Preserving Public Trust: Accreditation and Human Research Participant Protection Programs

Committee on Assessing the System for Protecting Human Research Subjects

Board on Health Sciences Policy

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
Washington, D.C.



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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs Preserving Public Trust: Accreditation and Human Research Participant Protection Programs Committee on Assessing the System for Protecting Human Research Subjects Board on Health Sciences Policy INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, DC 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 competences and with regard for appropriate balance. This project, N01-OD-4-2139, Task Order No. 80, received support from the evaluation set-aside Section 513, Public Health Service Act. The U.S. Department of Health and Human Services provided this support, with additional support provided by the Greenwall Foundation. The views presented in this report are those of the Institute of Medicine Committee on Assessing the System for Protecting Human Research Subjects and are not necessarily those of the funding agencies. International Book Standard No. 0-309-07328-6 Additional copies of this report are available for sale from the National Academy Press , 2101 Constitution Avenue, N.W., Box 285, Washington, D.C. 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's home page at www.nap.edu. The full text of this report is available at www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. Copyright 2001 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE Shaping the Future for Health

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council 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. Bruce M. Alberts 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. William A. Wulf 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. Kenneth I. Shine 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. Bruce M. Alberts and Dr. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs COMMITTEE ON ASSESSING THE SYSTEM FOR PROTECTING HUMAN RESEARCH SUBJECTS DANIEL D. FEDERMAN (Chair), Senior Dean for Alumni Relations and Clinical Teaching, Harvard University, Boston, MA DANIEL AZARNOFF, President, D.L. Azarnoff Associates, San Francisco, CA, and Vice President of Clinical and Regulatory Affairs, Cellegy Pharmaceuticals TOM BEAUCHAMP, Professor, Kennedy Institute of Ethics, Georgetown University, Washington, DC TIMOTHY STOLTZFUS JOST, Newton D. Baker-Baker and Hostetler Professor of Law and Health Services Management and Policy, Ohio State University, Columbus, OH PATRICIA A. KING, Carmack Waterhouse Professor of Law, Medicine, Ethics, and Public Policy, Georgetown University Law Center, Washington, DC RODERICK J.A. LITTLE, Chair, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI JAMES McNULTY, President, Depressive/Manic Depressive Association of Rhode Island, Bristol, RI ANNE PETERSEN, Senior Vice President-Programs, Kellogg Foundation, Battle Creek, MI BONNIE W. RAMSEY, Professor, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA LYDIA VILLA-KOMAROFF, Vice President for Research, Northwestern University, Evanston, IL FRAN VISCO, President, The National Breast Cancer Coalition, Washington, DC Expert Advisers KAY DICKERSIN, Associate Professor, Department of Community Health, Brown University, Providence, RI ALBERTO GRIGNOLO, Senior Vice President and General Manager for Worldwide Regulatory Affairs, PAREXEL International, Waltham, MA MARY FAITH MARSHALL, Professor of Medicine, School of Medicine, Kansas University Medical Center, Kansas City, KS CAROL SAUNDERS, President, Center for Clinical Research Practice, Wellesley, MA DENNIS TOLSMA, Director, Clinical Quality Improvement, Kaiser Permanente, Atlanta, GA Liaisons RICHARD J. BONNIE, John S. Battle Professor of Law and Director, Institute of Law, Psychiatry, and Public Policy, Charlottesville, VA

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs NANCY NEVELOFF DUBLER, Director, Division of Bioethics, Montefiore Medical Center; Co-Director, Certificate Program in Bioethics and Medical Humanities, Professor of Bioethics, Albert Einstein Medical College, Bronx, NY ELENA OTTOLENGHI NIGHTINGALE, Scholar-in-Residence, Institute of Medicine and National Research Council, Washington, DC PILAR OSSORIO, Assistant Professor of Law and Medical Ethics, Associate Director of the Center for the Study of Race and Ethnicity in Medicine, University of Wisconsin, Madison Law School, Madison, WI Study Staff LAURA LYMAN RODRIGUEZ, Study Director ROBERT COOK-DEEGAN, Senior Program Officer JESSICA AUNGST, Research Assistant NATASHA DICKSON, Project Assistant IOM Board on Health Sciences Policy Staff ANDREW POPE, Board Director ALDEN CHANG, Administrative Assistant CARLOS GABRIEL, Financial Associate Consultant KATHI HANNA Copy Editor MICHAEL HAYES

