INTENTIONAL HUMAN DOSING STUDIES FOR EPA REGULATORY PURPOSES

SCIENTIFIC AND ETHICAL ISSUES

Committee on the Use of Third Party Toxicity Research with Human Research Participants

Science, Technology, and Law Program

Policy and Global Affairs Division

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington D.C. ww.nap.edu



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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues INTENTIONAL HUMAN DOSING STUDIES FOR EPA REGULATORY PURPOSES SCIENTIFIC AND ETHICAL ISSUES Committee on the Use of Third Party Toxicity Research with Human Research Participants Science, Technology, and Law Program Policy and Global Affairs Division NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington D.C. ww.nap.edu

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues 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. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract No. 68-W-02-071, between the National Academies and the U.S. Environmental Protection Agency. The views presented in this report are those of the National Research Council Committee on the Use of Third Party Toxicity Research with Human Research Participants and are not necessarily those of the funding agencies. International Standard Book Number 0-309-09172-1 (Book) International Standard Book Number 0-309-53098-9 (PDF) 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. Copyright 2004 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues 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. 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. Wm. 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. 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. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues COMMITTEE ON THE USE OF THIRD PARTY TOXICITY RESEARCH WITH HUMAN RESEARCH PARTICIPANTS JAMES F. CHILDRESS, Cochair (IOM), John Allen Hollingsworth Professor of Ethics, Professor of Medical Education, and Director, Institute of Practical Ethics and Public Life, University of Virginia, Charlottesville, Virginia MICHAEL R. TAYLOR, Cochair, Senior Fellow and Director, Risk, Resource, and Environmental Management Division, Resources for the Future, Washington, D.C. JAMES V. BRUCKNER, Professor of Pharmacology and Toxicology, Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia ALICIA L. CARRIQUIRY, Associate Provost and Professor of Statistics, Office of the Provost, Iowa State University, Ames, Iowa ELLEN WRIGHT CLAYTON, Rosalind E. Franklin Professor of Genetics and Health Policy; Director of Genetics and Health Policy Center; Senior Fellow, Institute for Public Policy Studies; Professor of Pediatrics; Professor of Law, Vanderbilt University, Nashville, Tennessee JOHN DOULL, Professor Emeritus, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas HENRY T. GREELY, C. Wendell and Edith M. Carlsmith Professor of Law; Professor, by courtesy, of Genetics; Co-director, Program in Genomics, Ethics, and Society and Program in Law, Science, and Technology, Stanford University Law School, Stanford, California SIOBAN D. HARLOW, Associate Professor; Associate Director, International Institute; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan LESTER B. LAVE (IOM), University Professor, the Harry B. and James H. Higgins Professor of Economics; Professor, Engineering and Public Policy; Director, Green Design Initiative; Co-Director, University Electricity Industry Center, Graduate School of Industrial Administration, Carnegie Mellon University, Pittsburgh, Pennsylvania BERNARD LO (IOM), Professor of Medicine and Director, Program in Medical Ethics, University of California, San Francisco, California THOMAS A. LOUIS, Professor, Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland JOSEPH V. RODRICKS, Founding Principal, ENVIRON International Corporation, Arlington, Virginia

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues CHRISTOPHER H. SCHROEDER, Charles S. Murphy Professor of Law and Public Policy Studies and Director, Program in Public Law, Duke University Law School, Durham, North Carolina ROBERT TEMPLE, Director, Office of Medical Policy, Center for Drug Evaluation and Research; Acting Director, Office of Drug Evaluation, U.S. Food and Drug Administration, Rockville, Maryland Liaison to Science, Technology, and Law Program DAVID KORN (IOM), Senior Vice President for Biomedical and Health Sciences Research, Association of American Medical Colleges, Washington, D.C. Staff ANNE-MARIE MAZZA, Study Director MICHELLE C. CATLIN, Senior Program Officer KATHI E. HANNA, Consultant STACEY E. SPEER, Senior Project Assistant SARA DAVIDSON MADDOX, Editor CAMILLE M. COLLETT, Research Associate (through March 2003) SUSIE BACHTEL, Administrative Assistant (through August 2003)

