About Protecting Human Subjects
The Ethical Foundations of the Federal Regulations
Governing Human Subjects Research in the United States
I. The Evolution of Human Subjects Protection
Three documents addressing the ethical conduct of research with human
beings
have provided the ethical foundation for the evolution of federal regulations
for the
respect and protection of human subjects in the United States. Two of
these documents
are international codes of conduct; the other document, the Belmont
Report, provides an
ethical framework to guide the preparation, analysis, and evaluation
of biomedical and
behavioral research proposals that are conducted within the United States.
A. International Developments
1. The Nuremberg Code
The Nuremberg Code was developed in 1947, following the Nuremberg trials
of
physicians and scientists who had performed horrifying experiments on
prisoners during
the Nazi era. It was the first internationally recognized ethical code
for the conduct of
human research. The thrust of this document is manifest in its first
principle:
“1. The voluntary consent of the human subject is absolutely essential.
This
means that the person involved should have legal capacity to give consent;
should be so
situated as to be able to exercise free power of choice, without the
intervention of any
element of force, fraud, deceit, duress, overreaching, or other ulterior
form of constraint
or coercion; and should have sufficient knowledge and comprehension
of the elements of
the subject matter involved as to enable him to make an understanding
and enlightened
decision. This latter element requires that before the acceptance of
an affirmative
decision by the experimental subject there should be made known to him
the nature,
duration, and purpose of the experiment; the method and means by which
it is to be
conducted; all inconveniences and hazards reasonably to be expected;
and the effects
upon his health or person which may possibly come from his participation
in the
experiment.” (Nuremberg Military Tribunal, from U.S. v. Karl Brandt,
et al., The
Nuremberg Code, 1947).
Interestingly, prior to the rise of the Nazi regime, Germany had adopted
a strong
federal law in 1931 that set forth the obligations of physicians and
the rights of human
research subjects. Among other things, this law required special protections
for groups of
persons who were unable to protect their own interests as research participants.
Physicians and scientists of the Third Reich set aside this law, performing
experiments on
human subjects with no regard for their autonomous consent or their
wellbeing. Those
who were conscripted as research subjects in Nazi experiments were treated
as less than
2 full persons and as expendable in the pursuit of information that
might benefit the Nazi
regime.
In response to the abject disregard of the humanity, autonomy and interests
of
vulnerable persons and groups by the Nazis, the Nuremberg Code essentially
ruled out
the involvement of such populations in future research, including sick
patients. As a
result, the ten principles of the Nuremberg Code essentially read as
rules for the conduct
of research on “healthy volunteers.” Unfortunately, this provides
no guidance on the
questions of whether and how to involve persons who may be vulnerable,
that is,
compromised in terms of their ability to represent their own interests
in deciding whether
to participate in research.
2. The Declaration of Helsinki
In 1964, the World Medical Association issued the Declaration of Helsinki.
This
international code specifically focuses on medical research, acknowledges
the multiple
sources of vulnerability that must be taken into account in protecting
research subjects,
issues principles for the protection for the vulnerable who must sometimes
be involved in
such research, and prioritizes the duties of physician-researchers “to
protect the life,
health, privacy, and dignity of the human subject.” The Declaration
of Helsinki is a living
document: it has been amended five times, most recently in 2000. A much
more complex
code than the Nuremberg Code, the flavor of the Declaration of Helsinki
is captured in
one of its nine introductory principles:
“Medical research is subject to ethical standards that promote
respect for all
human beings and protect their health and rights. Some research populations
are
vulnerable and in need of protection. The particular needs of the economically
and
medically disadvantaged must be recognized. Special attention is also
required for those
who cannot give or refuse consent for themselves, for those who may
be subject to giving
consent under duress, for those who will not benefit personally from
the research and for
those for whom the research is combined with care.” (World Medical
Association,
Declaration of Helsinki: Ethical Principles for Medical research Involving
Human
Subjects (Edinburgh: October 2000)
B. Research Ethics Developments in the United States
1. Continuing research abuses in the U.S.
Despite worldwide attention to the abuses of human research subjects
following
World War II, the development of the Nuremberg Code and the Declaration
of Helsinki,
and a 1964 policy change by the National Institutes of Health that all
research funded by
the United States Public Health Service be reviewed by an ethics committee,
inadequate
attention to the rights and interests of human subjects remained. In
1966, a landmark
article appeared in the New England Journal of Medicine describing 22
examples of
3 unethical experimental medicine in the United States. In this article,
Dr. Henry K.
Beecher of the Harvard Medical School described instances of “experimentation
on a
patient not for his benefit but for that, at least in theory, of patients
in general” in which
consent was not obtained and/or patients were put at unacceptable risk.
These
experiments were hardly secrets buried deep in the past: Beecher had
gathered them from
recently published articles by leading researchers in U.S. medical journals.