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs Preface Although it is said that each stage of evolution can be explained (but not predicted) from the earlier ones, it is not easy to apply this insight to the specifically human phenomenon known as clinical investigation. With the possible exception of genes for altruism, it is hard to discern the evolutionary antecedents of the behaviors that characterize what we know as human research. The complex system that sustains research is ultimately premised on trust—trust in the people and organizations that conduct research. In the wake of revelations about lapses in research ethics, such trust must be earned, and trust hinges on concrete affirmation of trustworthiness. But trustworthiness to whom? To those who become the object of study in human research. Consider first those who join the human research system as participants. Those who are volunteers have little to gain by accepting drugs or answering a survey, each of which has a small but unquantified risk. Although a financial inducement is sometimes part of the lure, these individuals often accept considerable risk in the knowledge that the research in which they join cannot help them but does have the potential to help “unknown others”—surely a remarkably selfless behavior. The other key participants are patients who become the subject of research. At some point, all new drugs and devices are given experimentally to sick individuals who might benefit from the intervention. Even when they are explicitly informed of the relative risks and benefits, many patients choose to enroll in a clinical investigation when their own likelihood of benefiting is small. The outcome of this moment of decision affects in considerable measure how the clinician/researcher discharges his or her responsibility to inform.

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs Protecting research participants looms especially large in clinical research, where the risks are often the highest, professional roles are conflicted, and ethical lapses have been most salient. The physician doing research is wittingly cast in two different and often conflicting roles. Above all else, he or she is a doctor, sworn first to do no harm and always to act in the best interest of the patient. As investigator, however, the same person is trained to randomize his or her patient 's participation to an at least 50 percent likelihood of no benefit and, indeed, to treat all research participants with a neutral regard that puts the sought-after truth ahead of the research participant 's immediate interest. As if this dual identity of dedicated physician and disinterested inquirer were not enough of a weight to sustain, the physician researcher has two burdens of (self) interest. One of these, familiar now for more than half a century, is the linkage of research and publication to academic promotion and professional advancement. The other, newer pressure is that of obtaining additional income from sources that have a huge interest in a positive outcome of the research. Many and perhaps most clinical trials are now supported by pharmaceutical and biotechnology companies. Honoraria, speaker fees, paid travel, and further research support may all be available to the bearer of positive tidings. These emoluments, though, are dwarfed by the potential of equity participation in the sponsoring company by the investigator. The social and economic setting of research also is undergoing dramatic change. At first investigation was almost an avocation of scientists and clinicians whose curiosity and clinically derived puzzlement drove them to undertake a study. Later it was a virtual monopoly of academic health centers, where a dominant professional ethos and the constant gaze of skeptical trainees emphasized probity and ethics. In the 1970s, institutional review boards (IRBs) became increasingly common, applying independent review and intellectual rigor to the evaluation of the science and the protection of the individual subject participants. Now, however, clinical research is a multibillion dollar business with enormous potential profits riding on efficiency, aggressiveness, and positive outcomes. Research pervades marketing, census counting, national surveys of opinion, and myriad other aspects of our daily lives. Outputs of research define congressional districts, legal thresholds for poverty, and marketing campaigns that affect us all. Research is carried out in a ragged congeries of universities, for-profit and nonprofit research organizations, and drug companies. Reassurance about the conduct of some of research comes from professional independent review boards that have no anchor in universities or their academic health centers and that are often organized for profit. As a result of these changes plus the headlong advance in biomedical science, questions are surfacing around the enterprise and about its dedication to the human being at its center—the research participant. Given the complexity of the current science, can consent ever be truly informed? Given the inevitable asymmetry of the investigator-subject dyad, can real autonomy—the power to say no and the choice to change one's mind—be preserved? Can IRBs of such

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs different geneses handle the complex responsibilities being laid on them? Can professionalism be sustained without requiring saintliness? Can the occasional sinner be recognized before doing tragic harm? In short, how can a diffuse, chaotic, fast-moving, ever-changing nonsystem of evolutionarily unprecedented human behavior be organized and monitored to maximize its glorious potential and control its dark risks? Our committee was asked to take up these questions and others with the focus on the safety and rights of the participants who share the clinical research enterprise and who are indispensable to its success. In this first report, done in 6 months, we suggest ways in which accreditation might contribute to a new level of excellence. There are many other points of leverage, however, including decompressing the burdens on IRBs, educating and perhaps certifying investigators, improving research monitoring, and building greater institutional support and infrastructure. In another report to be rendered after more time, more study, and more reflection, we hope to contribute to these larger questions and thus to the research enterprise as a social good. Daniel D. Federman, M.D., Chair

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs 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 NRC'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: Eugene Braunwald, Partners HealthCare System Bette-Jane Crigger, The Hastings Center, IRB Norman Daniels, Tufts University, Department of Community Medicine Ralph Dell, National Research Council Janice Douglas-Baltimore, Case Western Reserve University, School of Medicine Frederick L. Grinnell, University of Texas, Southwestern Medical Center Eugene Hammel, University of California, Berkeley, Department of Demography Erica Heath, Independent Review Consulting, Inc. John G. Miller, Association for Assessment and Accreditation of Laboratory Animal Care Jonathan D. Moreno, University of Virginia, Center for Biomedical Ethics Thomas Puglisi, Pricewaterhouse Coopers, LLP John Sever, Children's National Medical Center Michael Silverstein, University of Chicago, Department of Anthropology Eve Slater, Merck & Co., Inc. 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 Francois Abboud, appointed by the Institute of Medicine, and Mary Jane Osborn, University of Connecticut Health Center, appointed by the NRC's Report Review Committee, who were 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 authoring committee and the institution.

