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Ezekiel J. Emanuel; David Wendler; Christine Grady
What Makes Clinical Research Ethical?
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SPECIAL COMMUNICATION
What Makes Clinical Research Ethical?
Ezekiel J. Emanuel, MD, PhD
David Wendler, PhD
Christine Grady, PhD
WHAT MAKES RESEARCH IN-volving human subjectsethical? Informed con-sent is the answer most
US researchers, bioethicists, and insti-
tutional review board (IRB) members
would probably offer. This response re-
flects the preponderance of existing
guidance on the ethical conduct of
esearch and the near obsession with
autonomy in US bioethics.1-4 While
informed consent is necessary in most
ut not all cases, in no case is it suffi-
cient for ethical clinical research.5-8 In-
deed, some of the most contentious con-
temporary ethical controversies in
clinical research, such as clinical
esearch in developing countries,9-13
the use of placebos,14-16 phase 1 re-
search,17-19 protection for communi-
ties,20-24 and involvement of chil-
dren,25-29 raise questions not of informed
consent, but of the ethics of subject se-
lection, appropriate risk-benefit ratios,
and the value of research to society. Since
obtaining informed consent does not en-
sure ethical research, it is imperative to
have a systematic and coherent frame-
work for evaluating clinical studies that
incorporates all relevant ethical consid-
erations.
In this article, we delineate 7 require-
ments that provide such a framework by
synthesizing traditional codes, declara-
tions, and relevant literature on the eth-
ics of research with human subjects. This
framework should help guide the ethi-
cal development and evaluation of clini-
cal studies by investigators, IRB mem-
ers, funders, and others.
THE 7 ETHICAL
REQUIREMENTS
The overarching objective of clinical re-
search is to develop generalizable
knowledge to improve health and/or in-
crease understanding of human biol-
ogy30,31; subjects who participate are the
means to securing such knowledge.32
By placing some people at risk of harm
for the good of others, clinical re-
search has the potential for exploita-
tion of human subjects.33,34 Ethical re-
quirements for clinical research aim to
minimize the possibility of exploita-
tion by ensuring that research sub-
jects are not merely used but are treated
with respect while they contribute to
the social good.30
For the past 50 years, the main sources
of guidance on the ethical conduct of
clinical research have been the Nurem-
erg Code,35 Declaration of Helsinki,36
Belmont Report,37 International Ethical
Guidelines for Biomedical Research In-
volving Human Subjects,38 and simila
documents (TABLE 1). However, many
of these documents were written in re-
sponse to specific events and to avoid fu-
ture scandals.50,51 By focusing on the in-
stigating issues, these guidelines tend to
Many believe that informed consent makes clinical research ethical. How-
ever, informed consent is neither necessary nor sufficient for ethical clinical
esearch. Drawing on the basic philosophies underlying major codes, dec-
larations, and other documents relevant to research with human subjects,
we propose 7 requirements that systematically elucidate a coherent frame-
work for evaluating the ethics of clinical research studies: (1) value—
enhancements of health or knowledge must be derived from the research;
(2) scientific validity—the research must be methodologically rigorous; (3)
fair subject selection—scientific objectives, not vulnerability or privilege, and
the potential for and distribution of risks and benefits, should determine com-
munities selected as study sites and the inclusion criteria for individual sub-
jects; (4) favorable risk-benefit ratio—within the context of standard clini-
cal practice and the research protocol, risks must be minimized, potential
enefits enhanced, and the potential benefits to individuals and knowledge
gained for society must outweigh the risks; (5) independent review—
unaffiliated individuals must review the research and approve, amend, o
terminate it; (6) informed consent—individuals should be informed about
the research and provide their voluntary consent; and (7) respect for en-
olled subjects—subjects should have their privacy protected, the opportu-
nity to withdraw, and their well-being monitored. Fulfilling all 7 require-
ments is necessary and sufficient to make clinical research ethical. These
equirements are universal, although they must be adapted to the health,
economic, cultural, and technological conditions in which clinical research
is conducted.
JAMA. 2000;283: XXXXXXXXXXwww.jama.com
Author Affiliations: Department of Clinical Bioeth-
ics, Wa
en G. Magnuson Clinical Center, National In-
stitutes of Health, Bethesda, Md.
Co
esponding Author and Reprints: Christine Grady,
PhD, Wa
en G. Magnuson Clinical Center, Bldg 10,
Room 1C118, National Institutes of Health, Bethesda,
MD XXXXXXXXXXe-mail: XXXXXXXXXX).
