GENOME-BASED THERAPEUTICS
Targeted Drug Discovery and Development
WORKSHOP SUMMARY
Adam C. Berger and Steve Olson, Rapporteurs
Roundtable on Translating Genomic-Based Research for Health
Board on Health Sciences Policy
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu
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 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 the American College of Medical Genetics and Genomics (unnumbered contract); American Heart Association (unnumbered contract); American Medical Association (unnumbered contract); American Society of Human Genetics (unnumbered contract); Blue Cross and Blue Shield Association (unnumbered contract); Centers for Disease Control and Prevention (Contract No. 200-2011-38807); College of American Pathologists (unnumbered contract); Department of the Air Force (Contract No. FA7014-10-P-0072); Department of Veterans Affairs (Contract No. V101(93) P-2238); Eli Lilly and Company (Contract No. LRL-0028-07); Genetic Alliance (unnumbered contract); Health Resources and Services Administration (Contract No. HHSH250201100119P); Johnson & Johnson (unnumbered contract); Kaiser Permanente Program Offices Community Benefit II at the East Bay Community Foundation (Contract No. 20121257); Life Technologies (unnumbered contract); National Cancer Institute (Contract No. N01-OD-4-2139, TO#189); National Coalition for Health Professional Education in Genetics (unnumbered contract); National Heart, Lung, and Blood Institute (Contract No. N01-OD-4-2139, TO#275); National Human Genome Research Institute (Contract No. N01-OD-4-2139, TO#264); National Institute of Mental Health (Contract No. N01-OD-4-2139, TO#275); National Institute on Aging (Contract No. N01-OD-4-2139, TO#275); National Society of Genetic Counselors (unnumbered contract); Office of Rare Diseases Research (Contract No. N01-OD-4-2139, TO#275); and Pfizer Inc. (Contract No. 140-N-1818071). Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the organizations or agencies that provided support for the project.
International Standard Book Number-13: 978-0-309-26024-4
International Standard Book Number-10: 0-309-26024-8
Additional copies of this report 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 2012 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). 2012. Genome-based therapeutics: Targeted drug discovery and development: Workshop summary. Washington, DC: The National Academies Press.
“Knowing is not enough; we must apply.
Willing is not enough; we must do.”
—Goethe
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
Advising the Nation. Improving Health.
THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
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 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 engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles 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 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 Vest are chair and vice chair, respectively, of the National Research Council.
PLANNING COMMITTEE1
GEOFFREY GINSBURG (Chair), Director, Center for Genomic Medicine, Institute for Genomic Sciences and Policy, Duke University, Durham, NC
THOMAS LEHNER, Director, Office of Genomics Research Coordination, National Institute of Mental Health, Bethesda, MD
GARRY NEIL, Corporate Vice President, Corporate Office of Science and Technology, Johnson & Johnson, New Brunswick, NJ
MICHELLE A. PENNY, Senior Director, Translational Medicine Group, Eli Lilly and Company, Indianapolis, IN
AIDAN POWER, Vice President and Global Head of Molecular Medicine, Pfizer Inc., Groton, CT
ALLEN D. ROSES, President and Chief Operating Officer, Cabernet, Shiraz and Zinfandel Pharmaceuticals; and Jefferson–Pilot Professor of Neurobiology and Genetics, Professor of Medicine (Neurology); Director, Deane Drug Discovery Institute; Senior Scholar, Fuqua School of Business, R. David Thomas Executive Training Center, Duke University, Durham, NC
SHARON TERRY, President and Chief Executive Officer, Genetic Alliance, Washington, DC
IOM Staff
ADAM C. BERGER, Project Director
SEAN P. DAVID, James C. Puffer, M.D./American Board of Family Medicine Fellow
SARAH H. BEACHY, Christine Mirzayan Science and Technology Policy Graduate Fellow (August to November 2011)
CLAIRE F. GIAMMARIA, Research Associate
TONIA E. DICKERSON, 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.
This page intentionally left blank.
