DISCLAIMER The following is a staff memorandum or other working document prepared for the members of the Advisory Committee on Human Radiation Experiments. It should not be construed as representing the final conclusions of fact or interpretation of the issues. All staff memoranda are subject to revision based on further information and analysis. For conclusions and recommendations of the Advisory Committee, readers are advised to consult the Final Report to be published in 1995. TAB H-1 ---DRAFT - FOR DISCUSSION PURPOSES ONLY--- MEMORANDUM TO: Members of the Advisory Committee on Human Radiation Experiments FROM: Advisory Committee Staff DATE: January 10, 1995 RE: History and Provisions of the Federal Policy for the Protection of Human Research Subjects ("Common Rule") This memorandum briefly reviews the development and provisions of the common Federal policy that governs the conduct of human subjects research for 16 Federal agencies. (Federal Policy for the Protection of Human Subjects; Notices and Rules, Federal Register, vol. 56, no. 117, 6/18/91, Attachment 1), known as the "Common Rule." It also discusses the key provisions of the Common Rule concerning institutional assurances, institutional review boards and requirements for informed consent. A separate memorandum (Tab H-2) details the more specific administrative and regulatory policies for protecting human subjects of each of the six agencies within the purview of the Advisory Committee. HISTORY OF THE COMMON RULE The Common Rule governs the use of human subjects in research conducted or supported by 16 Federal agencies. This policy was based on rules issued by Department of Health Education and Welfare (HEW, the predecessor to Department of Health and Human Services (HHS)) that developed from the recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which existed from 1974 to 1978 (herein referred to as the National Commission.) The first Federal regulations for the protection of human research subjects were issued by HEW on May 30, 1974. These regulations raised to regulatory status a Public Health Service (PHS) policy issuance (PPO #129). (The 1966 PHS policy was revised four times before becoming Departmental policy in 1971. At this time, the PHS policy was extended to cover all research involving risks to human subjects conducted or supported by HEW.) The 1974 regulations anticipated explicit statutory authority in Title II of the National Research Act by 42 days. Title II established statutory authority for the institutional review board (IRB) as one mechanism through which research involving human subjects would be overseen, both by prior review and ongoing monitoring. In August 1975 an addendum to the regulation that provided additional protections in research involving pregnant women, fetuses and in vitro fertilization was issued. 1 The National Commission issued reports and recommendations that set forth basic ethical principles to underlie the conduct of biomedical and behavioral research involving human subjects and that recommended policies to ensure that research be conducted according to those principles. Its report, Ethical Principles and Guidelines on the Protection of Human Subjects of Research, popularly known as The Belmont Report, was published in the Federal Register in April 1979 by the HEW Secretary as a general statement of policy. This report is the National Commission's most widely disseminated document [FR Doc 97-12065]. The National Commission also recommended that HEW require that each institution conducting research that is supported by the Department develop policies to ensure the protection of research subjects. In 1981, in response to the National Commission's reports and recommendations, HHS promulgated a revision of its human subjects regulation. This revision sets out in greater specificity the responsibilities of IRBs and the procedures IRBs were to follow. The HHS regulation, codified at Code of Federal Regulations, section 45, part 46 [45 CFR 46] was technically amended in March 1983. The Food and Drug Administration (FDA), a subagency of HHS, issued regulations on the protection of human subjects, codified at 21 CFR 50, 56, in May 1980 and subsequently revised them in 1981 and 1989. The provisions of FDA's regulation governing informed consent procedures are in Part 50 and those governing IRBs are in Part 56. The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, herein referred to as the President's Commission, met between 1980 and 1983. Its mandates included reviewing Federal rules and policies governing human subjects research and determining how well those rules were being implemented or enforced. In late 1981, the President's Commission, in its first biennial report, recommended that all Federal agencies adopt the HHS regulations (45 CFR 46) governing the protection of human subjects of research. In response to these recommendations, in mid-1982 the President's Science Advisor, Office of Science and Technology Policy (OSTP), appointed an ad hoc Committee for the Protection of Human Research Subjects under the auspices of the Federal Coordinating Council for Science, Engineering, and Technology, to respond to the recommendations of the President's Commission. (The ad hoc Committee is now a standing subcommittee of OSTP and convenes periodically to review and coordinate Federal policy on human subject protections.) The Federal agencies involved were Department of Agriculture, Department of Energy, National Aeronautics and Space Administration, Department of Commerce, Consumer Product Safety Commission, International Development Cooperation Agency (AID), Department of Housing and Urban Development, Department of Justice, Department of Defense, Department of Education, Veterans Administration (now Department of Veterans Affairs), Environmental Protection Agency, HHS, FDA, National Science Foundation, Department of Transportation, OSTP, and Office of Management and Budget. The Federal ad hoc Committee developed a model policy which OSTP later modified and, with all of the affected departments and agencies concurring, published a proposed common policy on human subjects protection in the Federal Register on June 3, 1986. 