Protecting Human Research Subjects: Human Subjects Research Handbook, Second Edition

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The Secretary of Energy MEMORANDUM FOR: ALL DEPARTMENTAL EMPLOYEES Revised Human Subject Han book Research on humans performed in accordance with ethical and humanitarian principles allows the experiments to be performed that provide medical and scientific benefits to individuals and to the Nation. Medical trials led to the development of the polio vaccine. Radiation research brought us treatments for cancer and X-rays to pinpoint medical problems. It is important to remember that many lives have been saved and many more will be saved using diagnoses and treatments of diseases derived through medical trials. To assure that human subjects are fully protected from potential abuses in research experimentation, Federal regulations have been promulgated. It is the policy of the Department that the rights and welfare of human subjects involved in research supported or sanctioned by the Department of Enersy be protected in accordance with 10 CFR Part 745 (Federal Policy for the Protection of Human Subjects); and, until the requirements of the Department policies and orders have been met, QQ new research activity involving human subjects shall be initiated. A Human Subjects Handbook was distributed by the Offce of Energy Research to provide guidance in the implementation of these regulations and a single resource for all of the basic reference information users may need. This newly revised version (spring 1995) has been prepared to provide broader and more current information. I t includes a more comprehensive and definitive description of the roles and responsibilities of each participant in the preparation and approval process for research involving human subjects. The presentation of research project assurances has been expanded and clarified. The format, organization of material, text layout, and graphics in the Handbook have been upgraded. Numerous tables and charts have been added for enhanced understanding and interpretation of data. An expanded glossary of terms, table of contents, and subject index have been added; and, lastly, special topics of currently significant importance have been introduced. The issuance and distribution ofthis Handbook serves as a reminder of the importance with which the Department views this topic and the leadership we have taken in overseeing the proper implementation of contemporary research ethics, rules, and regulations by our programs, laboratories, and field offices.

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Human Subjects Research U.S. Department of Energy Office of Health and Environmental Research

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This handbook was prepared by the U.S.Department of Energy (DOE), Office of Health and Environmental Research (OHER) under the direction of the Human Subjects Research Program Manager, Dr. Susan L. Rose. Significant contributions were made by the following people: Mr. Joseph Aaron, Oakland Operations Office; Ms. Sharon Betson, DOE, OHER; Ms. Chris Byme, Lawrence Berkeley National Laboratory; Mr. Pepin Carolan, Brookhaven Area Office; Dr. Gary Chadwick, U.S. Food and Drug Administration; Ms. Susan Dallas, Oak Ridge Institute for Science and National Laboratories; Dr. Martha W. Firestine, Walcoff & Associates, Inc.; Dr. Robert K. Jones, Inhalation Toxicology Research Institute; Ms. Tana M. Jorgensen, Walcoff & Associates, Inc.; Pietri, Chicago Operations Office; Dr. Joan P. Porter, National Institutes of Health (NIH), Office for Protection from Research Risks (OPRR); Dr. Thomas Puglisi, NIH, OPRR; Mr. Alan Rither, Pacific Northwest Laboratories; Ms. Joyce Rochek, DOE, OHER; Ms. Marya Rowan, DOE, Office of General Counsel; Ms. Patricia L. St. Clair, Idaho Operations Office; and Ms. Marilynn Thullen, Los Alamos Many of the materials and resources included in this handbook were collected from various human subjects research meetings and conferences, DOE laboratory resource manuals, and from other resources such as the OPRR 1993 Protecting Human Subjects Institutional Review Board Guidebook and the Food and Drug Administration Information Sheets for Institutional Review Boards and Clinical

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Purpose of This Handbook This handbook serves as a guide to understanding and implementing the Federal regulations and U.S. Department of Energy (DOE) Orders established to protect human research subjects. The first edition of this handbook was published in 1992, shortly after DOE and 15 other Federal agencies and departments formally adopted the Common Rule for the protection of human subjects in 1991. This revised edition incorporates many of the resources and instructional materials included in the first edition while addressing current issues and concerns in the human research arena. Material in the handbook is directed toward new and continuing institutional review board (IRB) members, researchers, institutional administrators, DOE officials, and others who may be involved or interested in human subjects research. It offers a comprehensive overview of the various requirements, procedures, and issues relating to human subjects research today. All DOE program offices and institutions that are involved in human subjects research should make this handbook an available resource at their office/facility. A Brief History of the Ethical Guidelines That Govern the Human Subjects Protection System The principles that underlie human subjects protections today are found in three main documents-the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report.' The Nuremberg Code was developed in the late 1940s for the Nuremberg military tribunal as standards by which to judge human experimentation conducted by the Nazis. The code captures many of what are now taken to be the basic principles governing the ethical conduct of research involving human subjects: voluntary consent, minimization of risk and harm, favorable risk to benefit ratio, qualified researchers using appropriate research design, and freedom of the subject to withdraw at any time. The Declaration of Helsinki, prepared by the World Medical Association in 1964 and revised in 1975 and 1989, endorses principles similar to those in the Nuremberg Code and distinguishes therapeutic from nontherapeutic research. - ' Reprints of these documents are included in the appendix (Chapter 15) of this handbook. DOE Human Subjects Research Handbook i

