Health, Boston, MA PRASHANT YADAV, Director, Healthcare Research, William Davidson Institute, University of Michigan, Ann Arbor IOM Staff GILLIAN BUCKLEY, Program Officer, Study Director KENISHA PETERS, Research Associate MEGAN GINIVAN, Research Assistant KATHLEEN BURNS, Intern JULIE WILTSHIRE, Financial Associate PATRICK W. KELLEY, Director, Boards on Global Health and African Science Academy Development v
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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance 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 report as sound as possible and to ensure that the report 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 deliberative process. We wish to thank the following individuals for their review of this report: Georges Benjamin, American Public Health Association Martha Brumfield, Martha A. Brumfield, LLC Stephen Byrn, Purdue University Philip Chen, formerly of Georgetown University Law Center Charles Clift, Chatham House Michael Greene, Centers for Disease Control and Prevention William Greene, St. Jude Children’s Research Hospital Noel Greis, University of North Carolina at Chapel Hill Harparkash Kaur, London School of Hygiene and Tropical Medicine Thomas Kubic, Pharmaceutical Security Institute Joshua Sharfstein, Maryland Department of Health & Mental Hygiene Marv Shepherd, University of Texas at Austin Andy Stergachis, University of Washington Chen Yang, Sidley Austin, LLP vii
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viii REVIEWERS Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Harold Fallon, Medical University of South Carolina, and Elaine Larson, School of Nursing and Mailman School of Public Health, Columbia University. Appointed by the National Research Council and the Institute of Medicine, they were respon- sible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
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Acknowledgments This report is a product of the cooperation and contributions of many people. The committee and staff are especially grateful to Danielle Turnipseed and Livia Navon for their work on the manuscript, and to Deepali Patel and Susan McCutchen for their fast and accurate refer- ence review. The project ran smoothly because of the contributions of Jim Banihashemi, Sarah Ziegenhorn, Laura Harbold DeStefano, Anne Claiborne, and Vilija Teel of the Institute of Medicine. Janice Mehler of the Report Review Committee oversaw a careful peer review of the manuscript. Many experts outside of the Academies helped the committee and staff with this project. Bryan Liang of the University of California, San Diego, was not able to serve on the committee but contributed to the first meeting. Michael Deats, Jitka Sabartova, and Sabine Kopp of the WHO shared their technical expertise; Tom Kubic of PSI, Inc. shared and explained his orga- nization’s unpublished data; Vincent Ahonkai of the Bill & Melinda Gates Foundation, Kelly Catlin of CHAI, and James Droop and Saul Walker of DFID shared information about medicine procurement and quality assur- ance; Mark Paxton of the FDA explained RFID technology; Ashifi Gogo of Sproxil explained mobile verification; Mariam Khan of BMI shared pharmaceutical sales data; and Lynda Scammell of the MHRA shared her technical expertise. Members of the committee and staff traveled to Brasília, Delhi, Ge- neva, Hyderabad, London, and São Paulo, during this project. Their meetings abroad were made easier because of the help and hospitality of Teija Katajainen of the WHO; Maria Alves of the EMA; Arthy Santhaku- mar of Chatham House; A. Srinivasa Chakravarthy, K.V. Surendra Nath, ix
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x ACKNOWLEDGMENTS and Syed Mohammed Arifullah of the U.S. Pharmacopeia–India; Carlos Morel of FIOCRUZ; and Laura Oliveira of the University of São Paulo. Charles Nwasor of the Altarum Institute, Kelley Badiane of USAID, Monica Eimunjeze of NAFDAC, Henrietta Williams of the Catholic Medical Asso- ciation of Nigeria, and Isaac Umunna also helped the staff and committee prepare for their meetings. The committee is grateful to the following participants who spoke at meetings and helped staff plan agendas: Martin Harvey Allchurch Laurie Garrett P.V. Appaji David R. Gaugh Amir Attaran Debora Germano Martin Auton Raj Shankar Ghosh Sunil Bahl Ashifi Gogo Roger Bate Antony Raj Gomes Ilisa Bernstein Subhash Gouda Katherine Bond L.C. Goyal Regina Brown Wendy Greenall Gian Luca Burci Jeffery Gren Claudio Henrique Cabral Catherine Hill-Herndon