About them,
he wrote:
“Human experimentation since World War II has created some difficult
problems
with the increasing employment of patients as experimental subjects
when it must be
apparent that they would not have been available if they had been truly
aware of the uses
that would be made of them….An experiment is ethical or not at
its inception; it does not
become ethical post hoc – ends do not justify means. There is no
ethical distinction
between ends and means.” (Henry K. Beecher, “Ethics and Clinical
Research,” New
England Journal of Medicine 274 (1966): 1354-60)
2. Steps toward regulation in the U.S.
In 1973, Senator Edward Kennedy led congressional hearings on the problem
of
unethical medical research in response to ongoing disclosures of the
abuse of research
subjects’ rights in both medical and behavioral research. These
abuses violated a number
of agreed upon ethical principles for the conduct of human research.
For example, some
experiments unjustifiably selected and failed to protect highly vulnerable
groups of
subjects (both institutionalized and non-institutionalized); some involved
the deception of
subjects or the violation a subjects’ privacy; and some even withheld
known effective
treatment from sick patients. Most seriously, one of the most egregious
violations of
respect, protection, and fairness to human subjects was a project of
the U.S. Public Health
Service from 1932-1972, the Tuskegee Syphilis Study. This project continued
for 6 years
after the National Institutes of Health had issued its policy requiring
ethics review
reflecting the principles of the two extant international codes discussed
above.
The Congressional response came in 1974 with the passage of the National
Research Act, which significantly changed the U.S. approach to regulating
human
subjects research in two ways. First, it established the National Commission
for the
Protection of Human Subjects of Biomedical and Behavioral Research (henceforth,
the
‘National Commission’) to develop the ethical standards and
regulatory principles and
rules that would govern human research. Second, the National Research
Act founded our
current Institutional Review Board (IRB) system. The central requirement
of this system
is that research funded by the Department of Health, Education, and
Welfare (DHEW)
(now by the Department of Health and Human Services (HHS)) must be reviewed
and
approved for their adherence to regulations for the respect and protection
of human
subjects. This review and approval is to be conducted by a research
review board
constituted according to federal regulations within institutions doing
research. These two
creations of the National Research Act (the National Commission and
the IRB structure)
of course go hand in hand: a regulatory structure requires clear regulations
if it is to
function effectively and consistently.
3. The work of the National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research
a. Addressing the respect and protection of vulnerable populations
The National Commission began its work in 1975, immediately focusing
on
the identification of vulnerable populations of special concern (children,
pregnant
women, prisoners, and persons with dementia), and the development of
ethical
frameworks for the use of such populations to shape the federal regulations
and
guidelines applicable to each population.
b. Generating an ethical framework for human subjects research: The
Belmont Report
From 1975-1978, the National Commission focused on frameworks protective
of vulnerable subject populations. In 1978, The National Commission
issued the Belmont
Report - a modest 8-page document containing the foundational ethical
framework for all
federal regulations and guidelines concerning research involving the
use of human
subjects in the U.S.
The Belmont Report has not only provided the ethical cornerstone for
human
subjects research since then, it has shaped the field of bioethics’
defining attention to
patient autonomy. The significance of this document is hard to overstate.
As an ethical
framework, it models a strategy characteristic of the fields of bioethics
and research
ethics: that one reasons from a framework of ethical principles considered
necessary and
sufficient to ground a thorough analysis of a problem, and justification
for a position, on
an ethically-challenging situation or policy question in health care
practice and human
research. Because the Belmont Report is the ethical foundation for the
U.S. regulations
concerning human research, let us look closely at its three ethical
principles, along with
the rules and applications associated with each of them in the Report.
The authors of the Belmont Report intended to provide more general ethical
principles, indeed, and adequate ethical framework, to use as the basis
for the ethical
analysis of questions arising in the conduct of human research. The
previous codes
(Nuremberg and Helsinki) consisted of specific guidelines or rules.
The Belmont Report
attempted to lay out the ethical grounding of those guidelines and rules.
It did so in the
form of three basic ethical principles: respect for persons, beneficence,
and justice.
Respectively, they derive from the ethical theories of Kantian ethics,
utilitarianism, and
theories of justice oriented to individual rights rather than social
justice. The status and
role of the three principles is explained in this way in the Report:
5
“These three [ethical principles] are comprehensive…and stated
at a level of
generalization that should assist scientists, subjects, reviewers, and
interested citizens to
understand the issues inherent in research involving human subjects.
These principles
cannot always be applied so as to resolve beyond dispute particular
ethical problems. The
objective is to provide an analytical framework that will guide the
resolution of ethical
problems arising from research involving human subjects.” (The
National Commission
for the Protection of Human Subjects of Biomedical and Behavioral Research,
The
Belmont Report: Ethical Principles and Guidelines for the protection
of Human Subjects
of Research (Washington, D.C.: Department of Health, Education, and
Welfare, 1979).
