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Commentary
What are we doing when we are doing research on humans?
Virginia A. Sharpe*
Center for Science in the Public Interest, 1875 Connecticut Avenue, NW, Suite 300, Washington, DC 20009-5728, USA
Received 10 January 2002; accepted 4 April 2002
1. Introduction
Human subjects research, research with vulnerable pop-
ulations, research that is not intended to benefit the subjects,
industry-sponsored research and community-based research
all raise important questions and challenges about the
interests of the researcher and the obligations of researcher
to subject. In this paper, I will lay out some of the basic
precepts of human subjects research and will then present a
number of frameworks for interpreting the scope of obliga-
tion and the competing, and sometimes, conflicting interests
that are part of the research process. My aim is to urge
greater attention to the different and sometimes conflicting
interests and values at stake in the research process.
2. The basics
The aim of research on humans is the generation of
knowledge. The aim of patient care is the cure of disease
and the alleviation of pain and suffering in this particular
patient. To be clear about these distinct aims, we call
research participants ‘‘subjects’’ and ill people seeking
clinical care, ‘‘patients.’’ Some patients decide to enroll in
research protocols and are then called ‘‘patient-subjects.’’
The distinct aims of clinical care and research can become
confused when one person acts both as physician and
researcher. This confusion can be exacerbated by the
patient’s expectations in the so-called ‘‘therapeutic
research.’’ Given that the aim of research is the generation
of knowledge, it is never possible at the outset to predict
whether a person will benefit from, be harmed or remain
unaffected by the research. Despite this fact, it is well known
that patients are often drawn to become research subjects
because of a ‘‘therapeutic misconception.’’ That is, they
believe and are often encouraged to believe that they will
benefit from the research protocol in which they are enrolled.
Some patients are aware of these uncertainties and choose,
nevertheless, to expose themselves to indeterminate risks in
the hope of even speculative benefit.
The hope of therapeutic benefit is only one type of
possible benefit that draws people to participate in research.
People who are not patients, that is, those who are healthy or
‘‘normal’’ volunteers, may enroll in research for altruistic
reasons, to receive financial compensation, medical check-
ups or other material benefits to which they might not
otherwise have access.
In the context of research, the term ‘‘vulnerable popu-
lation,’’ may refer to people who are socially vulnerable, that
is, those who are dependent on others because of age,
disability, language barriers and so on, or people whose
needs or circumstances make them susceptible to exploita-
tion or coercion. The term ‘‘vulnerable population’’ may also
refer to people who are physiologically vulnerable, that is,
those who, because of some physiological characteristic, are
particularly susceptible to toxic effects. For example, it is
well known that rapidly reproducing cells of fetuses, infants,
toddlers and children make them particularly susceptible to
harms associated with exposure to lead, PCBs, benzene,
outdoor and indoor air contaminants and other toxins.
Most human research subjects are vulnerable in one of
these ways. Children, however, are vulnerable in almost all
of these respects. They are often too young to comprehend
or consent to participation in research, they are dependent
on their parents to protect their interests, their naivete
makes them susceptible to exploitation and they are par-
ticularly sensitive to toxins. Children who are members of
socially disadvantaged or politically marginalized families
are also made vulnerable by the fact that their parent or
parents may not have economic or political access to needed
goods and services.
All human subjects are additionally vulnerable to con-
flicts of interest that may influence the conduct of research.
The interests of a researcher in new knowledge, peer
recognition, promotion and so on may conflict with the
patient-subject’s interest in the primacy of his or her health
0892-0362/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved.
PII: S0892 -0362 (02 )00237 -4
* Tel.: +1-202-777-8331; fax: +1-202-265-4954.
E-mail address: [email protected] (V.A. Sharpe).
www.elsevier.com/locate/neutera
Neurotoxicology and Teratology 24 (2002) 451–454
interests. Likewise, research subjects are vulnerable to the
financial interests of researchers or research sponsors.