Nicholas Cappuccino Meghana Inamdar Ranjan Chakrabarti Mariaou Tala Jallow Ranjit Chaudhury Kees de Joncheere Lim Chin Chin Connie Jung John Clark Mohga Kamal-Yanni Charles Clift Harparkash Kaur David Cockburn Sabine Kopp Emer Cooke Alan Leather Ediná Alves Costa Jamie Love Alan Coukell Rohit Malpani Elize Massard da Fonseca Paola Manchisini Filipe Soares Quirino da Silva Linda Marks Ashok Dang Sylvia Meek Joelle Daviaud Mayira Milano Leandro Teixeira de Morais Bejon Misra Jenifer Devine Archna Mudgal Pritu Dhalaria Koduru Surendra Nath Albinus D’Sa Paul Newton Douglas Duarte Fernando Nogueira Paul Ellis Doroteia Koparanova Ollivier Frederico Benite Filho Arun Panda Michele Forzley Sharon Peacock Odile Frank Patrícia Oliveira Pereira
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ACKNOWLEDGMENTS xi Rebeca Mancini Pereira Nirupa Sen Greg Perry Dilip Shah Terezinha de Jesus Andreoli Pinto Sangeeta Shashikant Aline Plancon Janice Soreth Flávia Poppe Sadu Srivinas Tiago Lanius Rauber Fergus Sweeny Subbi Reddy Nirmalya Syam Christophe Rérat Paulo Teixeira Judit Rius Mary Lou Valdez Nicolina Romano-Lieber German Velasquez Francis Roodt Tarun Vij Luciano Gonçalves Rosado Simeon Wilson Bruce Ross Mark Witkowski Percy Alberto Ocampo Rujel Shunmay Yeung Niall Sargent Regina Zamith Philippa Saunders Anthony Zook Lynda Scammell Howard Zucker Aluísio Segurado
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xiv ACRONYMS AND ABBREVIATIONS HIV human immunodeficiency virus HPLC high-performance liquid chromatography ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IFC International Finance Corporation IMPACT International Medical Products Anti-Counterfeiting Taskforce Medicrime Council of Europe Convention on the counterfeiting of Convention medical products and similar crimes involving threats to public health MSF Médecins Sans Frontières (Doctors Without Borders) MSH Management Sciences for Health NABP National Association of Boards of Pharmacy NGO nongovernmental organization NIST National Institute of Standards and Technology NSF National Science Foundation OECD Organisation for Economic Co-operation and Development OPIC Overseas Private Investment Corporation PhRMA Pharmaceutical Research and Manufacturers of America PQM Promoting the Quality of Medicines PSI Pharmaceutical Security Institute PSM Partnership for Safe Medicines RFID radio frequency identification SBIR Small Business Innovation Research SSFFC substandard, spurious, falsely-labeled, falsified, counterfeit TLC thin layer chromatography TRIPS Trade-Related Aspects of Intellectual Property Rights Unicef United Nations Children’s Fund UNODC United Nations Office on Drugs and Crime USAID United States Agency for International Development USP U.S. Pharmacopeia
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ACRONYMS AND ABBREVIATIONS xv VIPPS Verified Internet Pharmacy Practice Sites WCO World Customs Organization WHA World Health Assembly WHO World Health Organization WIPO World Intellectual Property Organization WTO World Trade Organization WWARN WorldWide Antimalarial Resistance Network
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Contents ACKNOWLEDGMENTS ix ACRONYMS AND ABBREVIATIONS xiii SUMMARY 1 1 INTRODUCTION 15 Background and Terms, 17 Intellectual Property and Public Health, 18 TRIPS and the Doha Declaration, 18 Patent and Trademark Infringement, 20 Competing Meanings of the Term Counterfeit, 22 Substandard and Falsified Drugs, 24 The Problem of Unregistered Medicines, 26 A Proposed Vocabulary, 28 Drug Quality Standards, 30 Pharmacopeia, 30 Registration Agencies and National Pharmaceutical Authorities, 31 References, 48 2 THE EFFECTS OF FALSIFIED AND SUBSTANDARD DRUGS 55 Public Health Consequences, 55 Poisoning, 55 Untreated Disease, Disease Progression, and Death, 57 xvii
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xviii CONTENTS Medications for Chronic Diseases, 58 Medications for Infectious Diseases, 60 Treatment Failure, 62 Antimicrobial Resistance, 63 Antimalarial Resistance, 65 Other Antiparasitic Resistance, 67 Economic and Social Consequences, 67 Costs to the Health System, 68 Social and Developmental Costs, 72 References, 78 3 THE MAGNITUDE OF THE PROBLEM 85 Industry and Government Data, 85 The Pharmaceutical Security Institute Incident Reporting System, 86 Government and Intergovernmental Investigations, 90 The FDA Office of Criminal Investigations, 90 International Police Investigations, 92 Case Reports and Convenience Samples, 94 Case Reports, 95 Convenience Samples, 96 