ADVANCING REGULATORY SCIENCE
FOR MEDICAL COUNTERMEASURE
DEVELOPMENT

Workshop Summary

Theresa Wizemann, Bruce M. Altevogt, and
Anne B. Claiborne, Rapporteurs

Forum on Drug Discovery, Development, and Translation

Forum on Medical and Public Health Preparedness
for Catastrophic Events

Board on Health Sciences Policy

INSTITUTE OF MEDICINE

                OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION ADVANCING REGULATORY SCIENCE F OR MEDICAL COUNTERMEASURE DEVELOPMENT Workshop Summary Theresa Wizemann, Bruce M. Altevogt, and Anne B. Claiborne, Rapporteurs Forum on Drug Discovery, Development, and Translation Forum on Medical and Public Health Preparedness for Catastrophic Events Board on Health Sciences Policy

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 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. This project was supported by contracts between the National Academy of Sciences and Department of Health and Human Services (Contract Nos. N01-OD-4-2139 TO #158, HHSF223001003T, HHSF22301022T TO #24, N01-OD-4-2139 TO #198, HHSP233200900680P, HH5P23320042509X1, and HHSP233200800498P), the American Diabetes Association, the American Society for Microbiology, Amgen Inc., the Association of American Medical Col - leges, Bristol-Myers Squibb, the Burroughs Wellcome Fund, Celtic Therapeutics, LLLP, the Critical Path Institute, the Doris Duke Charitable Foundation, Eli Lilly & Co., Faster- Cures, the Foundation for the NIH, Friends of Cancer Research, GlaxoSmithKline, Howard Hughes Medical Institute, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer, Inc, the American College of Emergency Physicians, the American Hospital Association, the American Medical Association, the American Nurses Association, the Association of State and Territorial Health Officials, the Centers for Disease Control and Prevention (Contract No. 200-2005-13434 TO #6), the Department of the Army (Con - tract No. W81XWH-08-P-0934), the Department of Homeland Security’s Office of Health Affairs (Contract No. HSHQDC-07-C-00097), the Department of Homeland Security, Federal Emergency Management Agency (Contract No. HSFEHQ-08-P-1800), the Department of Transportation’s National Highway Traffic Safety Administration (DTNH22-10-H-00287) the Department of Veterans Affairs (Contract No. V101(93)P-2136 TO #10), the Emergency Nurses Association, the National Association of Chain Drug Stores, the National Associa - tion of County and City Health Officials, the National Association of Emergency Medical Technicians, the Pharmaceutical Research and Manufacturers of America, The Robert Wood Johnson Foundation, and the United Health Foundation. Any opinions, findings, conclu - sions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-21490-2 International Standard Book Number-10: 0-309-21490-4 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www. iom.edu. Copyright 2011 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). 2011. Advancing Regulatory Science for Medi- cal Countermeasure Development: Workshop Summary. Washington, DC: The National Acad- emies 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 Academy has a mandate that requires it to advise the federal govern - ment 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 mem - bers, sharing with the National Academy of Sciences the responsibility for advis - ing the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president 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 Institute 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 Sciences 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 pro - viding 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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PLANNING COMMITTEE FOR THE WORKSHOP ON ADVANCING REGULATORY SCIENCE FOR MEDICAL COUNTERMEASURE DEVELOPMENT1 LESLIE Z. BENET (Co-Chair), University of California-San Francisco JOHN REX, (Co-Chair), AstraZeneca, Waltham, MA MARGARET ANDERSON, FasterCures, Washington, DC PHYLLIS ARTHUR, Biotechnology Industry Organization, Washington, DC ANTHONY BAHINSKI, Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA LUCIANA BORIO, Food and Drug Administration, Silver Spring, MD GAIL H. CASSELL, Harvard Medical School (visiting), Carmel, IN GARRET A. FITZGERALD, University of Pennsylvania School of Medicine, Philadelphia STEVEN K. GALSON, Amgen Inc., Thousand Oaks, CA JOHN GRABENSTEIN, Merck & Co., Inc., West Point, PA ROBERT KADLEC, PRTM Management Consultants, Washington, DC MICHAEL KATZE, University of Washington, Seattle, WA GEORGE KORCH, Department of Health and Human Services, Washington, DC MICHAEL KURILLA, National Institute of Allergy and Infectious Diseases, Bethesda, MD BERNARD MUNOS, InnoThink, Indianapolis, IN GERALD PARKER, Department of Defense, Washington, DC MARY PENDERGAST, Pendergast Consulting, Washington, DC NICKI PESIK, Centers for Disease Control and Prevention, Atlanta, GA ERIC TONER, Center for Biosecurity of the UPMC, Baltimore, MD IOM Staff ANNE B. CLAIBORNE, Director, Forum on Drug Discovery, Development, and Translation BRUCE M. ALTEVOGT, Director, Forum on Medical and Public Health Preparedness for Catastrophic Events ELIZABETH F. C. TYSON, Research Associate ANDREW M. POPE, Director, Board on Health Sciences Policy DONNA L. RANDALL, Administrative Assistant ROBIN GUYSE, Senior Program Assistant ALEX REPACE, Senior Program Assistant 1 Institute of Medicine planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v