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The Belmont Report was published by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1979. This report identifies three essential requirements for the ethcal conduct of research involving human subjects: respect for persons, beneficence, and justice. Respect for persons requires true informed consent, which entails dissemination of clear and adequate information about the research to the research subjects, full comprehension by participating subjects, and true voluntariness, which occurs when agreement to participate is free from coercion and undue influence. Beneficence includes the consideration of all possible harms, not just physical or psychological pain or injury. It suggests that consideration of possible benefits should involve not only the benefits to the individual, but also the societal benefits that might be gained from the research. Justice mandates that the selection of research subjects be the result of fair selection procedures and also result in fair selection outcomes. It further indicates that researchers must follow an order of preference in the selection of classes of subjects (e.g, adults before children) and that some Respect lor Persons4 recognition of the personal dignity and autonomy 03 individuals and special protectionfor those persons with diminished autonomy. Beneficence-dn obligation to protect persons from harm by maximizing anticipated benefirs and minimizing possible risks of ham. Justice-Fairness in distribution of burdens and benefits; ofen expressed in terms of treating persons of similar circumstances or characferisrics classes of potential subjects (e.g., the institutionalized, mentally infirm, or prisoners) may be involved as research subjects only in certain conditions, if at all. The Nuremberg Code, the Declaration of Helsinki, and the Belmont Report served as the cornerstone for the drafting of the Federal Policy for the Protection of Human Subjects (known as the Common Rule). The Common Rule was adopted by 16 Federal agencies that conduct, support, or otherwise regulate human subjects research. DOE adopted the Common Rule as Title 10 Code of Federal Regulations (CFR), Part 745. (See Chapter 2 for a copy of this regulation.) What follows in this handbook is a series of chapters that provide comprehensive guidance for complying with the requirements found in Federal regulations and associated DOE Orders for protection of human How to Use the Handbook This handbook is divided into three parts: procedures and responsibilities, special topics, and resources. Part 1 of the handbook (Chapters 1-6) provides an overview and general guidance concerning research involving human subjects. It gives direction on how to identify human subjects research and provides reprints of the Federal regulations and DOE orders established to protect human research subjects. These chapters detail the roles and responsibilities of the various entities-DOE program managers, field offices, laboratory administrators, institutional review boards, and investigators-that may be involved in human research processes and procedures. Part 2 of the handbook (Chapters 7-13) addresses special topics or issues regarding current human subject research. It includes guidance in cases where research projects involve classified or sensitive data or when research sponsors have proprietary concerns. It provides information on the use of W ii DOE Human Subjects Research Handbook

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personally identifiable human subjects data and general guidance on cooperative research projects including projects involving international collaborators. Additionally, Part I1 of the handbook covers issues such as the difference between occupational health surveillance and human subjects research, the reporting of adverse events, compensation for injury, research involving vulnerable populations, and various other significant issues that IRBs and others involved in human research must address. Toward the end of Part II, there is information on DOE’s performance review system and on audit systems established at other Federal agencies. Checklists are provided to help institutions evaluate their compliance with the Common Rule. Also included is a description of the purpose of the DOE Human Subjects Research Projects Database and the way to access it on the Internet, as well as the availability of various educational materials on the protection of human subjects developed by DOE’s Office of Health and Environmental Research (OHER). Part 3 of the handbook (Chapters 14-17) consists of reference chapters, including an appendix, a list of DOE and other Federal agency contacts, a glossary, and a list of additional resources on human research topics that handbook users may find valuable for in-depth review of topics of - DOE Human Subjects Research Handbook iii

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Table of Contents Table of Contents List of Figures Acronyms and Abbreviations Part 1 : Procedures and Regulations Chapter 1: Protecting Human Research Subjects Within the Department of Energy B. Identifying Human Subjects Research C. Roles and Responsibilities Chapter 2: Applicable Federal Rules and U.S. Department of Energy Orders B. 10 CFR Part 745, Federal Policy for the Protection of Human Subjects; Notices and Rules C . DOE Order 1300.3, Policy on the Protection of Human Subjects F. 45 CFR 46,Research Activities Which May Be Reviewed Through Expedited Services, Protection of Human Subjects Chapter 3: Institutional Responsibilitiesand Administrative Matters B. Establishing an Institutional Review Board C. Violations of Regulations: Sanctions D. Voicing Concerns Regarding Current Human Subjects Research - DOE Human Subjects Research Handbook V