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Acknowledgments The committee gratefully acknowledges the contributions of many individuals who provided invaluable information and data for the study: Stanley H. Abramson, Arent Fox Kinter Plotkin & Kahn, PLLC; John Adgate, University of Minnesota; Stephen W. Brimijoin, Mayo Clinic; Angus Cameron, Roslin BioCentre; Arthur L. Caplan, University of Pennsylvania; Neil Carmichael, Bayer CropScience; Gail Charnley, HealthRisk Strategies; Ian Chart, AMVAC Chemical Corporation; Shelley Davis, Farm Worker Justice Fund; Michael L. Dourson, Technology Excellence for Risk Assessment; Monty Eberhart, Bayer CropScience; William H. Farland, U.S. Environmental Protection Agency; Daniel D. Federman, Harvard Medical School; Penelope A. Fenner-Crisp, International Life Sciences Institute; Lynn R. Goldman, Johns Hopkins Bloomberg School of Public Health; Suzanne T. Ildstad, University of Louisville; Stephen L. Johnson, U.S. Environmental Protection Agency; William Jordan, U.S. Environmental Protection Agency; Jeffrey P. Kahn, University of Minnesota; Nancy E. Kass, Johns Hopkins University Bloomberg School of Public Health; William Kelly, Center for Regulatory Effectiveness; Steven Lamm, Consultants in Epidemiology and Occupational Health, Inc.; Philip J. Landrigan, Mt. Sinai School of Medicine; Alan H. Lockwood, State University of New York; Judith A. MacGregor, Toxicology Consulting Services; Susan Makris, U.S. Environmental Protection Agency; Karen M. Martin, U.S. Environmental Protection Agency; Ray S. McAllister, CropLife America; Ernest E. McConnell, ToxPath, Inc.; Deidre L. Murphy, U.S. Environmental Protection Agency; Herbert L. Needleman, University of Pittsburgh Medical School; Erik D. Olson, Natural Resources Defense Council;

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Jacqueline Patterson, Technology Excellence for Risk Assessment; Christopher J. Portier, National Institute of Environmental Health Sciences; Peter W. Preuss, U.S. Environmental Protection Agency; Jennifer Sass, Natural Resources Defense Council; Rita S. Schoeny, U.S. Environmental Protection Agency; Vera Hassner Sharav, Alliance for Human Research Protection; Bob Sielken, Sielken & Associates Consulting, Inc.; Christina B. Swartz, U.S. Environmental Protection Agency; Abraham J. Tobia, Bayer CropScience; Richard Wiles, Environmental Working Group; and Chris F. Wilkinson, C. Wilkinson, LLC. 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: William Cain, University of California, San Diego; Daniel Farber, University of Minnesota; Penelope Fenner-Crisp, International Life Sciences Institute; Lynn Goldman, Johns Hopkins University; Bernard Goldstein, University of Pittsburgh; Fernando Guerra, San Antonio Metropolitan Health District; Carol Henry, American Chemistry Council; David Hoel, Medical University of South Carolina; Jeffrey Kahn, University of Minnesota; Mary Faith Marshall, Kansas University Medical Center; Thomas McGarity, University of Texas; Gary Rischitelli, Oregon Health and Science University; and Jonathan Samet, Johns Hopkins University. 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 R. Alta Charo, University of Wisconsin, and Donald Mattison, National Institutes of Health. Appointed by the National Research Council, they 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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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Preface One of the Environmental Protection Agency’s (EPA’s) most important and difficult tasks is regulation of the use of chemicals in order to protect human health and the environment. For several years it has struggled to determine whether in discharging this responsibility it should consider, accept, and rely on data from third-party studies that deliberately expose humans to toxicants. In accepting EPA’s request for assistance in resolving this question, the National Academy of Sciences established an interdisciplinary committee under the auspices of the Science, Technology, and Law Program to prepare a report and make recommendations. EPA’s difficulty—and the committee’s difficulty—in resolving this question arises from several conflicting interests and social values. For many the idea of research that intentionally exposes humans to toxicants is repugnant. Yet for others the potential of such studies to define more accurately human risk makes them worthwhile and acceptable. Recognizing the range of views, the committee proceeded to analyze and assess the arguments for and against intentional human dosing studies. Supporters of these studies see them as similar to Phase 1 drug trials, which expose participants to chemicals without the prospect of direct benefit to them and which can be ethically justified if they assiduously follow certain standards and procedures, such as those embedded in the Common Rule. However, critics contend that third-party studies conducted for EPA regulatory purposes, but not conducted or sponsored by EPA, usually fail to follow those standards and procedures. Defenders of human dosing studies hold that they can provide scientific data that are more relevant for

