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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