Antimicrobial Drugs, 96 Systematic Random Samples of Drug Quality, 100 A Need for More Field Surveys, 102 Global Prevalence Estimates, 103 The WHO Global Capacity-Building Project, 107 References, 134 4 CAUSES OF FALSIFIED AND SUBSTANDARD DRUGS 137 Reasons for Substandard Drugs, 137 Uneven Manufacturing Quality, 137 The IFC and OPIC, 142 Tiered Production, 144 Procurement and Substandard Medicines, 146 Applying the Model Quality Assurance System to Secondary Procurement, 152 Reasons for Falsified Drugs, 153 Corruption and Organized Crime, 154 Enforcement and Punishment, 157 Reasons for Both, 162 Expense and Scarcity, 162 Reducing the Costs of Market Authorization, 165 Weak Regulatory Systems, 166
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CONTENTS xix Gaps in Regulatory Oversight, 171 Lack of Awareness and Action, 173 Uneven Awareness, 173 Public Action, 176 References, 187 5 WEAKNESSES IN THE DRUG DISTRIBUTION CHAIN 197 An Overview of Drug Distribution in Developed and Developing Countries, 197 The Wholesale System, 203 The U.S. Wholesale Market, 208 The Wholesale Market in Low- and Middle-Income Countries, 209 Drug Diversion, 210 Pilfering and Heists, 211 Drug Resale and Late Diversion, 213 Tracking and Tracing Products Through the Supply Chain, 214 Barcodes, 215 Electronic Product Codes and Radio Frequency Identification, 217 Mobile Verification, 218 Medicines Retail, 222 Unregistered Pharmacies in Low- and Middle-Income Countries, 223 Shortage of Quality-Assured Drug Shops, 224 Shortage of Trained Pharmacy Staff, 224 Improving Retail, 228 Pharmaceutical Task Shifting, 229 Giving Incentives to Pharmaceutical Personnel, 232 Internet Pharmacies in Middle- and High-Income Countries, 233 The Legality of Internet Drugs Retail, 233 The Attraction of Internet Pharmacies, 236 Distinguishing Rogue Pharmacies from Legitimate Ones, 238 References, 243 6 DETECTION TECHNOLOGY 255 Qualitative and Quantitative Methods, 255 Overview of Detection, Screening, and Analytical Techniques, 257 Visual Inspection and Package Technologies, 257 Physical and Bulk Property Testing, 260 Colorimetry and Other Chemical Testing, 261 Chromatography, 261
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xx CONTENTS Spectroscopy, 265 Mass Spectrometry, 271 Emerging Technologies, 273 Using Technology, 274 Combining Techniques, 277 Using Technology in Developing Countries, 279 Field Technologies, 279 Detection in Every Setting, 281 The Technological Landscape, 284 References, 290 7 AN INTERNATIONAL CODE OF PRACTICE FOR FALSIFIED AND SUBSTANDARD MEDICINES 295 The Role of the WHO, 297 Engaging Stakeholders, 298 Content of the Code, 300 International Surveillance, 300 Medicines Regulation, 301 Law Enforcement, 303 Compliance by States and Stakeholders, 304 References, 305 APPENDIXES A GLOSSARY 309 B COMMITTEE BIOGRAPHIES 331 C MEETING AGENDAS 339
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Boxes, Figures, and Tables BOXES 1-1 Statement of Task, 18 1-2 Definitions of Terms, 29 2-1 Defective Glucose Test Strips, 59 2-2 Deaths from Substandard and Falsified Vaccines, 61 2-3 The WorldWide Antimalarial Resistance Network, 68 4-1 The Medicines Manufacturing Process, 140 4-2 Fatal Falsified Iron, 155 4-3 Adulterated Cancer Drugs, 156 4-4 Pharmaceutical Security Institute Crime and Arrest Data, 159 4-5 Manuel Calvelo, 161 4-6 Dissolution of the Pakistani Drug Regulatory Authority, 169 4-7 A National Awareness Campaign in Nigeria, 175 4-8 Health Worker Guidelines, 177 5-1 Drug Distribution in Humanitarian Emergencies, 202 5-2 Falsified Avastin’s Circuitous Path to the United States, 206 5-3 CareShop Franchisee Profiles, 230 5-4 The Australian Rural Pharmacy Workforce Program, 234 6-1 Classifying Falsified Medicines, 257 6-2 PharmaCheck, 273 xxi
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xxii BOXES, FIGURES, AND TABLES 6-3 Chinese Mobile Laboratories, 280 6-4 The Global Pharma Health Fund Minilab, 282 FIGURES 1-1 two-dimensional description of medicine quality and A registration, 27 2-1 Increasing incidence of multidrug-resistant tuberculosis (MDR-TB), 64 2-2 Percentage of nosocomial Staphylococcus aureus isolates with resistance to meticillin in studies in Latin American countries, 66 2-3 The increasing costs of drug development, 71 2-4 Comparative values of trafficking flows in West Africa, 73 3-1 Results of packaging and product analysis, 2011, 90 3-2 Geographic distribution of pharmaceutical sales in $U.S. billions, 2011 data, 91 3-3 Geographic distribution of Pharmaceutical Security Institute