2 The Federal policy, known as the Common Rule, was finalized and published in the Federal Register on June 18, 1991. Each of the agencies listed above, except for FDA, codified the Common Rule under its own regulatory authority at that time. The distinct requirements of FDA's statutory authority for regulated research necessitated somewhat different rules, as discussed below. The Central Intelligence Agency (CIA) has not adopted specific human subjects regulations, but follows the HHS regulations pursuant to an Executive Order. The Common Rule is identical to the "Basic HHS Policy for Protection of Human Research Subjects," 45 CFR 46, Subpart A. Additional sections of the HHS regulation, which have not been adopted by the other Federal departments and agencies as part of the Common Rule, provide additional protections for fetuses, pregnant women, and human in vitro fertilization (Subpart B), prisoners (Subpart C), and children (Subpart D). The current versions of Subparts B and C became final in 1978 and that of Subpart D in 1983. As detailed in the memorandum on individual agency policies, several have adopted Subparts B, C, and D as administrative guidelines. The FDA made conforming changes to its regulations governing informed consent and IRBs in the June 18, 1991, Federal Register. In the preamble to its regulatory changes, the FDA states that it "is committed to being as consistent with the final Federal Policy as it can be, given the unique requirements of the [Food, Drug, and Cosmetic Act] and the fact that FDA is a regulatory agency that rarely supports or conducts research under its regulations." Two departures from the common policy are that FDA does not allow for the substitution of local procedures for informed consent in research conducted abroad (this is permitted subject to several constraints in the Common Rule) and FDA does not allow IRBs to approve waivers of the elements of informed consent (the Common Rule does allow for certain waivers, subject to several stringent conditions). Additional information on the ways in which FDA policy and oversight procedures differ for human subject research that the agency regulates is provided below in the section on FDA. FDA intramural and FDA-sponsored research is, however, subject to the provisions of the HHS regulation, in addition to those of the FDA regulation. In some cases, then, FDA research, both intra- and extra-mural, is subject to two sets of regulatory provisions. Differences between the Common Rule and the FDA regulations are discussed in the memorandum on individual agency policies. PROVISIONS OF THE COMMON RULE The Common Rule provides the framework for Federal agency oversight activities for research subjects' protection. These protections are effected through institutional assurances of compliance with the provisions of the Common Rule. The 16 agencies identified above have uniform policies for IRB review of research involving human subjects and for informed consent procedures (with minor differences in the case of FDA due to its distinctive legislative mandate). Each agency or office responsible for oversight and enforcement of these policies, however, has somewhat different administrative practices, conducting centralized reviews of research documentation to a greater or lesser degree, providing more or less detailed guidance to subsidiary intramural research offices and to contractors and grantees, and auditing and reviewing IRB performance routinely or on an exceptions or complaint basis only. These practices are discussed further in the memorandum on individual agency policies. The review procedures that each department or agency has in place for assessment of the scientific merit of research proposals 3 that involve the use of human subjects will also affect the protection of subjects, because these intra- and extramural peer reviews determine the nature of the research that will be performed, entail judgments about the intrinsic value of the research that affect calculations of the risk-benefit analysis, and confirm that institutionally based reviews of human subjects research have taken place. Agency oversight of human subjects protections are characterized below as a distinct activity, as is the institution-level review of research proposals from the perspective of the adequacy of the protection of subjects. These more or less discrete activities, however, are not the only variables that determine the quality of human subject protections. The experience of human subjects in research ultimately depends both on subject protection oversight and on the soundness of judgments of scientific merit and the research priorities pursued. Institutional Assurances and IRBs Each institution engaged in human subject research covered by the Common Rule must provide written assurance to the head of the sponsoring agency that the institution will comply with the requirements of the Common Rule. The Common Rule specifies the contents of such institutional assurances, including the designation of one or more IRBs, the number and types of its members, the written policies and procedures of the IRB's conduct of initial and continuing review, and written procedures for the reporting of any unanticipated problems involving risks to subjects or any serious noncompliance to the IRB, institution officials and the appropriate Federal agency. The Federal agency determines the scope and duration of any assurance that it negotiates with the institution (it may apply only to a single research project or to multiple projects) and may place conditions on such assurances as it deems appropriate. If the institution has negotiated a Multiple Project Assurance (MPA) with the Office for the Protection from Research Risks (OPRR) within NIH, according to the Common Rule this assurance must be accepted