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Orphans and Incentives: Developing Technologies to Address Emerging Infections

Workshop Report

Forum on Emerging Infections

Polly F. Harrison and Joshua Lederberg, Editors

Division of Health Sciences Policy


Washington, D.C.

The National Academies of Sciences, Engineering, and Medicine
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--> Orphans and Incentives: Developing Technologies to Address Emerging Infections Workshop Report Forum on Emerging Infections Polly F. Harrison and Joshua Lederberg, Editors Division of Health Sciences Policy INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C. 1997

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--> NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, D.C. 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competencies and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under both the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. Support for this project was provided by Centers for Disease Control and Prevention, National Institute of Allergy and Infectious Diseases/NIH, Veterans Administration, Department of State, Food and Drug Administration, several private pharmaceutical companies, private foundations and associations. The views presented are those of the Institute of Medicine Forum on Emerging Infections and are not necessarily those of the funding organizations. International Standard Book No. 0-309-05941-0 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's on-line bookstore at For more information about the Institute of Medicine, visit the IOM home page at Copyright 1997 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 image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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--> FORUM ON EMERGING INFECTIONS JOSHUA LEDERBERG1 (Chair), Sackler Foundation Scholar, The Rockefeller University, New York VINCENT I. AHONKHAI, Vice President and Director, Anti-Infectives and Biologicals, SmithKline Beecham Corporation, Collegeville, Pennsylvania STEVEN J. BRICKNER, Manager of Medicinal Chemistry, Central Research Division, Pfizer, Inc., Groton, Connecticut GAIL H. CASSELL,2 Charles H. McCauley Professor and Chair, Department of Microbiology, University of Alabama at Birmingham, and American Society for Microbiology, Washington, D.C. GORDON H. DEFRIESE,2 Director and Professor of Social Medicine, Epidemiology, Health Policy, and Administration, Sheps Center for Health Services Research, University of North Carolina, Chapel Hill NANCY CARTER FOSTER,3 Director, Program for Emerging Infections and HIV/AIDS, Department of State, Washington, D.C. MARGARET A. HAMBURG,2 New York City Health Commissioner, New York City Department of Health DIETER HINZEN, Professor and Head of Preclinical Research, F. Hoffmann-LaRoche, A.G., Basel, Switzerland JAMES M. HUGHES,3 Assistant Surgeon General, and Director, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta J. STANLEY HULL, Disease Director, Herpes and Dermatology, Glaxo Wellcome plc. Middlesex, United Kingdom SAMUEL L. KATZ,2 Chairman of the Board, Burroughs Wellcome Fund, and Wilburt C. Davison Professor, Department of Pediatrics, Duke University Medical Center KENNETH W. KIZER,3 Under Secretary for Health, Veterans Health Administration, Department of Veterans Affairs, Washington, D.C. WILLIAM KOHLBRENNER, Director, Antiviral Research, Abbott Laboratories, Abbott Park, Illinois JOHN R. LAMONTAGNE,3 Director, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland CAROLS LOPEZ, Executive Director, Infectious Disease Research, Eli Lilly Research Laboratories, Indianapolis, Indiana STEPHEN S. MORSE, Assistant Professor of Epidemiology, Columbia University School of Public Health, and Defense Advanced Research Projects Agency/Defense Sciences Office, Washington, D.C. 1   Member, Institute of Medicine and National Academy of Sciences. 2   Member, Institute of Medicine. 3   Ex-officio member.

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--> SOLOMON MOWSHOWITZ, Vice President, Research and Development, Applied Microbiology, Inc., Tarrytown, New York STUART L. NIGHTINGALE,3 Associate Commissioner for Health Affairs, Food and Drug Administration, Department of Health and Human Services, Rockville, Maryland MICHAEL T. OSTERHOLM, State Epidemiologist and Chief, Acute Disease Epidemiology Section, Minnesota Department of Health, Minneapolis CAROLE A. SABLE, Associate Director for Infectious Diseases, Clinical Research Laboratories, Merck Research Laboratories, Blue Bell, Pennsylvania DAVID M. SHALES, Vice President, Infectious Disease Research, Wyeth-Ayerst Research, Pearl River, New York JOHN D. SIEGFRIED, Deputy Vice-President, Science and Regulatory Affairs, Pharmaceutical Research and Manufacturers of America (PhRMA), Washington, D.C. P. FREDERICK SPARLING, Chair of Medicine, University of North Carolina, Chapel Hill, and President, Infectious Diseases Society of America, Washington, D.C. Liasons to the Forum RUTH L. BERKELMAN, Deputy Director, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta BARRY R. BLOOM,2 Investigator, Howard Hughes Medical Institute, and Albert Einstein College of Medicine, Yeshiva University, Hastings-on-Hudson, New York ENRIQUETA C. BOND, President, Burroughs Wellcome Fund, Morrisville, North Carolina GARY CHRISTOPHERSON, Senior Advisor, Health Affairs, Department of Defense, Washington, D.C. MICHAEL HUGHES, Office of the Undersecretary, Veterans Health Administration, Department of Veterans Affairs, Washington, D.C. STEPHANIE JAMES, Parasitology and International Programs Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland STEPHEN M. OSTROFF, Acting Deputy Director, and Associate Director for Epidemiologic Science, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta FRED TENOVER, Chief, Nosocomial Pathogens Laboratory Branch, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta