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Table of Contents Chapter 4: Single and Multiple Project Assurances Common Requirements for SPA and MPA Institutions Vulnerable Populations Requirements How To Qualify for MPA Status How To Apply for SPA or MPA Status Chapter 5: IRB Responsibilities and Procedures B. Types of IRB Review e Full Board Review Exempt Research Projects Continuing Reviews and Project Oversight Considerations D. Incentives for Participation Chapter 6: Investigator Responsibilities and Procedures B. Proposal Preparation and Review C. Informed Consent Preparation Part 2: Special Topics Chapter 7: Data Protection B. Classified or Sensitive Research C. Proprietary Concerns and the Freedom of Information Act (FOIA) D. Legal Aspects of the Use of Personally Identifiable Human Subjects Data vi DOE Human Subjects Research Handbook

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Table of Contents Chapter 8: Cooperative Research B. General Guidance on Cooperative Research Projects C. Cooperative Research Projects Legal Requirements: 10 CFR 745 Section 114 Types of Cooperative Assurances Types of Cooperating Institutions Types of Cooperative Agreement Funding Mechanisms IRB Review Options Recommended IRB Review-Domestic Cooperative Agreements Chapter 9: International Research Recommended IRB Review-International Agreements International Research Considerations Chapter 10: Guidance on Occupational, Clinical, and Other Studies B. Occupational Health Surveillance as Opposed to Research D. Adverse Event Reporting F. Liability: Compensation for Injury Sample Statements About Compensation G. Types of Research That May Not Require IRB Review viiDOE Human Subjects Research Handbook

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Table of Contents Chapter 11: Special Classes of Subjects: Vulnerable Populations Identifying Vulnerable Subjects Including Vulnerable Populations Protecting Vulnerable Populations B. Fetal and Human In Vitro Fertilization Research E. Children and Minors Chapter 12: The DOE Human Subjects Research Projects Database Confidential and Proprietary Information B. The FY 1994 Human Subjects Research Projects Database Accessing the FY 1994 Database Through the Internet C. The FY 1995 Human Subjects Research Projects Database FY 1995 Database Update FY 1995 Database Questionnaire and Instructions Chapter 13: Performance Review and Educational Outreach D. Compliance Investigations by Other Federal Agencies E. DOE Educational Outreach Materials viii DOE Human Subjects Research Handbook

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Table of Contents A. DOE Human Subjects Research Points of Contact B. DOE Human Subjects Working Group Members C. Human Subjects Research Points of Contact at Other Federal Agencies and Departments A. The Nuremberg Code C. The Belmont Report D. 21 CFR Part 50, et al., Protection of Human Subjects; Informed Consent; Proposed Rule E. Institutions With a National Institutes of Health (NIH) Multiple Project Assurance (MPA) F. The National Bioethics Advisory Commission (Department of Health and Human Services, Food and Drug Administration) as of May 10, 1995 Chapter 17: Additional References DOE Human Subjects Research Handbook ix

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List of Figures Sample Institutional Policy Delegating Authority to the IRB ............. 3-7 Sample Transmittal Letter Requesting Approval of a New Project Sample Transmittal Letter Documenting Continuing Review List of Assurances Held by DOE Laboratories ...................... 4-27 Sample IRB Review Request Form ............................... 6-7 Sample Request for Continuing Review Form ....................... 6-9 Human Studies Review Process Flow Chart ........................ 6-11 Sample Research Subject Consent Form .......................... 6-19 Sample Human Subjects Bill of Rights ........................... 6-25 DOE Human Subjects Research Handbook xi

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List of Figures Sample Interinstitutional Assurance (Between Institutions A and B) ........ 8-5 Observations on the Negotiation of Single Project Assurance With Institutions in Foreign Countries ......................................... 9-5 DHHS Documents Related to International Collaborations ............... 9-7 Background Information for U.S. Government Department and Agency Personnel: Protection of Human Subjects in Studies Conducted Outside the United States ........................ 9-9 For United States Department and Agency Staff Use: Points to Consider. Protection of Human Subjects. Narrative Format for Providing an Assurance for Sample Assurance of Protection of Human Subjects in International Research ..................................... 9-17 4U.S. Food and Drug Administration. Emergency Use of an Medical News and Perspectives. JAMA. April 28. 1993 ..............1 1-15 FY 1995 Database Questionnaire ............................... 12-9 FY 1995 Database Questionnaire Instructions ...................... 12- 17 Specific Items for Review or Verification During a Protection of Human Subjects Performance Review .......................... 13-5 HERAC Response Checklist ................................... 13-7 X i i DOE Human Subjects Research Handbook

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List of Figures Figure No. Title Page for Institutional Review Boards ................................ 13-15 Figure 13d. NIH, Office for Protection from Research Risks-Compliance - DOE Human Subjects Research Handbook xiii

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The following is a list of acronyms and abbreviations that appear in this handbook or that are in some way associated with human subjects research at the Department of Energy. Alcohol, Drug Abuse and Mental Health Administration Argonne National Laboratory Applied Research Ethics …