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Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
×

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

Washington, D.C.

www.nap.edu

Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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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.

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International Standard Book Number-10: 0-309-29662-5

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Copyright 2014 by the National Academy of Sciences. All rights reserved.

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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.

Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
×

Knowing is not enough; we must apply.
Willing is not enough; we must do.
”      

                                                —Goethe

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INSTITUTE OF MEDICINE
              OF THE NATIONAL ACADEMIES

Advising the Nation. Improving Health.

Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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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. 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

Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
×

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

Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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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 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 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

Page viii Cite
Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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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.

Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
×

Preface

In the following report, the Institute of Medicine (IOM) Committee on the Independent Review and Assessment of the Activities of the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (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 scientific advancement. Thus, the committee considered it vital to ensure that the recommended processes adequately safeguard the ethical integrity 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

Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
×

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 scientific, social, and ethical questions, and while gene transfer research is constantly 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 consistent across scientific realms.

After careful study of the social and historical context of recombinant 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 modernization 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 opportunity to conduct this timely review. Gene transfer research remains highly important to the public and scientific community, and the RAC’s oversight standards and processes can serve as a model for other areas of evolving science.

Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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I am deeply appreciative of the expert work of our dedicated committee 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 offered exceptional guidance. Over a course of about 5 months, we convened 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 participants 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 openness and responsiveness to the committee’s many requests for information 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

Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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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
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Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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OTD

ornithine transcarbamylase deficiency

RAC

Recombinant DNA Advisory Committee

rDNA recombinant DNA
RNA ribonucleic acid

SCID

severe combined immune deficiency

Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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Suggested Citation:"Front Matter." 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. doi: 10.17226/18577.
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Gene transfer research is a rapidly advancing field that involves the introduction of a genetic sequence into a human subject for research or diagnostic purposes. Clinical gene transfer trials are subject to regulation by the U.S. Food and Drug Administration (FDA) at the federal level and to oversight by institutional review boards (IRBs) and institutional biosafety committees (IBCs) at the local level before human subjects can be enrolled. In addition, at present all researchers and institutions funded by the National Institutes of Health (NIH) are required by NIH guidelines to submit human gene transfer protocols for advisory review by the NIH Recombinant DNA Advisory Committee (RAC). Some protocols are then selected for individual review and public discussion.

Oversight and Review of Clinical Gene Transfer Protocols provides an assessment of the state of existing gene transfer science and the current regulatory and policy context under which research is investigated. This report assesses whether the current oversight of individual gene transfer protocols by the RAC continues to be necessary and offers recommendations concerning the criteria the NIH should employ to determine whether individual protocols should receive public review. The focus of this report is on the standards the RAC and NIH should use in exercising its oversight function. Oversight and Review of Clinical Gene Transfer Protocols will assist not only the RAC, but also research institutions and the general public with respect to utilizing and improving existing oversight processes.

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