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues regulatory purposes than data from animal studies, while critics charge that most of these studies lack scientific validity and, in any event, see little benefit in raising acceptable limits for toxicants, the usual purpose of such studies. These conflicting views represent a sample of the concerns, found among members of the committee as well as in society at large, that have animated the debate. Like other groups that have addressed this subject, we note that such testing should be approached with the utmost caution and care. This committee consisted of members with expertise in ethics, law, pharmacology, toxicology, genetics, pediatrics, statistics/biostatistics, economics, epidemiology, risk assessment, and clinical trials. We met 6 times over 12 months in open and closed sessions and invited testimony from a number of individuals. In addition, we convened one public forum on January 8, 2003, to receive public input on the topics under consideration. During the course of the study, we received and reviewed voluminous studies voluntarily provided by a number of pesticide companies that had previously conducted intentional dosing studies and submitted their results to EPA for consideration. Some of these submissions were complete files on a particular chemical, while others were partial files. All of these materials were placed in the National Academies’ public access file for this project. In addition, committee staff filed a Freedom of Information request with EPA for all information relevant to the intentional dosing studies that had been submitted to the Office of Pesticide Programs. Committee staff reviewed these studies and briefed the full committee on their findings. In addressing EPA’s questions, members of the committee read and listened carefully and thought rigorously and imaginatively about the recommendations that could be made and the rationale for those recommendations. As a result, every member of the committee changed his or her mind on some important topic in this report in the course of the extended and intense discussions and deliberations. As cochairs of this committee, we express our deep gratitude to committee members and staff, all of whom devoted enormous time and intellectual energy to the development of this report. James F. Childress and Michael R. Taylor Cochairs

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Contents     ACRONYMS   xvii     EXECUTIVE SUMMARY AND RECOMMENDATIONS   1 1   INTRODUCTION AND BACKGROUND   21      EPA’s Regulation of Chemicals,   24      The Potential Role of Human Studies,   26      Events in EPA’s Pesticide Program That Prompted This Study,   30      Prior EPA Advisory Panel Review,   35      EPA’s Policy Regarding Ethical Oversight of Human Studies,   37      Charge to the Committee,   40      National Academy of Sciences Committee Process,   41      Organization of the Report,   44      References,   45 2   THE REGULATORY FRAMEWORK FOR PROTECTING HUMANS IN RESEARCH   46      Introduction,   46      History of the Development of Federal Regulations,   47      The Common Rule,   51      Minimal Risk,   53      Institutional Review Board Approval of Research,   54      Balancing Risks and Probable Benefits,   56      Continual Review and Monitoring,   56      Reporting Adverse Events,   57

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues      Monitoring by Federal Agencies,   58      Office for Human Research Protections,   58      Food and Drug Administration,   58      Nongovernmental Accreditation Programs,   60      Enforcement,   60      Recent Concerns about Human Research Participants,   61      Other Ethical Frameworks,   63      Summary,   63      References,   64 3   SCIENTIFIC JUSTIFICATION FOR AND CONDUCT OF INTENTIONAL HUMAN DOSING STUDIES   66      Introduction,   66      Scientific Elements,   67      Types of Intentional Human Dosing Studies,   67      Studies That Seek to Elicit Pharmacokinetic Information,   68      Pharmacodynamic Studies That Examine Low-Dose Effects on Biomarkers,   69      Pharmacodynamic Studies That Examine Low-Dose Effects That May Be Adverse to Participants,   70      Justification for Intentional Human Dosing Studies,   72      Criteria for Study Justification,   72      Documentation of Study Justification,   75      Protocols for Intentional Human Dosing Studies,   76      Overall Study Plan,   76      Aspects of Study Design,   76      Conducting and Recording Statistical Analysis of Results,   79      Protection of Research Participants,   79      The Protocol Document,   80      Study Reporting to EPA,   80      Summary,   81      References,   82 4   A RISK-BENEFIT FRAMEWORK FOR ASSESSING INTENTIONAL HUMAN DOSING STUDIES   84      Introduction,   84      Potential Benefits from Intentional Human Dosing Studies,   85      Personal Benefits,   85      Societal Benefits,   88      Reliability in Implementing the Current Regulatory Framework,   90      Balancing Risks and Benefits,   98      Assessing the Risks,   99      Assessing the Benefits,   103