ROUNDTABLE ON TRANSLATING GENOMIC-BASED RESEARCH FOR HEALTH1
WYLIE BURKE (Co-Chair), Professor and Chair, Department of Bioethics and Humanities, University of Washington, Seattle
SHARON TERRY (Co-Chair), President and Chief Executive Officer, Genetic Alliance, Washington, DC
NAOMI ARONSON, Executive Director, Technology Evaluation Center, Blue Cross and Blue Shield Association, Chicago, IL
EUAN ANGUS ASHLEY, Representative of the American Heart Association; Director, Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Palo Alto, CA
PAUL R. BILLINGS, Chief Medical Officer, Life Technologies, Carlsbad, CA
BRUCE BLUMBERG, Institutional Director of Graduate Medical Education, Northern California Kaiser Permanente, The Permanente Medical Group, Oakland, CA
DENISE E. BONDS, Medical Officer, Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD
JOANN A. BOUGHMAN, Executive Vice President, American Society of Human Genetics, Bethesda, MD
C. THOMAS CASKEY, Professor, Baylor College of Medicine, Houston, TX
SARA COPELAND, Acting Chief, Genetic Services Branch, Health Resources and Services Administration, Rockville, MD
VICTOR DZAU, President and Chief Executive Officer, Duke University Health System; Chancellor for Health Affairs, Duke University, Durham, NC
W. GREGORY FEERO, Special Advisor to the Director for Genomic Medicine, National Human Genome Research Institute, Bethesda, MD
ANDREW N. FREEDMAN, Branch Chief, Clinical and Translational Epidemiology Branch, Epidemiology and Genetics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD
GEOFFREY GINSBURG, Director, Center for Genomic Medicine, Institute for Genomic Sciences and Policy, Duke University, Durham, NC
RICHARD J. HODES, Director, National Institute on Aging, Bethesda, MD
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.
SHARON KARDIA, Professor and Chair of Epidemiology; Director, Public Health Genetics Program; Director, Life Science and Society Program; Co-Director, Center for Public Health and Community Genomics, University of Michigan School of Public Health, Ann Arbor
MOHAMED KHAN, Representative of the American Medical Association; Leader of Radiation Oncology, Vancouver Cancer Centre, BC Cancer Agency, Vancouver, BC, Canada
MUIN KHOURY, Director, National Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA
THOMAS LEHNER, Director, Office of Genomics Research Coordination, National Institute of Mental Health, Bethesda, MD
DEBRA LEONARD, Representative of the College of American Pathologists; Professor and Vice Chair for Laboratory Medicine; Director of the Clinical Laboratories; Director of the Pathology Residency Training Program, Weill Cornell Medical Center of Cornell University, New York, NY
MICHELE A. LLOYD-PURYEAR, Representative of the Office of Rare Diseases Research; Senior Medical and Scientific Advisor, National Institute of Child Health and Human Development
ELIZABETH MANSFIELD, Director of the Personalized Medicine Staff, Office of In Vitro Diagnostic Device Evaluation and Safety, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD
GARRY NEIL, Corporate Vice President, Corporate Office of Science and Technology, Johnson & Johnson, New Brunswick, NJ
ROBERT L. NUSSBAUM, Chief, Division of Medical Genetics, Department of Medicine and Institute of Human Genetics, University of California, San Francisco, School of Medicine
MICHELLE A. PENNY, Senior Director, Translational Medicine Group, Eli Lilly and Company, Indianapolis, IN
AIDAN POWER, Vice President and Global Head of Molecular Medicine, Pfizer Inc., Groton, CT
VICTORIA M. PRATT, Chief Director, Molecular Genetics, Quest Diagnostics Nichols Institute, Chantilly, VA
RONALD PRZYGODZKI, Associate Director for Genomic Medicine and Acting Director of Biomedical Laboratory Research and Development, Department of Veterans Affairs, Washington, DC
ALLEN D. ROSES, President and Chief Operating Officer, Cabernet, Shiraz and Zinfandel Pharmaceuticals; and Jefferson–Pilot Professor of Neurobiology and Genetics, Professor of Medicine (Neurology); Director, Deane Drug Discovery Institute; Senior Scholar, Fuqua School of Business, R. David Thomas Executive Training Center, Duke University, Durham, NC
KEVIN A. SCHULMAN, Professor of Medicine and Business Administration; Director, Center for Clinical and Genetic Economics; Associate Director, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC
JOAN A. SCOTT, Executive Director, National Coalition for Health Professional Education in Genetics, Lutherville, MD
DAVID VEENSTRA, Professor, Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington, Seattle
MICHAEL S. WATSON, Executive Director, American College of Medical Genetics and Genomics, Bethesda, MD
DANIEL WATTENDORF, Deputy Chief, Medical Innovations, Department of the Air Force; Program Manager, DARPA/Defense Sciences Office, Arlington, VA
CATHERINE A. WICKLUND, Past President, National Society of Genetic Counselors; Director, Graduate Program in Genetic Counseling; Associate Professor, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL
IOM Staff
ADAM C. BERGER, Project Director
SEAN P. DAVID, James C. Puffer, M.D./American Board of Family Medicine Fellow
SARAH H. BEACHY, Christine Mirzayan Science and Technology Policy Graduate Fellow (August to November 2011)
CLAIRE F. GIAMMARIA, Research Associate
TONIA E. DICKERSON, Senior Program Assistant
ANDREW POPE, Director, Board on Health Sciences Policy
This page intentionally left blank.