4. The Common Rule
In 1981, the Department of Health and Human Services (HHS) promulgated
the
federal regulations for the respect and protection of human subjects
Title 45, Part 46 of
the Code of Federal Regulations (45 CFR 46). These regulations guide
researchers in the
development of their research proposals, and IRBs in their evaluation
of them. On
occasion, revisions are made to these regulations. There are many ethically
contested
issues in human subjects research – some of these issues were hinted
at in the brief
discussion of the Belmont Report above. In 1991, the regulations at
45 CFR 46 were
adopted by 17 federal agencies. Because so many federal agencies now
subscribe to 45
CFR 46, it is referred to as the Common Rule. Any institution engaged
in human subjects
research that is funded from a federal source is obligated to have an
infrastructure in
place for the evaluation of that research (an IRB infrastructure), and
to adhere to the
Common Rule in the evaluation, approval, and ongoing scrutiny of that
research as it is
being conducted. Most institutions choose to apply the Common Rule to
all of the
research done within their walls. Since some of the research done at
St. Olaf College is
funded from federal sources, St. Olaf’s compliance with 45 CFR
46 (in terms of its IRB
infrastructure and its application of the Common Rule) is federally
mandated. In addition,
St. Olaf is strongly committed to the ethical review of all research
done under the
auspices of St. Olaf College.
II. The Belmont Report: Principles for the Respect and Protection of
Human
Research Subjects
A. Respect for persons
The first of the Belmont Report principles, respect for persons, requires
in the
main that we identify and honor the capacity for self-determination
of anyone who is
approached to participate, or who is participating, in human research.
To do so, we must
(i) treat individuals as autonomous agents, and (ii) protect persons
of diminished
autonomy.
Applying the principle of respect for persons, then, we must provide
for informed
consent to participation in the research project (either by the prospective
subject herself
6
or a qualified surrogate). The duty to obtain informed consent to participation
in research
carries with it three requirements: information, comprehension, and
voluntariness. For the
present purpose, that of summarizing the requirements of the Belmont
Report, it will
suffice to say that in relation to every individual research proposal,
special issues may
arise in relation to any or all of these elements of informed consent.
The crucial framing
principle is the focus on enabling the individual to make an autonomous
choice: what
counts as sufficient information may vary from one person to another;
assuring
comprehension may require the conveying of information in multiple,
and perhaps unique
ways; and conditions that may compromise the voluntariness of consent
must be
addressed.
In recruiting subjects incapable of autonomous choice, the Belmont Report
allows
for the use of surrogate decision-makers. Of course, the same high standards
of informed
consent obtain. The task of such surrogates becomes that of either representing
the
presumed values and wishes of the potential subject (if that is possible),
or representing
their best interests.
B. Beneficence
The ethical principle of beneficence imposes two obligations: “(1)
do not harm
and (2) maximize possible benefits and minimize possible harms.”
One of the primary
commitments of this principle is to not harm an individual, even when
the potential
benefits to others might seem to be of overwhelming, overriding importance.
The other commitment of the principle of beneficence is a “favorable
risk/benefit
assessment.” Applying this principle, that is, performing the risk/benefit
calculations
required by it, is a complex and demanding task.
One of the problems with performing this calculation is the multi-factorial
nature
of benefit. Benefit from research participation may accrue to the subjects
themselves, to
others, or to “society.” How much risk (i.e., possibility
of harm) is it ethically acceptable
to invite potential subjects to assume, in exchange for what positive
returns or benefits
(either to themselves, to others, or to society)? What risk/benefit
equation should we use
to determine when it is ethical to offer participation in research as
an option to a person?
And, should that equation differ depending on the subject population
in question?
To complicate matters more, risk is a matter of both probability and
magnitude.
How should the magnitude of harm and the probability of harm be factored
into the
determination that benefits have been maximized and risks have been
minimized? The
risk/benefit assessment the Belmont Report requires is that the probabilities
and
magnitudes of possible harms be weighed against the anticipated benefits
of the research.
The multi-factorial nature of benefit must somehow be calculated, and
the types or risks
must be considered. Risks may include risks of physical and psychological
harm, legal,
economic, and social harm; and of course the benefits in these categories
must be
identified and weighed as well.
7
C. Justice
The third principle in the Belmont Report’s ethical framework is
the principle of
justice. Clearly, many of the abuses of research subjects both during
and after WWII had
not only dishonored individual autonomy and ignored the elements of
beneficence, but
also exploited vulnerable or marginalized individuals, groups or populations.
The
Tuskegee Syphilis Study is a prime example, among many others.
With the addition of the principle of justice to the ethical framework,
it was clear
that it was not only ethically required to identify and assess the favorability
of the
risk/benefit ratio in relation to research, it was equally important
to assure that the
distribution of the burdens (risks) and benefits of the research be
fair. The burdens and
benefits of research should be equally distributed so that those who
bear the burdens of
research also stand to receive its benefits, that potentially beneficial
research be fairly
accessible, and that risky research not be inequitably imposed. This
required attention to
the selection of subjects on both the individual and social levels:
the Belmont Report
called for fairness to individual subjects and social justice to classes
of subjects in subject
selection.
When this principle of justice was articulated in the Belmont Report,
it stood
against the exploitation of individuals and groups for the sake of others
– it was more
about eliminating the custom of unfairly distributing research burdens
among those who
lacked personal, economic, and social power than it was about assuring
that research in
the interests of marginalized or underrepresented groups be pursued.
So the principle of
justice, as articulated in the Belmont Report, was primarily about protecting
the rights of
some not to be used to benefit others only; not about rethinking the
research agenda to
address the needs and interests of groups/populations with less economic
and social
power.