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs Acronyms AAALAC Association for Assessment and Accreditation of Laboratory Animal Care AAHRPP Association for the Accreditation of Human Research Protection Programs AAMC Association of American Medical Colleges ACHRE Advisory Committee on Human Radiation Experiments AMA American Medical Association CIOMS Council for International Organizations of Medical Sciences DHHS U.S. Department of Health and Human Services DSMBs data safety and monitoring boards FDA Food and Drug Administration GAO General Accounting Office HCFA Health Care Financing Administration HRPP human research protection program HRPPP human research participant protection program ICH-GCP International Conference on Harmonisation Guideline for Good Clinical Practice IND investigational new drug application (FDA) IOM Institute of Medicine IRB institutional review board JCAHO Joint Commission on Accreditation of Healthcare Organizations MCMC Medical Care Management Corporation MCOs managed care organizations

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs NBAC National Bioethics Advisory Commission NCI National Cancer Institute NCQA National Committee for Quality Assurance NHRPAC National Human Research Protections Advisory Committee NIH National Institutes of Health OHRP Office for Human Research Protections OIG Office of the Inspector General (U.S. Department of Health and Human Services) OPRR (former) Office for Protection from Research Risks ORCA Office of Research Compliance and Assurance (VA) PHS U.S. Public Health Service PRIM&R Public Responsibility in Medicine and Research VA U.S. Department of Veterans Affairs

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs Contents     EXECUTIVE SUMMARY   1      Abstract,   1      The Committee's Task,   5      Major Findings,   6      Recommendations,   10      Concluding Remarks,   20  1   INTRODUCTION, BACKGROUND, AND DEFINITIONS   23      Organization of the Report,   23      A Short History of Human Subjects Protections in the United States,   24      More Recent Events,   26      A Call for Accountability,   31      Statement of Task,   32      Definitions,   32  2   MODELS OF ACCREDITATION   45      Models of Accreditation,   45      Elements of an Accreditation Process,   48      Applying the Models to Human Research Oversight,   53      Some Issues That Accreditation Alone Cannot Address,   57      Will Accreditation Enhance Performance?,   61  3   STANDARDS FOR ACCREDITATION   63      Standards for Standards,   64      Developing Measures to Accompany Standards,   67

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs      Need for Standards to Encompass Multiple Research Settings and Methods,   69      Relation of the Standards to the Existing Regulatory Requirements,   71      Standards for Quality Improvement and Self-Study,   72      Need for Standards to Enhance the Role of Research Participants,   73      Need for Standards Regarding Roles and Responsibilities of Research Sponsors,   75      Review of Available Draft Standards,   76      International Conference on Harmonization Guideline for Good Clinical Practice,   83      Recommendation for Initial Standards to Begin Pilot Testing,   84  4   EVALUATING HRPPP PILOT ACCREDITATION PROGRAMS   89     REFERENCES   95     APPENDIXES       A  Data Sources and Methods,   105     B  PRIM&R Accreditation Standards,   115     C  VA Human Research Protection Accreditation Program Draft Accreditation Standards,   135     D  Committee, Expert Adviser, and Staff Biographies,   197     INDEX   209

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Preserving Public Trust: Accreditation and Human Research Participant Protection Programs LIST OF TABLES, FIGURES, AND BOXES Tables  1   Comparison of Draft NCQA and PRIM&R Accreditation Standards,   8  3-1   Elements in Three Sets of Standards and Guidelines,   78  C-1   Draft Accreditation Outcomes and Remedial Action,   138  C-2   Institutional Reponsibilities,   145  C-3   Individual IRB Structure and Operations,   156  C-4   Considerations of Risks and Benefits,   171  C-5   Recruitment and Subject Selection,   177  C-6   Privacy and Confidentiality,   180  C-7   Informed Consent,   183 Figures  1   Human research participant protection programs (HRPPPs),   3  1-1   Human research participant protection programs (HRPPPs),   37 Boxes  1   Summary of Committee's Recommendations According to the Three Implementation Phases of an Accreditation Process,   22  1-1   Relevant International Codes,   27  3-1   The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use,   85  A-1   Organizations and Individuals Appearing Before the Committee,   106

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