In the last decade, pharmaceutical and biotechnology
companies have increasingly shifted their research sponsor-
ship from academic medical centers to both private office-
based physicians, as well as to contract research organizations
(CROs) and site management organizations (SMOs) that
contract with those companies to design and conduct a broad
range of studies on drug safety and efficacy. Because the 20-
year timeline on a new drug patent begins before a drug has
cleared the Food and Drug Administration (FDA) approval
process, a pharmaceutical company has a financial interest in
expediting the conduct of these studies. As a result, compan-
ies may offer considerable financial incentives to CROs,
SMOs or physicians for participant recruitment or retention.
Although the federal government in the United States is
paying closer attention to financial conflicts of interest and
their potential to undermine scientific integrity and human
subjects’ protection, there are still considerable obstacles to
oversight in this area [4]. These research arrangements
underscore the multiple, often competing, sometimes frankly
conflicting interests at stake in the research process, as well as
the need for ethical and regulatory limits.
3. Frameworks for human subjects research
Since the Nuremberg Code was created after the Second
World War, ethical (and legal) norms have been established
to govern the conduct of human subjects research [5]. In
order to understand the scope of a researcher’s obligations,
it is useful to lay out five approaches to the ethics of human
subjects research, the premises of which have all figured in
the thinking of policymakers charged with its regulation.
These approaches are: utilitarianism, paternalistic protec-
tionism, respect for persons, consumer choice and human
rights. In what follows, I present these frameworks with an
eye towards research involving healthy children from vul-
nerable populations.
4. Utilitarianism
A utilitarian approach to human subjects research takes
as its guiding principle the achievement of utility, that is, the
greatest good for the greatest number. Under a utilitarian
justification for research, therefore, the interests of the
individual (whether subject or researcher) are subordinate
to the ultimate aim of aggregate welfare. The individual is
valued only instrumentally, and harms to the individual are
seen to be justified if they support this end. The researcher’s
only obligation in this context is to maximize utility and to
do so in a way that at most considers the interests of each
individual relative to the whole. Although the interests of an
individual may turn out to be compatible with those of the
majority, the majority’s interest can never be trumped by the
interest of one individual. We need only think of the Nazi
experiments to understand that until the end of World War
II, human subjects research was implicitly and often explic-
itly justified in this way, with individuals being sacrificed to
ostensibly greater ends.
5. Paternalistic protectionism
The idea of protecting human subjects is at least as old as
experimental medicine. Physicians who undertook research
in the 19th century were already governed by a paternalistic
ethic that required them to use their best judgment in the
care of their patients. When they undertook research on
these now patient-subjects, they likewise believed that their
own judgment was a sufficient guarantee of the legitimacy
of the research and of the patient-subject’s safety. The
atrocities of the Nazi experiments, as well as a host of
research in the United States, including the infamous
Tuskeegee syphilis experiments, suggested that the good
will of the researcher was insufficient, especially in a
political context where utility, defined as ‘‘progress,’’ was
generally believed to take priority over the interests of
individual research subjects, especially when they were
from socially disvalued groups. Many of these cases also
made clear that when research was conducted outside the
traditional physician–patient relationship, on ‘‘normal vol-
unteers,’’ there were no established standards to govern the
researcher’s conduct. In the 1960s and 1970s in the US, the
federal government responded with guidelines for the estab-
lishment of Institutional Review Boards and other require-
ments for the review of proposed research. Paternalistic
protectionism by the researcher was no longer deemed
sufficient, and oversight of research became more respons-
ive to public and democratic norms [2].
6. Respect for persons
By the 1970s, international bodies and policymakers in the
US and elsewhere recognized that neither a utilitarian
approach to research nor an approach that relied solely on
the researcher’s conscience was sufficient to safeguard the
interests of individual research subjects. Policies and norms
established at this time, emphasized a corrective principle
more in line with the democratic principle of respect for
autonomy. The Nuremberg Code’s first principle is that ‘‘the
voluntary consent of the human subject is absolutely essen-
tial’’ [9]. Unlike the utilitarian justification for research, the
principle of respect for persons expresses and reinforces the
intrinsic (rather than instrumental) value of the individual.