©2000 American Medical Association. All rights reserved. (Reprinted) JAMA, May 24/31, 2000—Vol 283, No XXXXXXXXXX
at Wake Forest Univ Sch of Med on June 4, 2008 www.jama.comDownloaded from
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emphasize certain ethical requirements
while eliding others. For instance, the
Nuremberg Code35 was part of the judi-
cial decision condemning the atrocities
of the Nazi physicians and so focused on
the need for consent and a favorable risk-
enefit ratio but makes no mention of fai
subject selection or independent re-
view. The Declaration of Helsinki36 was
developed to remedy perceived lacunae
in the Nuremberg Code, especially as re-
lated to physicians conducting research
with patients, and so focuses on favor-
able risk-benefit ratio and independent
eview; the Declaration of Helsinki also
emphasizes a distinction between thera-
peutic and nontherapeutic research that
is rejected or not noted by other docu-
ments.30,52 The Belmont Report37 was
meant to provide
oad principles that
could be used to generate specific rules
and regulations in response to US re-
search scandals such as Tuskegee53 and
Willow
ook.54,55 It focuses on in-
formed consent, favorable risk-benefit ra-
tio, and the need to ensure that vulner-
able populations are not targeted for risky
esearch. The Council for International
Organizations of Medical Sciences
(CIOMS) guidelines38 were intended to
apply the Declaration of Helsinki “in de-
veloping countries . . . [particularly for]
large-scale trials of vaccines and drugs.”
The CIOMS guidelines lack a separate
section devoted to risk-benefit ratios, al-
though the council considers this issue
in commentary on other guidelines. It
also includes a section on compensa-
tion for research injuries not found in
other documents. Because the Advisory
Committee on Human Radiation Experi-
ments was responding to covert radia-
tionexperiments, avoidingdeceptionwas
among its 6 ethical standards and rules;
most other major documents do not
highlight this.56 This advisory commit-
tee claims that its ethical standards are
general, but acknowledges that its
choices were related to the specific cir-
cumstances that occasioned the re-
port.56 Finally some tensions, if not
outright contradictions, exist among
the provisions of the various guide-
lines.5,19,30,51,52,57,58 Absent a universally ap-
plicable ethical framework, investiga-
tors, IRB members, funders, and others
lack coherent guidance on determining
whether specific clinical research pro-
tocols are ethical.
There are 7 requirements that pro-
vide a systematic and coherent frame-
work for determining whether clinical re-
search is ethical (TABLE 2). These
equirements are listed in chronologi-
cal order from the conception of the re-
search to its formulation and implemen-
tation. They are meant to guide the
ethical development, implementation,
and review of individual clinical proto-
cols. These 7 requirements are in-
tended to elucidate the ethical stan-
dards specific for clinical research and
assume general ethical obligations, such
as intellectual honesty and responsibil-
ity. While none of the traditional ethi-
cal guidelines on clinical research ex-
plicitly includes all 7 requirements, these
equirements systematically elucidate the
fundamental protections embedded in
the basic philosophy of all these docu-
ments.30 These requirements are not lim-
ited to a specific tragedy or scandal or to
the practices of researchers in 1 coun-
try; they are meant to be universal, al-
though their application will require ad-
aptation to particular cultures, health
conditions, and economic settings. These
Table 1. Selected Guidelines on the Ethics of Biomedical Research With Human Subjects*
Guideline Source Year and Revisions
Fundamental
Nuremberg Code35 Nuremberg Military Tribunal
decision in United States
v Brandt
1947
Declaration of Helsinki36 World Medical Association 1964, 1975, 1983,
1989, 1996
Belmont Report37 National Commission for the
Protection of Human Subjects
of Biomedical and Behavioral
Research
1979
International Ethical Guidelines fo
Biomedical Research Involving
Human Subjects38
Council for International
Organizations of Medical
Sciences in collaboration with
World Health Organization
Proposed in 1982;
evised, 1993
Othe
45 CFR 46, Common Rule8 US Department of Health and
Human Services (DHHS) and
other US federal agencies
DHHS guidelines in
1981; Common
Rule, 1991
Guidelines for Good Clinical
Practice for Trials on
Pharmaceutical Products42
World Health Organization 1995
Good Clinical Practice:
Consolidated Guidance44
International Conference on
Harmonisation of Technical
Requirements for Registration of
Pharmaceuticals for Human Use
1996
Convention on Human Rights and
Biomedicine43
Council of Europe 1997
Guidelines and Recommendations
for European Ethics
Committees45
European Forum for Good
Clinical Practice
1997
Medical Research Council
Guidelines for Good Clinical
Practice in Clinical Trials46
Medical Research Council,
United Kingdom
1998
Guidelines for the Conduct of
Health Research Involving
Human Subjects in Uganda47
Uganda National Council fo
Science and Technology
1998
Ethical Conduct for Research
Involving Humans48
Tri-Council Working Group, Canada 1998
National Statement on Ethical
Conduct in Research Involving
Humans49
National Health and Medical
Research Council, Australia
1999
*CFR indicates Code of Federal Regulations. More extensive lists of international guidelines on human subjects research
can be found in Brody39 and Fluss.40 An extensive summary of US guidelines can be found in Sugarman et al.41
ETHICAL REQUIREMENTS FOR CLINICAL RESEARCH
2702 JAMA, May 24/31, 2000—Vol 283, No. 20 (Reprinted) ©2000 American Medical Association. All rights reserved.
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7 requirements can be implemented well
or ineffectively. However, their system-
atic delineation is important and con-
ceptually prior to the operation of an en-
forcement mechanism. We need to know
what to enforce.
Value
To be ethical, clinical research must be
valuable,4,35 meaning that it evaluates
a diagnostic or therapeutic interven-
tion that could lead to improvements
in health or well-being; is a prelimi-
nary etiological, pathophysiological, o
epidemiological study