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Institutional Review Board * INTRODUCTION *
A. History of the Human Subjects Protection System
A. THE HISTORY OF THE HUMAN SUBJECTS PROTECTION SYSTEM The modern story of human subjects protections begins with the Nuremberg Code, developed for the
Nuremberg Military Tribunal as standards by which to judge the 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. The first provision of the Code states that "the voluntary
consent of the human subject is absolutely essential." Freely given consent to participation in research is
thus the cornerstone of ethical experimentation involving human subjects. The Code goes on to provide the
details implied by such a requirement: capacity to consent, freedom from coercion, and comprehension of
the risks and benefits involved. Other provisions require the minimization of risk and harm, a favorable
risk/benefit ratio, qualified investigators using appropriate research designs, and freedom for the subject to
withdraw at any time. Similar recommendations were made by the World Medical Association in its
Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research
Involving Human Subjects, first adopted by the 18th World Medical Assembly in Helsinki, Finland, in
1964, and subsequently revised by the 29th World Medical Assembly, Tokyo, Japan, 1975, and by the 41st
World Medical Assembly, Hong Kong, 1989. The Declaration of Helsinki further distinguishes
therapeutic from nontherapeutic research. In the United States, regulations protecting human subjects first became effective on May 30, 1974.
Promulgated by the Department of Health, Education and Welfare (DHEW), those regulations raised to
regulatory status NIH's Policies for the Protection of Human Subjects, which were first issued in 1966.
The regulations established the IRB as one mechanism through which human subjects would be protected. In July of 1974, the passage of the National Research Act established the National Commission for the
Protection of Human Subjects of Biomedical and Behavioral Research. The Commission met from 1974
to 1978. In keeping with its charge, the Commission issued reports and recommendations identifying the
basic ethical principles that should underlie the conduct of biomedical and behavioral research involving
human subjects and recommending guidelines to ensure that research is conducted in accordance with
those principles. The Commission also recommended DHEW administrative action to require that the
guidelines apply to research conducted or supported by DHEW. References for the Commission's reports
are listed in Appendix 1 (General Bibliography). The Commission's report setting forth the basic ethical
principles that should underlie the conduct of biomedical and behavioral research involving human subjects
is titled The Belmont Report, and is discussed in depth below. In 1981, in response to the Commission's reports and recommendations, both the Department of Health
and Human Services (DHHS, formerly DHEW) and the FDA promulgated significant revisions of their
human subjects regulations. As Levine (1986) points out, these revisions "do not alter the general
principles of IRB review as they had evolved over the preceding three decades. Rather, they are concerned
with some of the details of what the IRB is expected to accomplish and some of the procedures it must
follow" [p. 324]. The DHHS regulations are codified at Title 45 Part 46 of the Code of Federal Regulations. Those "basic"
regulations became final on January 16, 1981, and were revised effective March 4, 1983, and June 18,
1991. The June 18, 1991, revision involved the adoption of the Federal Policy for the Protection of
Human Subjects. The Federal Policy (or "Common Rule," as it is sometimes called) was promulgated by
the sixteen federal agencies that conduct, support, or otherwise regulate human subjects research; the FDA
also adopted certain of its provisions. As is implied by its title, the Federal Policy is designed to make
uniform the human subjects protection system in all relevant federal agencies and departments. The
Federal Policy is discussed in depth in Chapter 2, Section A(i). Additional protections for various vulnerable populations have been adopted by DHHS, as follows: Subpart B, "Additional Protections Pertaining to Research, Development, and Related
Activities Involving Fetuses, Pregnant Women and Human in Vitro Fertilization" became
final on August 8, 1975, and was revised effective January 11, 1978, and November 3, 1978. Subpart C, "Additional Protections Pertaining to Biomedical and Behavioral Research
Involving Prisoners as Subjects" became final on November 16, 1978. Subpart D, "Additional Protections for Children Involved as Subjects in Research" became
final on March 8, 1983, and was revised for a technical amendment on June 18, 1991. FDA regulations on the protection of human subjects are codified at Title 21 Parts 50 and 56 of the Code
of Federal Regulations. Part 50, which sets forth the requirements for informed consent, became final on
May 30, 1980, and was revised effective January 27, 1981, March 3, 1989, and June 18, 1991. Subpart C,
which provides special protections for prisoners, was adopted on July 7, 1981; the effective date of
Subpart C has been stayed until further notice. Part 56, which sets forth the provisions for institutional
review boards, was adopted on January 27, 1981, with revisions to some sections effective February 27,
1981, March 3, 1989, and June 18, 1991. Additional FDA regulations that are relevant to IRB review of research are Parts 312 (Investigational New
Drug Application), 812 (Investigational Device Exemptions) and 860 (Medical Device Classification
Procedures). The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and
Behavioral Research, which met from 1980 to 1983, produced numerous reports on various aspects of
medical ethics and biomedical and behavioral research. Its mandate with respect to the protection of human
subjects was, first, to review the federal rules and policies governing human subjects research, and second,
to determine how well those rules were being implemented or enforced. References for the President's
Commission's reports are listed in Appendix 1 (General Bibliography). Several excellent sources trace the history of human subjects research and the development of the IRB