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FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1 GAIL H. CASSELL (Co-Chair), Harvard Medical School (visiting), Carmel, IN JEFFREY M. DRAZEN (Co-Chair), New England Journal of Medicine, Boston, MA BARBARA ALVING, National Center for Research Resources, Bethesda, MD MARGARET ANDERSON, FasterCures, Washington, DC 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 SCOTT CAMPBELL, Foundation for the National Institutes of Health, Bethesda, MD C. THOMAS CASKEY, University of Texas-Houston Health Science Center PETER B. CORR, Celtic Therapeutics, LLLP, New York, NY ANDREW M. DAHLEM, Eli Lilly and Company, Indianapolis, IN JAMES H. DOROSHOW, National Cancer Institute, Bethesda, MD GARY L. FILERMAN, ATLAS Research, McLean, VA GARRET A. FITZGERALD, University of Pennsylvania School of Medicine, Philadelphia ELAINE K. GALLIN, QE Philanthropic Advisors, Potomac, MD STEVEN K. GALSON, Amgen Inc., Thousand Oaks, CA HARRY B. GREENBERG, Stanford University School of Medicine, Stanford, CA STEPHEN GROFT, National Institutes of Health, Bethesda, MD ANNALISA JENKINS, Bristol-Myers Squibb, Plainsboro, NJ 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, New York, NY MARK B. McCLELLAN, The Brookings Institution, Washington, DC CAROL MIMURA, University of California-Berkeley 1Institute of Medicine forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the work - shop 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, Arlington, VA ELLEN STRAHLMAN, GlaxoSmithKline, Research Triangle Park, NC NANCY SUNG, Burroughs Wellcome Fund, Research Triangle Park, NC JORGE A. TAVEL, National Institute of Allergy and Infectious Diseases, Bethesda, MD JANET TOBIAS, Mt. Sinai School of Medicine, New York, NY JOANNE WALDSTREICHER, Johnson & Johnson, Raritan, NJ JANET WOODCOCK, Food and Drug Administration, White Oak, MD RAYMOND L. WOOSLEY, The Critical Path Institute, Tucson, AZ IOM Staff ANNE B. CLAIBORNE, Forum Director 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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FORUM ON MEDICAL AND PUBLIC HEALTH PREPAREDNESS FOR CATASTROPHIC EVENTS1 ROBERT KADLEC (Co-Chair), PRTM Management Consultants, Washington, DC LYNNE KIDDER (Co-Chair), Center for Excellence in Disaster Management and Humanitarian Assistance, Tripler AMC, Hawaii ALEX ADAMS, National Association of Chain Drug Stores Foundation, Alexandria, VA DAMON ARNOLD, Association of State and Territorial Health Officials, Arlington, VA GEORGES BENJAMIN, American Public Health Association, Washington, DC VICTORIA DAVEY, Department of Veterans Affairs, Washington, DC JEFFREY DUCHIN, Seattle & King County and University of Washington, Seattle ALEXANDER GARZA, Department of Homeland Security, Washington, DC JULIE GERBERDING, Merck Vaccines, West Point, PA LEWIS GOLDFRANK, New York University Medical Center, New York DAN HANFLING, Inova Health System, Falls Church, VA JACK HERRMANN, National Association of County and City Health Officials, Washington, DC JAMES JAMES, American Medical Association, Chicago, IL JERRY JOHNSTON, National Association of Emergency Medical Technicians, Mt. Pleasant, IA BRIAN KAMOIE, The White House, Washington, DC LISA KAPLOWITZ, HHS Office of the Assistant Secretary for Preparedness and Response, Washington, DC ALI KHAN, Centers for Disease Control and Prevention, Atlanta, GA MICHAEL KURILLA, National Institute of Allergy and Infectious Diseases, Bethesda, MD JAYNE LUX, National Business Group on Health, Washington, DC ANTHONY MACINTYRE, American College of Emergency Physicians, Washington, DC ANGELA McGOWAN, Robert Wood Johnson Foundation, Princeton, NJ MARGARET McMAHON, Emergency Nurses Association, Williamstown, NJ MATTHEW MINSON, Texas A&M University, College Station, TX 1Institute of Medicine forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the work - shop rapporteurs and the institution. ix