Respect for the individual is an absolute limit on research.
This principle is authenticated first and foremost through the
informed consent process. The premise of this approach is
that authorization to expose a research subject to the risks,
uncertainties and possible benefits of research can only come
V.A. Sharpe / Neurotoxicology and Teratology 24 (2002) 451–454452
from the informed subject, him or herself. Once it has been
determined that the research protocol has scientific merit and
is not unduly risky, the researcher has a duty to provide
accurate and sufficient information to the subject about the
known risks and possible benefits, to assure the subject’s
comprehension of the information and to obtain the subject’s
voluntary consent.
This approach obviously presents a challenge for
research involving children or others who lack the capacity
to give consent. In these cases, there is general agreement
that such research is justified only if certain conditions are
met. These conditions include that: There is a possibility of
benefit to the subject (in the case of therapeutic research),
the research does not entail any suffering, there is a valid
proxy consent and there are no apparent objections on the
part of the subject. If the proposed research is nontherapeu-
tic, that is, if it entails no possibility of benefit, the research
is considered justifiable if the above conditions are joined
by a condition of minimal risk to the child.
7. Consumer choice
As the additional conditions above indicate, the duty of
respect for persons is one of a host of ethical and legal
obligations imposed on researchers. That having been said,
however, the embrace of consumerism has led many to
believe that with adequate disclosure by the researcher, the
proxy or patient’s own consent provides sufficient protection
to the research subject. For research involving normal vol-
unteers, this is especially the case. The emerging model for
research on normal subjects, thus, seems to be one of buyer
and seller negotiating in the marketplace. Beyond ‘‘truth in
advertising,’’ the researcher is increasingly seen to have no
duty of care or other obligation. Indeed, the burden seems to
rest primarily with the research subject to be a savvy
consumer. The argument of the defense in the cases of Erika
Grimes v. Kennedy Krieger and Myron Higgins v. Kennedy
Krieger [1] exemplifies this consumer choice model.
In these cases, which involved research on children to
determine the minimum level of effective lead abatement in
their homes, the Kennedy Krieger Institute (KKI), which
conducted the research, argued that it had no legal duty to
warn subjects of the presence of lead dust in their apartments.
When questioned by the Court of Appeals, the KKI argued
that there was no special relationship between itself and the
subjects creating a duty on the researchers. The relationship
was not even contractual, KKI argued. ‘‘Informed consent [is
not contractual, it] is just that. It’s Kennedy informing the
participant what it intends to do.’’ In addition, KKI argues
that it is not contractual because ‘‘either side could withdraw
without any claim for breach of contract from the other’’ [1].
Leaving the legal questions in these as-yet-unresolved
cases aside, we can see that there are serious pitfalls to
consumer choice as the model for human subjects research.
From the point of view of prevailing and codified ethical
standards, the KKI claims that informed consent consists
only of ‘‘Kennedy informing the participant what it intends
to do’’ is preposterous. Even conservative standards of
disclosure for informed consent require researchers to pro-
vide information about risks associated with the research.
KKI’s position also entirely ignores the fact that the research
subjects are children for whom their parent/s have given
proxy consent. As such, the minimal risk requirement for
nontherapeutic research on children is not met. Although it
would be easy to interpret Kennedy Krieger’s position as
grounded in the principle of utility (with the risks to the
children justified by the knowledge to be gained), this is not
the argument that the KKI has presented. Its argument is,
instead, that it had no special relationship and no obligations
to the study subject beyond ‘‘informing the participant what
it intends to do.’’ Again, the implication here is that only the
minimal norms of a market transaction pertain. As the drive
to test pharmaceuticals and new genetic therapies intensi-
fies, there will be an intensification of the rhetoric of
consumer choice as the guiding principle of research par-
ticipation. At stake here is whether the laissez-faire norms of
the market are sufficient to guarantee research integrity and
human subjects protection.