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 process. We wish to thank the following individuals for their review of this report:
Jeffrey A. Bluestone, Executive Vice Chancellor and Provost, University of California, San Francisco
Walter M. Capone, Chief Operating Officer, Multiple Myeloma Research Foundation, Norwalk, CT
Steven E. Hyman, Harvard Distinguished Service Professor; Professor of Stem Cell and Regenerative Biology, The Broad Institute, Cambridge, MA
Gary Palmer, Senior Vice President, Medical Affairs and Commercial Development, Foundation Medicine, Inc., Cambridge, MA
Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the report before its release. The review of this report was overseen by Melvin Worth.
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 author and the institution.
Acknowledgments
The support of the sponsors of the Institute of Medicine Roundtable on Translating Genomic-Based Research for Health was crucial to the planning and conduct of the workshop New Paradigms in Drug Discovery: How Genomic Data Are Being Used to Revolutionize the Drug Discovery and Development Process and the development of the workshop summary report titled Genome-Based Therapeutics: Targeted Drug Discovery and Development. Federal sponsors are the Centers for Disease Control and Prevention; Department of the Air Force; Department of Veterans Affairs; Health Resources and Services Administration; National Cancer Institute; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Mental Health; National Institute on Aging; and Office of Rare Diseases Research. Nonfederal sponsorship was provided by the American College of Medical Genetics and Genomics; the American Heart Association; the American Medical Association; the American Society of Human Genetics; the Blue Cross and Blue Shield Association; the College of American Pathologists; Eli Lilly and Company; the Genetic Alliance; Johnson & Johnson; the Kaiser Permanente Program Offices Community Benefit II at the East Bay Community Foundation; Life Technologies; the National Coalition for Health Professional Education in Genetics; the National Society of Genetic Counselors; and Pfizer Inc.
The Roundtable wishes to express its gratitude to the expert speakers whose presentations helped outline the challenges in as well as the opportunities for genomics-guided strategies for drug development. The Roundtable also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda. The project director would like to thank project staff who worked diligently to develop both the workshop and the resulting summary.
This page intentionally left blank.
Contents
Challenges for Genomic-Based Approaches
The Development of Crizotinib for Treatment of Non-Small-Cell Lung Cancer
Use of Genetics to Inform Drug Development for the Treatment of Schizophrenia
A Genetic Approach to the Treatment of Cystic Fibrosis
4 EMERGING TECHNOLOGIES IN DRUG DEVELOPMENT
Large-Scale Whole-Genome Sequencing
The Value of Clinical Next-Generation Sequencing to Drug Developers
Table, Figures, and Boxes
TABLE
2-1 Pharmacogenomic Biomarkers in Drug Labels
FIGURES
2-1 A number of factors influence the market potential for targeted therapeutics with the prospect of reduced market size leading to increased market share
2-2 The number of new drugs approved per billion dollars spent has declined steadily on a logarithmic scale for more than a half-century
3-1 The development of crizotinib proceeded rapidly from compound identification to target discovery to clinical results to FDA approval
3-2 The development of the diagnostic for ALK alterations also proceeded rapidly from a Phase I laboratory-developed test to PMA approval
3-3 Administration of ivacaftor produced a rapid and sustained improvement in forced expiratory volume (FEV), which is a measure of lung function
3-4 Approximately 5 percent of people with CFTR mutations have gating mutations such as G551D
5-1 In the current paradigm of drug discovery and development, the approval of a drug rigidly separates the domains of regulators and payers
5-2 In the future, the responsibilities of regulators and payers could overlap, resulting in a dynamic interplay between evidence generation and drug approval
BOXES
ALK | anaplastic lymphoma kinase |
CDER | Center for Drug Evaluation and Research |
CDRH | Center for Devices and Radiological Health |
CFTR | cystic fibrosis transmembrane conductance regulator |
CLL | chronic lymphocytic leukemia |
CMS | Centers for Medicare & Medicaid Services |
DARPA | Defense Advanced Research Projects Agency |
FDA | U.S. Food and Drug Administration |
FEV | forced expiratory volume |
FFPE | formalin-fixed paraffin-embedded |
FISH | fluorescence in situ hybridization |
GWAS | genome-wide association studies |
IUO | investigational use only |
MMRC | Multiple Myeloma Research Consortium |
MMRF | Multiple Myeloma Research Foundation |
NCATS | National Center for Advancing Translational Sciences |
NIH | National Institutes of Health |
NPC | NCATS Pharmaceutical Collection |
NSCLC | non-small-cell lung cancer |
PwC | PricewaterhouseCoopers |
SNP | single nucleotide polymorphism |