Oversight and Review of
Clinical Gene Transfer Protocols

Assessing the Role of the Recombinant DNA Advisory Committee

Committee on the Independent Review and Assessment of the
Activities of the NIH Recombinant DNA Advisory Committee

Board on Health Sciences Policy

Rebecca N. Lenzi, Bruce M. Altevogt, Lawrence O. Gostin, Editors

INSTITUTE OF MEDICINE
          OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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Oversight and Review of Clinical Gene Transfer Protocols Assessing the Role of the Recombinant DNA Advisory Committee Committee on the Independent Review and Assessment of the Activities of the NIH Recombinant DNA Advisory Committee Board on Health Sciences Policy Rebecca N. Lenzi, Bruce M. Altevogt, 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 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 competences and with regard for appropriate balance. This project was supported by Contract/Grant No. HHSN263201200074I between the National Academy of Sciences and the National Institutes of Health. 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: 978-0-309-29662-5 International Standard Book Number-10: 0-309-29662-5 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 2014 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). 2014. Oversight and review of clinical gene transfer protocols: Assessing the role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press.

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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 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. C. D. Mote, Jr., 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. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON THE INDEPENDENT REVIEW AND ASSESSMENT OF THE ACTIVITIES OF THE NIH RECOMBINANT DNA ADVISORY COMMITTEE LAWRENCE O. GOSTIN (Chair), Georgetown University Law Center KENNETH I. BERNS, University of Florida College of Medicine R. ALTA CHARO, University of Wisconsin–Madison School of Law HOWARD J. FEDEROFF, Georgetown University School of Medicine JEFFREY P. KAHN, Johns Hopkins University Berman Institute of Bioethics TERRY MAGNUSON, University of North Carolina at Chapel Hill JOSEPH G. PERPICH, JBS International, Inc. SHARON F. TERRY, Genetic Alliance INDER M. VERMA, Salk Institute for Biological Studies JOHN E. WAGNER, University of Minnesota Medical School DANIEL J. WATTENDORF, Defense Advanced Research Projects Agency Study Staff REBECCA N. LENZI, Study Director BRUCE M. ALTEVOGT, Senior Program Officer INDIA HOOK-BARNARD, Senior Program Officer MARILYN J. FIELD, Senior Program Officer (until August 2013) MONICA L. GONZALEZ, Research Associate SHELLI GOLDZBAND, Senior Program Assistant LORA K. TAYLOR, Financial Associate ANDREW M. POPE, Director, Board on Health Sciences Policy 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: RITA COLWELL, University of Maryland at College Park JENNIFER FARMER, Fredreich’s Ataxia Research Alliance THEODORE FREIDMANN, University of California, San Diego HENRY T. GREELY, Stanford University KATHERINE A. HIGH, University of Pennsylvania BRIGID HOGAN, Duke University MICHAEL KATZ, March of Dimes Foundation SUSAN M. WOLF, University of Minnesota Although the reviewers listed above have provided many construc- tive comments and suggestions, they were not asked to endorse the con- clusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Wylie Burke, University of Washington, and Floyd E. Bloom, Scripps Research Institute. Appointed by the Institute of Medicine, they were responsible for making certain that an independent examination of this vii

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viii REVIEWERS 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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Preface In the following report, the Institute of Medicine (IOM) Committee on the Independent Review and Assessment of the Activities of the Na- tional Institutes of Health (NIH) Recombinant DNA Advisory Commit- tee (RAC) sought to provide an assessment of the state of existing gene transfer science and the current regulatory and policy context under which research is investigated. The charge to this committee, reproduced in the report, had two main aspects, the first of which was to assess whether the current oversight of individual gene transfer protocols by the RAC continues to be necessary. This task required understanding the circumstances that led to the creation of the RAC and assessing the current validity of these, and other, concerns. It was thus important to root our report in both scientific and historical contexts. The second major aspect of the committee’s charge was to offer recommendations concerning the criteria the NIH should employ to determine whether individual protocols should receive public review. The issue was not simply should individual protocol review continue, but, if so, what standards the RAC and the NIH should use in exercising its oversight function. An examination of criteria could assist not only the RAC, but also research institutions and the general public with respect to utilizing and improving existing oversight processes. The committee strove, above all, to maintain the public’s confidence in the integrity of gene transfer research, consistent with the value of sci- entific advancement. Thus, the committee considered it vital to ensure that the recommended processes adequately safeguard the ethical integri- ty of the conduct of human subject research, including human subjects’ and patients’ rights and safety. At the same time, the committee aimed to achieve a regulatory and oversight environment that would advance the ix