system as a mechanism for the protection of human subjects. An account of the history of human subjects
research and the human subjects protection system in the United States can be found in David J. Rothman's
Strangers at the Bedside: A History of How Law and Bioethics Transformed Medical Decision Making
(Chapters 1-5 and Epilogue) and in Dennis Maloney's Protection of Human Research Subjects. Rothman
details the abuses to which human subjects were exposed, culminating in Henry Beecher's 1966 article,
"Ethics and Clinical Research," published in the New England Journal of Medicine, and ultimately
contributing to the impetus for the first NIH and FDA regulations. Other equally useful sources include
Robert J. Levine's Ethics and Regulation of Clinical Research (Chapter 14), Joan E. Sieber's Planning
Ethically Responsible Research, Robert M. Veatch's "Human Experimentation Committees: Professional
or Representative?," and William J. Curran's "Government Regulation of the Use of Human Subjects in
Medical Research: The Approaches of Two Federal Agencies." On September 30, 1978, the National Commission for the Protection of Human Subjects of Biomedical
and Behavioral Research submitted its report entitled "The Belmont Report: Ethical Principles and
Guidelines for the Protection of Human Subjects of Research." The Report, named after the Belmont
Conference Center at the Smithsonian Institution where the discussions which resulted in its formulation
were begun, sets forth the basic ethical principles underlying the acceptable conduct of research involving
human subjects. Those principles, respect for persons, beneficence, and justice, are now accepted as the
three quintessential requirements for the ethical conduct of research involving human subjects. Respect for persons involves a recognition of the personal dignity and autonomy of
individuals, and special protection of those persons with diminished autonomy. Beneficence entails an obligation to protect persons from harm by maximizing anticipated
benefits and minimizing possible risks of harm. Justice requires that the benefits and burdens of research be distributed fairly. The Report also describes how these principles apply to the conduct of research. Specifically, the
principle of respect for persons underlies the need to obtain informed consent; the principle of
beneficence underlies the need to engage in a risk/benefit analysis and to minimize risks; and the principle
of justice requires that subjects be fairly selected. As was mandated by the congressional charge to the
Commission, the Report also provides a distinction between "practice" and "research." The text of the
Belmont Report is thus divided into two sections: (1) boundaries between practice and research; and (2)
basic ethical principles. The full text of the Belmont Report, which describes each of the three principles
and its application, is provided in the Guidebook in Appendix 6; a summary follows. Boundaries Between Practice and Research While recognizing that the distinction between research and therapy is often blurred, practice is described
as "interventions that are designed solely to enhance the well-being of an individual patient or client and
that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide
diagnosis, preventive treatment, or therapy to particular individuals." The Commission distinguishes
research as designat[ing] an activity designed to test an hypothesis, permit conclusions to be drawn, and
thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories,
principles, and statements of relationships). Research is usually described in a formal protocol that sets
forth an objective and a set of procedures designed to reach that objective. "The Report recognizes that "experimental"
procedures do not necessarily constitute research, and that research and practice may occur
simultaneously. It suggests that the safety and effectiveness of such "experimental" procedures should be
investigated early, and that institutional oversight mechanisms, such as medical practice committees, can
ensure that this need is met by requiring that "major innovation[s] be incorporated into a formal research
project." Applying the Ethical Principles Respect for Persons. Required by the moral principle of respect for persons (see definition, above),
informed consent contains three elements: information, comprehension, and voluntariness. First, subjects
must be given sufficient information on which to decide whether or not to participate, including the
research procedure(s), their purposes, risks and anticipated benefits, alternative procedures (where therapy
is involved), and a statement offering the subject the opportunity to ask questions and to withdraw at any
time from the research. Responding to the question of what constitutes adequate information, the Report
suggests that a "reasonable volunteer" standard be used: "the extent and nature of information should be
such that persons, knowing that the procedure is neither necessary for their care nor perhaps fully
understood, can decide whether they wish to participate in the furthering of knowledge. Even when some
direct benefit to them is anticipated, the subjects should understand clearly the range of risk and the
voluntary nature of participation." Incomplete disclosure is justified only if it is clear that: (1) the goals of
the research cannot be accomplished if full disclosure is made; (2) the undisclosed risks are minimal; and
(3) when appropriate, subjects will be debriefed and provided the research results. Second, subjects must be able to comprehend the information that is given to them. The presentation of
information must be adapted to the subject's capacity to understand it; testing to ensure that subjects have
understood may be warranted. Where persons with limited ability to comprehend are involved, they should
be given the opportunity to choose whether or not to participate (to the extent they are able to do so), and
their objections should not be overridden, unless the research entails providing them a therapy unavailable
outside of the context of research. [See discussions on this issue in other sections of the Guidebook,
including Chapter 6, "Special Classes of Subjects."] Each such class of persons should be considered on its
own terms (e.g., minors, persons with impaired mental capacities, the terminally ill, and the comatose).