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--> Study Staff POLLY F. HARRISON, Senior Study Director GRETCHEN GANZLE KIDDER, Research Assistant CHRISTINA THACKER, Project Assistant Division Staff VALERIE P. SETLOW, Director LINDA DEPUGH, Administrative Assistant JAMAINE TINKER, Financial Associate

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--> Preface The Forum The Forum on Emerging Infections was created in response to a request from the Centers for Disease Control and Prevention (CDC) and the National Institute of Allergy and Infectious Diseases (NIAID). Its goal is to provide structured opportunities for regular, open, nonadversarial communication among representatives from academia, industry, professional and interest groups, and government.1 Their interest—and the Forum's mandate—is to examine and discuss scientific and policy dilemmas of shared interest that are specifically related to research on and prevention, detection, and management of emerging infections.2 In accomplishing this task, the Forum can foster exchange of information and ideas, identify areas in need of greater attention, clarify policy issues by enhancing knowledge and identifying points of agreement, and inform decision makers about science and policy issues. We underscore here that the Forum seeks to illuminate issues rather than resolve them directly; it does not provide advice or recommendations on any policy pending before any agency or organization. Its strength rests on its diversity of membership and the commitment of individual members to attend on a recurrent basis. The linchpin of the Forum's work is a series of workshops focused on linked topics. The first, on which this document reports, was organized around the broad theme of public-/private-sector collaboration. The topic for the second workshop is antimicrobial resistance, surveillance, and response. The third workshop will examine the implications of health care restructuring for addressing emerging and re-emerging infectious diseases.

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--> The Topic In today's world, infectious diseases remain a leading cause of prolonged illness, premature mortality, and soaring health costs. According to the World Health Organization (WHO), of 52 million deaths of all ages in 1995, approximately one-third were attributable to infectious diseases. Worldwide, acute respiratory tract disease and pneumonia accounted for 4.4 million deaths, diarrheal disease and tuberculosis for 3.1 million each, malaria for 2.1 million, hepatitis B for 1.2 million, and measles and HIV/AIDS for 1.1 million each. In the United States in that year, infectious diseases constituted the third leading cause of death, just behind heart disease and cancer, with mortality mounting over time, owing to HIV/AIDS, to pneumonia, especially in the elderly, and to septicemia, with drug resistance playing an ever-increasing role in each of these disease categories. Infectious diseases also account for over 25 percent of visits to health care providers yearly, as well as an ever greater percentage of hospital admissions. The underlying premise of the Forum is that the mortality and morbidity deriving from infectious diseases are, all things equal, untimely and unnecessary. The reasons for the global emergence over the past two decades of new diseases and of old diseases with new faces, are various and complex; so are their ramifications. Both were explored in the 1992 Institute of Medicine report, Emerging Infections: Microbial Threats to Health in the United States. That report laid a basis for the strategic plan developed in 1994 by the CDC in partnership with others concerned with those threats: federal agencies; state and local health departments; academic institutions; professional societies; international organizations; and experts in public health, infectious diseases, clinical practice, and medical microbiology.3 The CDC strategy, in turn, was the catalyst for the deliberations of the Committee on International Science, Engineering, and Technology (CISET) of the National Science and Technology Council, convened to review and make strategic recommendations concerning the U.S. role in detection, reporting, and response to outbreaks of new and reemerging infections. 4 And, for years, NIAID has been calling attention to "orphan" diseases, for example malaria, and trying to stimulate both industry and government R&D investment. Both the CDC and CISET strategies pointed to the utterly critical function of cross-sectoral partnerships in responding to emerging diseases. CISET's recommendation is explicit: The U.S. Government and private sector should work together to establish a better investment environment for the production of urgently needed medical products. This can be accomplished by combining the resources of national and international government institutions with the technical expertise in the U.S. pharmaceutical industry and in other sectors of the private health care industry. The rationale for this collaboration is straightforward, as recently argued before the U.S. Congress:

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--> No biotechnology or pharmaceutical company can afford to support, at the level needed, the kind of work carried out by thousands of laboratory and clinical investigators in our nation's universities, medical schools, and independent research institutes. In turn, only the for-profit biopharmaceutical industry can translate into products the fundamental insights gained from such publicly supported investments.5 The CISET recommendation goes to the heart of the Forum's mandate and was therefore chosen as the topic of its first workshop, the objective of which was to shed light on the primary constraints in that investment environment and on what might serve to ease them. The workshop title, "Orphans and Incentives," refers to the fact that those constraints have left an undefined group of "urgently needed medical products" in an orphaned condition which demands special attention. The Report And Its Organization We ask the reader to remember, first, that any single workshop is necessarily incomplete and, second, that its proceedings can only report on what was said. Thus, the report does not pretend to be an exhaustive exploration of its subject matter. It is organized as a topic-by-topic synthesis of exchanges during the workshop; its purpose is to highlight lessons from relevant experience, delineate a range of pivotal issues and the problems they present, and put on the table some simplified ideas about possible responses. An appendix to the document contains a compendium of mechanisms and strategies attempted over the past couple of decades to promote research and the development of health technologies that constitute particular market challenges. The original purpose of the compendium was to provide food for thought for the Forum members about past models and available options; it was incorporated into this report as a similar resource for the reader. Although speakers are not identified by name in the text, the reader should understand that the material presented reflects the views and opinions of those participating in the workshop, not the deliberations of a formally constituted Institute of Medicine (IOM) study committee. All members of the Forum have reviewed the document and responded that they thought the report accurately reflected what happened at the workshop. All information reported in the text emerged in the workshop itself; where presenters and discussants referred to a specific document or a key allusion needed more explication to be intelligible to the reader, an endnote is provided. Acknowledgments On behalf of the Forum and the IOM, we wish to express our warmest appreciation to the individuals and organizations who gave valuable time to

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--> provide information and advice to the Forum through participation in this workshop. Each of the following contributed greatly: Amie Batson, WHO Global Program for Vaccines and Immunization; Seth Berkley, Rockefeller Foundation; Anne Bridgman, National Research Council/IOM Board on Children, Youth, and Families; Charles Caruso, Merck and Company; Anne Marie Finley, Committee on Government Reform and Oversight, Subcommittee on Human Resources, United States House of Representatives; Pamela Johnson, United Nations; William Hausdorff, Wyeth-Lederle; Jack Melling, Salk Institute; William Muraskin, Department of History, Queens College; Phillip Russell, Johns Hopkins School of Hygiene and Public Health; Veerle Coignez Sterling, World Bank; Roy Widdus, Children's Vaccine Initiative, WHO; and finally, Elaine Esber, Mark Goldberger, and Jeffrey Murray of the Food and Drug Administration. We also want to note the fine work of Gretchen Kidder and Christina Thacker and their authorship of the Inventory (Appendix C), summaries of public-sector agendas (Appendix A), and drafting of the section on the Children's Vaccine Initiative. Notes 1.   Representatives of federal agencies serve in an ex officio capacity. 2.   Emerging infectious diseases are diseases of infectious origin whose incidence in humans has increased within the past two decades or threatens to increase in the near future (Institute of Medicine. Emerging Infections: Microbial Threats to Health in the United States . J Lederberg, RE Shope, SC Oaks Jr, eds. Washington, D.C.: National Academy Press, 1992.) 3.   U.S. Department of Health and Human Services, Public Health Service. Addressing Emerging Infectious Disease Threats: A Prevention Strategy for the United States. Atlanta: Centers for Disease Control and Prevention, 1994. 4.   National Science and Technology Council (NSTC). Report of the NSTC Committee on International Science, Engineering, and Technology (CISET), Working Group on Emerging and Re-Emerging Infectious Diseases . Washington, D.C.: Office of the President, 1995. 5.   L Rosenberg, cited in: B Metheny, Testimony from industry, academia, and professional societies supports status quo in resource allocation at National Institutes of Health, Washington Fax Life Science, May 8, 1997.

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--> Contents     SUMMARY   1     INTRODUCTION   6     Background   6     The Workshop   8     WORKSHOP SUMMARY   9     The Children's Vaccine Initiative   9     A Brief History   9     Defining and Implementing Cross-Sectoral Collaboration   10     Defining, Creating, and Stabilizing the Market   11     Technology Transfer   15     Individual Product Experiences   16     Other Models   17     The Malaria Vaccine Development Board   17     The International AIDS Vaccine Initiative (IAVI)   19     An Industry Perspective on the Emerging Infections Agenda   20     Industry's Response to HIV/AIDS   22     The Emerging Infections Scenario and HIV/AIDS   23     Barriers   24     Legal and Regulatory Issues   25     Accelerated Approval and Development of Drugs for Serious and Life-Threatening Illnesses   26     Product Labeling   28     Product Availability   29     International Harmonization of Technical Requirements to Register Pharmaceuticals   30     Intellectual Property Rights Revisited   30     Orphan Drug Legislation   31

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-->     Public-Sector Agendas and Priorities   33     Lessons Learned and Issues for Resolution   33     Lessons from the Children's Vaccine Initiative   34     Issues for Resolution   37     A Final Observation   40     APPENDIXES     A   Emerging Infectious Diseases Research and Development Agendas: Principal Public-Sector Institutions   47 B   Workshop Agenda   60 C   Public-/Private-Sector Collaboration in Pharmaceutical Research and Development: Inventory of Mechanisms   63