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ERIN MULLEN, Pharmaceutical Research and Manufacturers of America, Washington, DC CHERYL PETERSON, American Nurses Association, Silver Spring, MD STEVEN PHILLIPS, National Library of Medicine, Bethesda, MD ROSLYNE SCHULMAN, American Hospital Association, Washington, DC RICHARD SERINO, Federal Emergency Management Agency, Washington, DC MICHAEL SKIDMORE, Office of Assistant Secretary of Defense for Health Affairs, Department of Defense, Washington, DC SHARON STANLEY, American Red Cross, Washington, DC ERIC TONER, University of Pittsburgh Medical Center, Pittsburgh, PA REED TUCKSON, UnitedHealth Group, Minneapolis, MN MARGARET VANAMRINGE, The Joint Commission, Washington, DC GAMUNU WIEJETUNGE, National Highway Traffic Safety Administration, Washington, DC IOM Staff BRUCE M. ALTEVOGT, Forum Director CLARE STROUD, Program Officer KRISTIN VISWANATHAN, Research Associate ANDREW M. POPE, Director, Board on Health Sciences Policy ALEX REPACE, Senior Program Assistant x

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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 pub- lished 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 process. We wish to thank the following individuals for their review of this report: Gigi Kwik Gronvall, Center for Biosecurity of UPMC Richard Jaffe, ANSER/Analytic Services Inc. Jon Mogford, Defense Sciences Office, DARPA Raymond L. Woosley, The Critical Path Institute Although the reviewers listed above have provided many construc- tive comments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was overseen by Peter Honig, AstraZeneca. Appointed by the Institute of Medicine, he was responsible 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 authors and the institution. xi

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Contents ACRONYMS xvii 1 INTRODUCTION 1 Defining Regulatory Science, 4 Charge to the Workshop Participants, 5 Implementing the 2010 PHEMCE Review, 5 Overview of the FDA MCM Initiative, 7 Summary of Key Workshop Themes, 8 2 MCM ENTERPRISE AND STAKEHOLDER PERSPECTIVES 15 FDA Regulatory Science Research Needs, 15 Enterprise Partner and Stakeholder Perspectives, 22 3 CUTTING-EDGE EFFORTS TO ADVANCE MCM REGULATORY SCIENCE 29 Nonclinical Approaches to Assessing Efficacy, 29 Safety and Real-Time Monitoring, 38 Antimicrobials, 42 Vaccines and Adjuvants, 45 Synthetic and Computational Biology and Platform Technologies, 50 Diagnostics, 56 Statistical Techniques, 59 xiii