by the agency sponsoring the research without further conditions. This provision was adopted so that research institutions would not face several sets of possibly conflicting requirements from different Federal sponsors. OPRR only negotiates MPAs with those institutions that perform such volume of HHS-funded research to justify devoting OPRR's resources to this activity. IRB review of cooperative or collaborative research, which involves several institutions or even private practitioners in a single research protocol, may be handled in various ways. The Common Rule states that every institution that is involved in a research project is responsible for the protection of human subjects within that institution. Initial and continuing IRB review, however, may be conducted by IRBs at each participating institution or, with the approval of the Federal agency that is supporting the research, joint review by a single IRB, either at one of the participating institutions or organizationally distinct from the participating research sites. Such arrangements have become more common because of the increasing number of cooperative clinical research studies and the growing diversity in sponsorship of biomedical research. The Common Rule specifies minimum IRB size (five members) and requirements for representation and diversity. 4 The IRB's authority to review, require modifications in and approve all research activities covered by the Common Rule is detailed, as are expedited review procedures for research involving no more than minimal risk or for minor changes in the research protocol. If research qualifies for expedited review, it may be approved by the IRB chair without convening the full IRB. Further, the criteria for IRB approval of research are outlined. These criteria reflect the ethical principles and guidelines of the National Commission's Belmont Report. Research proposals are to be evaluated in terms of the extent to which they minimize risks to subjects, involve risks that are reasonable in relation to anticipated benefits, select subjects equitably, have adequate procedures for obtaining and documenting informed consent, provide for ongoing monitoring for safety, as appropriate, and protect subjects' privacy and confidentiality. An institution may further review research that is covered by the Common Rule, but it may not overrule an IRB's disapproval of a project. IRBs have the authority to suspend or terminate approval of research if such research is not being conducted according to the IRB's requirements or if serious, unexpected harm to subjects has occurred. IRBs must conduct continuing review of research, "at intervals appropriate to the degree of risk," but at least annually, and they have the authority to observe the consent process and the research activities themselves. An IRB or its sponsoring institution must maintain documentation of all of the IRB's activities, including copies of research proposals, scientific evaluations, consent forms, progress reports, reports of injuries to subjects, minutes of meetings and copies of correspondence with investigators. Such records are retained for at least three years after completion of the project under consideration. In addition, the institution must retain records of research for at least three years after its completion. All records must be accessible to the Federal agency conducting or supporting the research. The agency may terminate or suspend support for any project for noncompliance with the terms of the Common Rule for the protection of research subjects. This is the only sanction provided for by the Common Rule in the case of noncompliance with or violation of its terms. Requirements for Informed Consent The Common Rule specifies in detail the elements of informed consent by a subject or a subject's legal representative to participate in a research project. The IRB must review the written informed consent documents proposed for use by an investigator and may monitor the informed consent process and records to ascertain that the requirements have been met. The informed consent process may consist of a written document containing information on all of the elements listed below, or it may consist of a short written document stating that all the following elements have been presented orally. In this case the IRB must approve a written summary of the content of the oral presentation. The basic elements of the informed consent process are: . a statement that the study involves research, an explanation of the purposes of the research, and a description of the procedures to be followed; 5 . a description of any reasonably forseeable risks or discomforts to the subject; . a description of any benefits to the subjects or others that might reasonably be expected; . disclosure of alternative procedures or courses of treatment; . a statement describing the extent to which confidentiality of records identifying the subject will be maintained; . an explanation of the availability and nature of any compensation or medical treatment if injury occurs and where further information can be obtained; . information regarding whom to contact for further information about the research and subjects' rights and whom to contact in case of injury; and . a statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time [sec.__.116 (a)]. The Common Rule lists several additional elements of consent that may be appropriate under particular circumstances and the circumstances under which an IRB may waive the informed consent requirement in the case of a particular research project [sec.__.116(b) and (d)]. The Common Rule does not specify the nature of oversight activities to be conducted by Federal agencies with respect to the performance of institutional human subjects protections. Thus such activities are programatically distinct for each of the agencies governed by the Common Rule. The oversight policies and practices of HHS, FDA, DOD, VA, DOE, NASA, and CIA are reviewed in the following memorandum. 6