A fourth approach to human subjects research provides a
richer conception of the context in which research occurs.
8. Human rights
In recent years, a new model of research has emerged,
which is conducted by, with, and for communities. Unlike
traditional academic research, which is driven by the intel-
lectual interests of scientists, or industry-sponsored research,
which seeks to develop marketable products, community-
based or participatory research is oriented to the self-defined
needs of a particular group. As one advocacy organization
puts it, community-based research is ‘‘coupled relatively
tightly with community groups that are eager to know the
research results and to use them in practical efforts to
achieve constructive social change’’ [7]. Community-based
research might focus on environmental or public health
initiatives, land-use planning or epidemiologic surveys to
ascertain information on disease incidence. Unlike dominant
quantitative research methodologies, whose gold standard is
the randomized control trial, participatory research is inten-
tionally contextualized, rather than intentionally random; the
community benefits from the research; and the methodology
itself is explicitly designed to promote capacity building
within community participants.
As I mentioned above, in biomedical research on healthy
volunteers, there is often an independent, ancillary benefit
such as monetary compensation offered to subjects. In
participatory research, direct benefit to the community is
integral to the research process and outcomes.
Participatory research is grounded in the conception of
human rights articulated in the United Nations Declaration
V.A. Sharpe / Neurotoxicology and Teratology 24 (2002) 451–454 453
on Human Rights and more recently in the United Nations
Human Development Report [10]. The premise of the
human rights framework is that to a significant and docu-
mented degree, the determinants of health and illness are
social, economic and political with societies with the great-
est relative income disparities having not only the expected
health disparities between rich and poor, but also poor
overall health statistics relative to more egalitarian societies
[3]. The remedy for poor health outcomes is, thus, sought in
social rather than in specific biological interventions. These
interventions involve capacity building, strengthening social
cohesion and civil society [8]. Research conducted from this
perspective has as its aim, not generalizable knowledge, or
drug product development, but the flourishing and capacity
building of a particular community.
It should be clear that the obligations entailed by human
rights-based research are more extensive than utility max-
imization, more democratic than paternalism, more mutual
than informed consent and more responsive to social
inequities than are consumer preference satisfaction and
caveat emptor. Interestingly, a new theory, the ‘‘right to be
treated with dignity,’’ has been put forward in litigation on
behalf of harmed research subjects [11]. It is not clear that
this theory will survive legal scrutiny. It is also not clear
whether it is compatible with the reductionistic scientific
paradigm on which most biomedical research is based.
However, it does represent, albeit retrospectively, after a
harm has occurred, an attempt to introduce the richer notion
of human rights into the arena of human subjects research.
9. Conclusion
Research on human subjects entails a host of competing
and sometimes conflicting interests and values. It is no
secret that from its beginnings in the 19th century, human
research has targeted marginalized and socially disvalued
people; people seen, from a crude utilitarian perspective, as
dispensable in the achievement of social progress. Though
the imperative of progress is still very much with us, in the
form of economic growth, advances in science and tech-
nology and the expansion of global markets, its force is
tempered by values of respect, dignity, equality, freedom,
solidarity, transparency and social justice. Indeed, from the
perspective of the United Nations Human Development
Index, it is these values, not simply economic indicators,
that constitute the markers of social health and well being,
or, in other words, progress [6,12]. So, when we consider
engaging in human research, we need to consider all of
these values, not simply the minimal, transactional obliga-
tions imposed on us by regulation or marketplace etiquette.
Specific recommendations in this regard include: (1) ethics
training with an emphasis on conflicts-of-interest for all who
conduct human subjects research, not simply those who
receive federal funding; (2) full disclosure to research
subjects and the authorized IRB of a researcher or research
institution’s financial interests in the outcome of the study;
(3) restrictions on recruitment and retention incentives; and
(4) public debate on the type and level of conflicts of
interest that are unacceptable in the research setting.
References
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V.A. Sharpe / Neurotoxicology and Teratology 24 (2002) 451–454454