Respect for persons requires that the permission of third persons also be given in order to further protect
them from harm. Finally, consent to participate must be voluntarily given. The conditions under which an agreement to
participate is made must be free from coercion and undue influence. IRBs should be especially sensitive to
these factors when particularly vulnerable subjects are involved. Beneficence. Closely related to the principle of beneficence (see definition, above), risk/benefit
assessments "are concerned with the probabilities and magnitudes of possible harms and anticipated
benefits." The Report breaks consideration of these issues down into defining the nature and scope of the
risks and benefits, and systematically assessing the risks and benefits. All possible harms, not just physical
or psychological pain or injury, should be considered. The principle of beneficence requires both
protecting individual subjects against risk of harm and consideration of not only the benefits for the
individual, but also the societal benefits that might be gained from the research. In determining whether the balance of risks and benefits results in a favorable ratio, the decision should be
based on thorough assessment of information with respect to all aspects of the research and systematic
consideration of alternatives. The Report recommends close communication between the IRB and the
investigator and IRB insistence upon precise answers to direct questions. The IRB should: (1) determine
the "validity of the presuppositions of the research;" (2) distinguish the "nature, probability and magnitude
of risk...with as much clarity as possible;" and (3) "determine whether the investigator's estimates of the
probability of harm or benefits are reasonable, as judged by known facts or other available studies." Five basic principles or rules apply when making the risk/benefit assessment: (1) "brutal or inhumane
treatment of human subjects is never morally justified;" (2) risks should be minimized, including the
avoidance of using human subjects if at all possible; (3) IRBs must be scrupulous in insisting upon
sufficient justification for research involving "significant risk of serious impairment" (e.g., direct benefit
to the subject or "manifest voluntariness of the participation"); (4) the appropriateness of involving
vulnerable populations must be demonstrated; and (5) the proposed informed consent process must
thoroughly and completely disclose relevant risks and benefits. Justice. The principle of justice mandates that the selection of research subjects must be the result of
fair selection procedures and must also result in fair selection outcomes. The "justness" of subject
selection relates both to the subject as an individual and to the subject as a member of social, racial,
sexual, or ethnic groups. With respect to their status as individuals, subjects should not be selected either because they are favored
by the researcher or because they are held in disdain (e.g., involving "undesirable" persons in risky
research). Further, "social justice" indicates an "order of preference in the selection of classes of subjects
(e.g., adults before children) and that some classes of potential subjects (e.g., the institutionalized
mentally infirm or prisoners) may be involved as research subjects, if at all, only on certain
conditions." Investigators, institutions, or IRBs may consider principles of distributive justice relevant to determining
the appropriateness of proposed methods of selecting research subjects that may result in unjust
distributions of the burdens and benefits of research. Such considerations may be appropriate to avoid the
injustice that "arises from social, racial, sexual, and cultural biases institutionalized in society." Subjects should not be selected simply because they are readily available in settings where research is
conducted, or because they are "easy to manipulate as a result of their illness or socioeconomic
condition." Care should be taken to avoid overburdening institutionalized persons who "are already
burdened in many ways by their infirmities and environments." Nontherapeutic research that involves risk
should use other, less burdened populations, unless the research "directly relate[s] to the specific
conditions of the class involved." SUGGESTIONS FOR FURTHER READING Return to Index Page
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Guidebook
B.
The Belmont Report || C. Suggestions for Further Reading
Introduction