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x PREFACE important mission of science—including removing as much regulatory duplication and delay as possible. Even when a new discovery or novel technology offers the potential for valuable treatment, it can also bring with it troublesome scientific and technical challenges, as well as social and ethical concerns. The committee found that while gene transfer research continues to raise important scien- tific, social, and ethical questions, and while gene transfer research is con- stantly evolving, not all of gene transfer research is still considered an entirely new scientific enterprise or novel technology and therefore not all protocols warrant special/public oversight by the RAC. It is also important to stress that a number of applications of emerging technologies with the potential to make significant contributions to clinical medicine may also raise questions of significant and/or uncertain risk. These technologies could benefit from the model of oversight established by the RAC. This led the committee to the conclusion that the time had arrived for the NIH director to consider developing a rigorous review process that—instead of being limited to a single body of gene transfer research—was fair and con- sistent across scientific realms. After careful study of the social and historical context of recombi- nant DNA research, the committee concluded that the RAC had served all parties admirably, ranging from human subjects and their families, to the research community and broader society. The RAC’s commitment to providing a public forum in which the scientific, technical, and ethical considerations of gene transfer research were discussed instilled public confidence in a controversial new research field that at the time was not well understood. After 40 years of experience, the time for moderniza- tion has arrived. The committee concluded that the NIH should consider developing a process—using the RAC as a model—to rigorously review human subject research that is so novel, and carries significant unknown risks, that the normal regulatory apparatus lacks the capacity to conduct an adequate review. Until such a process is developed and agreed upon, the RAC should continue to review individual gene transfer protocols but should use new, more focused criteria in order to direct its resources to exceptional cases that warrant special oversight. We are most grateful to the NIH for entrusting us with the opportuni- ty to conduct this timely review. Gene transfer research remains highly important to the public and scientific community, and the RAC’s over- sight standards and processes can serve as a model for other areas of evolving science.

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PREFACE xi I am deeply appreciative of the expert work of our dedicated com- mittee members and their extraordinary commitment and contributions to the task at hand. Our committee comprised some of the most eminent scientists and ethicists in the United States. Our study director Rebecca Lenzi—together with Monica Gonzalez and Shelli Goldzband—offered superb leadership and guidance. Andy Pope and Bruce Altevogt also of- fered exceptional guidance. Over a course of about 5 months, we con- vened 3 in-person committee meetings, 2 public meetings, including scientific presentations, and an abundance of teleconferences and e-mail exchanges. We trust that this report will assist not only the NIH in its vital efforts, but also the broader research and patient community. It is the committee’s sincere hope that policy makers, scientists, research par- ticipants and their families, and others concerned about or hopeful of the promise of gene therapy, will find the report valuable. The committee gave generously of its time, demonstrating tireless devotion to this task. I also wish to express the committee and staff’s appreciation to the NIH Office of Biotechnology Activities for its open- ness and responsiveness to the committee’s many requests for infor- mation during the course of this study. Lawrence O. Gostin, Chair Committee on the Independent Review and Assessment of the Activities of the NIH Recombinant DNA Advisory Committee

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Contents ACRONYMS AND ABBREVIATIONS xvii SUMMARY 1 1 INTRODUCTION 9 2 GENE TRANSFER RESEARCH: THE EVOLUTION OF THE CLINICAL SCIENCE 21 3 OVERSIGHT OF GENE TRANSFER RESEARCH 41 4 EVOLUTION OF OVERSIGHT OF EMERGING CLINICAL RESEARCH 77 APPENDIXES A Data Sources and Methods 95 B Historical and Policy Timelines for Recombinant DNA Technology 103 C Committee Biographies 109 xiii

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Boxes, Figure, and Tables BOXES 1-1 Charge to the Committee, 10 4-1 Case Study 1, 84 4-2 Case Study 2, 85 4-3 Case Study 3, 86 FIGURE 3-1 Summary of the human gene transfer protocol review process, 52 TABLES B-1 Timeline of Key Developments in rDNA Technology During the Late 1960s and Early 1970s, 103 B-2 Timeline of Notable Events in the Oversight of rDNA Research, 104 xv

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Acronyms and Abbreviations AAV adeno-associated virus BLA Biologic License Application CBER Center for Biologics Evaluation and Research CMC chemistry, manufacturing, and controls DNA deoxyribonucleic acid EMA European Medicines Agency FDA U.S. Food and Drug Administration GeMCRIS Genetic Modification Clinical Research Information System HHS U.S. Department of Health and Human Services IBC institutional biosafety committee IND investigational new drug IOM Institute of Medicine IRB institutional review board NAS National Academy of Sciences NIH National Institutes of Health OBA Office of Biotechnology Activities OCTGT Office of Cellular, Tissue, and Gene Therapies OHRP Office of Human Research Protections xvii

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xviii ACRONYMS AND ABBREVIATIONS OTD ornithine transcarbamylase deficiency RAC Recombinant DNA Advisory Committee rDNA recombinant DNA RNA ribonucleic acid SCID severe combined immune deficiency