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues      Finding the Balance,   107      Summary,   108      References,   109 5   ETHICAL CONSIDERATIONS IN THE REVIEW OF INTENTIONAL HUMAN DOSING STUDIES   110      Introduction,   110      Selection of Research Participants,   114      Payment for Participation in Research,   117      Informed Consent,   120      Compensation for Research-Related Injuries,   124      The Use of Results from Ethically Problematic Studies,   125      Studies Submitted for Regulatory Decisions After EPA Establishes New Standards,   125      Studies Completed before Publication of EPA’s New Rules,   128      Summary,   130      References,   131 6   PROCEDURES FOR EPA REVIEW OF INTENTIONAL HUMAN DOSING STUDIES   132      Introduction,   132      Independent Review of Intentional Human Dosing Studies,   132      Creation of an EPA Human Studies Review Board,   134      Pre-Experiment EPA Review,   137      Post-Experiment EPA Review,   140      Ongoing Assessment and Monitoring,   141      Summary,   142      Reference,   143 7   EPA’S USE OF DATA FROM INTENTIONAL HUMAN DOSING STUDIES IN RISK ASSESSMENT   144      Introduction,   144      EPA’s Risk Assessment Framework,   144      Implications of the Use of Intentional Human Dosing Studies in the Risk Assessment Process,   148      Eliminating the UFA,   150      The Case of Cholinesterase Inhibition,   152      Other Uses of Data,   153      Conclusions and Recommendations,   153      Summary,   156      References,   157

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues     APPENDIXES     A   VALUES AND LIMITATIONS OF ANIMAL TOXICITY DATA   159 B   PHARMACOKINETICS AND METABOLISM OF PESTICIDES   168 C   BIOGRAPHICAL SKETCHES OF THE MEMBERS AND STAFF OF THE COMMITTEE ON THE USE OF THIRD PARTY TOXICITY RESEARCH WITH HUMAN RESEARCH PARTICIPANTS   173 D   BIOGRAPHICAL SKETCHES OF THE MEMBERS OF THE SCIENCE, TECHNOLOGY, AND LAW PANEL   185 E   MEETING AGENDAS   192 F   COMBINED REGISTRANTS LIST FOR ALL MEETINGS   201

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues List of Tables and Boxes TABLES 1.1   Relevant Pesticide Studies Received by EPA Since April 1991,   33 2.1   Federal Agencies Subject to the Common Rule,   52 BOXES 1.1   Legal Statutes for EPA Regulation of Chemicals,   25 1.2   Four-Step Process for Human Health Risk Assessment,   28 1.3   Common Rule Requirements for IRB Review,   38 1.4   Specific Statement of Task,   42 3.1   Committee’s Use of Risk Terminology for Data Derived from Intentional Human Dosing Studies,   71 3.2   Criteria for Judging the Adequacy of the Scientific Justification for Intentional Human Dosing Studies,   75 3.3   Examples of Study Designs That Identify a NOELHU,   78 7.1   Committee’s Use of Risk Terminology for Data Derived from Intentional Human Dosing Studies,   149

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Acronyms AChE Acetylcholinesterase DHEW U.S. Department of Health, Education, and Welfare DHHS U.S. Department of Health and Human Services DMC Data Monitoring Committee DSMB Data and Safety Monitoring Board EPA U.S. Environmental Protection Agency FDA U.S. Food and Drug Administration FFDCA Federal Food, Drug, and Cosmetic Act FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality and Protection Act GCP Good Clinical Practice GI Gastrointestinal HED Human Equivalent Dose IND Investigational New Drug IOM Institute of Medicine IRB Institutional Review Board IRIS Integrated Risk Information System

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues LOAEL Lowest Observed Adverse Effect Level LOEL Lowest Observed Effect Level MTD Maximally Tolerated Doses NAS National Academy of Sciences NBAC National Bioethics Advisory Commission NCQA National Committee on Quality Assurance NIH National Institutes of Health NOAEL No Observed Adverse Effect Level NOEL No Observed Effect Level NRC National Research Council OHRP Office for Human Research Protections OIG Office of Inspector General OP Organophosphates OPRR Office for Protection from Research Risks PBPK Physiologically-Based Pharmacokinetic PD Pharmacodynamic PHS U.S. Public Health Service PK Pharmacokinetic RAC Recombinant DNA Advisory Committee RfC Reference Concentrations RfD Reference Dose SAB Science Advisory Board SAP Science Advisory Panel TSCA Toxic Substance Control Act UF Uncertainty Factor VOC Volatile Organic Chemicals