incident reports, affected countries, 2011 data, 91 3-4 Registration status of antimalarial samples by distribution level, 98 3-5 Quality failures of registered and unregistered antimalarials in 267 samples, 99 3-6 Results of full quality-control analysis in 267 samples, 99 4-1 Schematic block diagram of a pharmaceutical manufacturing process, 140 4-2 Arrests by activity, 2010-2011, 159 4-3 Average of country-level mean percentage availability of medicines by World Bank income group, 164 4-4 Number of sub-Saharan African countries out of 26 surveyed meeting the main functions of a regulatory authority, 168 4-5 FDA public service announcement that promotes the Verified An Internet Pharmacy Practice certification, 179 4-6 The English translation of a Cambodian poster encouraging consumers to buy medicines only from licensed pharmacies and to examine the drug’s color, shape, and taste for abnormalities, 180 5-1 The drug distribution system, 199 5-2 The private, public, and NGO drug distribution systems for essential medicines in developing countries, 200 5-3 Risks in the medicine distribution system, 212
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BOXES, FIGURES, AND TABLES xxiii 5-4 Number of pharmacists per 10,000 people and number of pharmacies per 10,000 people in 50 countries, 226 5-5 The world’s pharmacists, pharmacy technicians, and pharmacy assistants, 2006 data, 227 5-6 Legislation of internet pharmacy operations by WHO region, 235 6-1 More sophisticated fakes require more sophisticated technologies to detect them, 258 6-2 The printing on a fake Cialis blister pack is less crisp at 32× magnification, 260 6-3a n HPLC chromatogram with distinct peaks for chloroquine, A quinine, and mefloquine can be used to identify cheap chloroquine and quinine treatments labeled as the more expensive mefloquine, 264 6-3b he similar chemical structures of chloroquine, quinine, and T mefloquine, 264 6-4 Infrared Spectra for artemisinin (top) and artemether, an artemisinin-derivative (bottom) illustrate differences in their chemical composition, 266 6-5 Use of FT-IR spectroscopy to distinguish between real (left) and falsified (right) packaging in Singapore, 267 6-6 Image (a) is a pain relief tablet, image (b) its near-infrared spectra, 268 6-7 Proton NMR spectrum of aspirin (o-acetoxybenzoic acid), 270 6-8 Nearly identical analogues of tadalafil (left, 389.40 g/mol), aminotadalafil (right, 390.39 g/mol), 272 6-9 CODFIN analysis flowchart, 276 6-10 enuine (left) and falsified (right) holograms on artesunate blister G packs found in Southeast Asia, 284 TABLES 1-1 Definitions of Counterfeit Pharmaceuticals, 34 1-2 National Definitions of Counterfeit Pharmaceuticals, 37 1-3 Definitions of Substandard Pharmaceuticals, 42 1-4 National Definitions of Substandard Pharmaceuticals, 44 1-5 Other Terms of Interest, 45 2-1 Medicines Use to Treat the Most Common Causes of Child Death Are Compromised in Developing Countries, 75 3-1 Ranking of Seizures or Detections by Country, 2011, 88 3-2 Ten Countries Most Named in PSI Incident Reports, 2011, 89
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xxiv BOXES, FIGURES, AND TABLES 3-3 Operation Pangea Against Online Pharmacies, 2008-2012, 93 3-4 Operations Storm, Mamba, and Cobra, 2008-2011, 94 3-5 The Pharmaceutical Security Institute’s 2011 Open-Source Review, 111 3-6 Major Studies of Falsified and Substandard Antibiotics, 1996-2006, 118 3-7 Reports of Poor-Quality Antimalarial Drugs by Region in Southeast Asia and Sub-Saharan Africa, 1999-2011, 126 3-8 Medicine Quality Assessment Reporting Guidelines, 105 3-9 Information Collected in the WHO Rapid Alert System, 109 4-1 Overview of Selected Donors’, Procurement Service Agencies’, and Quality-Assurance Organizations’ Quality-Assurance Policies, 149 4-2 Pharmaceutical Procurement Best Practices, 153 4-3 Top Countries for Arrests, 2011, 158 4-4 Top 10 Countries Ranked by Number of Counterfeit Drug Seizures and Discoveries in 2006, 160 4-5 Penalties for Falsifying Medicine, 182 4-6 Penalties for Patent Infringement, 184 4-7 Penalties for Trademark Infringement, 186 4-8 Response to the Question “Are You Aware of the Presence of Fake Medicine in This Country?”, 174 5-1 Differences in Overall Structure of the Pharmaceutical Market in Developed and Developing Countries, 201 5-2 Number of Pharmaceutical Thefts in the United States, 2006- 2011, 213 5-3 Advantages and Disadvantages of Internet Pharmacies, 237 6-1 Techniques for Detecting Poor-Quality Drugs, 286 6-2 Product Quality Attributes and Assessments, 275