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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

What are we doing when we are doing research on humans?

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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

[1] Circuit Court for Baltimore City, MD. Case Nos. 24-C-99-000925 and

24-C-95066067CL 193461. Availabe at: http://www.courts.state.

md.us/opinions/coa/2001/128a00.pdf.

[2] 45 Code of Federal Regulations, pt. 46, known as the ‘‘Common

Rule’’ governing the Department of Health and Human Services,

and comparable regulations at 21 Code of Federal Regulations, pt.

50, 56, governing the FDA.

[3] N. Daniels, B. Kennedy, I. Kawachi, Why justice is good for our

health: The social determinants of health inequalities, Daedalus 128

(1999) 215–252.

[4] Government Accounting Office, HHS Direction Needed to Address

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[8] V.A. Sharpe, Environmental justice and the social determinants of

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[11] J. Washburn, Informed consent, Washington Post Mag. (2001) 13

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[12] R. Wilkinson, Unhealthy Societies: The Afflictions of Inequality,

Routledge, New York, 1996.

V.A. Sharpe / Neurotoxicology and Teratology 24 (2002) 451–454454