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4 MCM REGULATORY SCIENCE NEEDS FOR AT-RISK POPULATIONS 65 Children, 65 Pregnant Women, 67 5 CROSSCUTTING THEMES AND FUTURE DIRECTIONS 71 Advancing Regulatory Science, 71 Benefit and Risk, 72 Platforms, Processes, and Tools, 73 Collaboration, Partnerships, and Data Sharing, 75 FDA Resources and Infrastructure Issues Affecting Regulatory Science, 77 A Framework for Defining Regulatory Science Needs, 77 6 CLOSING REMARKS 79 REFERENCES 81 APPENDIXES A WORKSHOP AGENDA 83 B PARTICIPANT BIOGRAPHIES 99 xiv

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Tables, Figures, and Boxes TABLES 2-1 Examples of Potential Areas for Pillar 2 Research in CDER, 18 2-2 Examples of Potential Areas for Pillar 2 Research in CBER, 19 3-1 Prediction of Clinical Outcomes: Preclinical Toxicology Studies vs. Clinical Studies, 39 5-1 Rapid, Efficient Processes for Acquiring and Integrating Data and Predicting Favorable Benefit-Risk Ratios in Humans, 73 FIGURES 2-1 FDA regulatory review cycle, 16 3-1 In silico modeling of disease mechanisms for drug development, 30 3-2 Human tissue engineering as a potential tool for testing medicines in lieu of animal models, 46 3-3 Mobile bioprocessing facilities (MBFs), 46 3-4 Synthesis of bacterial cells, 51 3-5 Accelerating seasonal influenza virus vaccine development, 52 xv

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xvi TABLES, FIGURES, AND BOXES BOXES 1-1 Workshop Objectives, 3 1-2 Highlights of Keynote Address, 6 4-1 Pediatric Vulnerabilities, 66 5-1 FDA Resource and Infrastructure Observations, 77 5-2 MCM Data Issues as Tactical, Operational, and Strategic Concerns, 78 6-1 Seven Regulatory Science Focus Areas of the FDA MCM Initiative (Pillar 2), 79

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Acronyms ASPR HHS Assistant Secretary for Preparedness and Response BARDA Biomedical Advanced Research and Development Authority BUN blood urea nitrogen CBER FDA Center for Biologics Evaluation and Research CBRN chemical, biological, radiological, nuclear CDC Centers for Disease Control and Prevention CDER FDA Center for Drug Evaluation and Research CDISC Clinical Data Interchange Standards Consortium CDRH FDA Center for Devices and Radiological Health CNS central nervous system C-Path Critical Path Institute DARPA Defense Advanced Research Projects Agency DoD Department of Defense EUA emergency use authorization FDA U.S. Food and Drug Administration GLP good laboratory practice GMP good manufacturing practice xvii

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xviii ACRONYMS HHS U.S. Department of Health and Human Services HL7 Health Level Seven International IND investigational new drug IOM Institute of Medicine IRB institutional review board LRN CDC Laboratory Response Network MBF mobile bioprocessing facility MCM medical countermeasure MIMIC Modular IMmune In Vitro Constructs MRSA methicillin-resistant Staphylococcus aureus NBSB National Biodefense Science Board NCTR FDA National Center for Toxicological Research NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NRC National Research Council PCAST President’s Council of Advisors on Science and Technology PCR polymerase chain reaction PHEMCE Public Health Emergency Medical Countermeasures Enterprise PK/PD pharmacokinetic/pharmacodynamic PSTC Predictive Safety Testing Consortium RNA ribonucleic acid SNS Strategic National Stockpile VAERS Vaccine Adverse Event Reporting System VXDS Voluntary Exploratory Data Submission program