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Ethical Issues
in Human Subjects
Research
Judy Stone, MD
The first step in the evolution of ethics is a
sense of solidarity with other human eings.
— Albert Sweiter
Milestones in Ethical Development
1932–72 Tuskegee experiment on syphilis
1939–45 Nazi experiments
1944–74 Human radiation experiments by U.S. government
1946 Nuremberg Trial of doctors responsible for the Nazi experiments
1947 Nuremberg Code outlining ethical principles required for research
1948 United Nations adoption of Universal Declaration of Human Rights
Milestones in Ethical Development
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1953 NIH policy, the first U.S. federal policy introducing
independent reviewers to
examine research, forerunners of the IRBs
1963–66 Willowbrook Study, involving hepatitis research on
mentally retarded children,
raising issues access to care, consent, and coercion
1964 Declaration of Helsinki international agreement on
recommendations for the ethical
conduct of medical research
1972 Public exposure of Tuskegee syphilis study
1974 First federal protections for human research participants
Milestones in Ethical Development
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1979 Belmont Report promoting three principles for research
1980 Food and Drug Administration regulations (CFR 21 (50)
1982 Council for the International Organization of Medical
Sciences (CIOMS) publication of the International Ethics
Guidelines for Biomedical Research Involving Human Subjects
1985 U.S. Public Health Service Task Force on Women’s Health
issues report encouraging inclusion of women in research
1990 Society for Women’s Health Research
Milestones in Ethical Development
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1993 Public exposure of U.S. human radiation
experiments
1993 NIH Revitalization Act mandating
inclusion of women and minorities in research
1993 NIH Office of Research on Women’s
Health
Milestones in Ethical Development
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1997 Food and Drug Modernization Act (FDAMA)
requiring the FDA, NIH, and pharmaceutical industry
to develop guidance on the inclusion of women and
minorities in trials
1998 Pediatric Rule passed by Congress, stipulating that
new drugs for children must include specific pediatric
labeling information
2000 Further publicized ethical abuses prompting
establishment of the Office of Human Research
Protections (OHRP)
Belmont Report
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National Commission for the Protection of
Human Subjects of Biomedical and Behavioral
Research
3 basic principles for research
Belmont Report
Respect for persons, or an individual’s autonomyelements of the informed consent requiring that:
 Information necessary to make a decision must be
presented that is,the risks and benefits, if any, of
participation.
 The information must be presented at a level that can
be understood by the patient or study subject.
 Participation must be voluntary.
Belmont Report
Benificience, or benefit to the participant
Who decides whether there is benefit?
Belmont-Beneficence
Loss of substantial benefits that might be gained from
research
Paternalism
Pregnancy
Life-threatening illness (AIDS/Cancer)
Belmont-Justice
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Risks and benefits should be equitably
distributed among different populations

“Do onto others…” rather than taking advantage of
Vulnerable populations
Vulnerable Populations
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Military
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1944-1979: radiation, chemical,
Mustard gas, lewisite
 Venezuelan equine encephalitis virus and the nerve
gas agent VX
 Operation Whitecoat (tularemia, anthrax, Q fever)

1994 Congressional review: the Department of Defense
“has demonstrated a pattern of misrepresenting the danger
of various military exposures that continues today”

Vulnerable Populations
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Unsuspecting civilians
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Radiation experiments: atomic weapons testing in
South Pacific
 Oak Ridge
 Los Alamos
 Hanford, Washington
 Plutoniaum injections (ACHRE report)

Vulnerable Populations
What studies are being done now under
the guise of counter terrorism, hidden
from the public by the “Patriot Act?”
Vulnerable Populations-Children
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Pint-size people vs. real data
10 drugs most commonly prescribed for
children that lacked pediatric labeling—drugs
were prescribed more than 5 million times
HIV studies in foster children
Too vulnerable? vs denying access to potentially lifesaving drugs
 (all HIV + kids were being offered the trials)

Vulnerable Populations-Women

Pregnancy
Paternalism
 Woman vs Fetus

Daily Ethical Encounters
Participants who are vulnerable from:
Abuse from Doctor-patient relationship
“whatever you say, doc” syndrome
Indigent patients
Daily Ethical Encounters

Financial Pressures and Conflict of Interest
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Financial
Income for Department
 Bonuses
 Structure of grant (pay per visit or end-loaded)
 Pay for screening
 Pay for quality of data, rather than # of patients
 Avoid disincentives for dropping a patient (e.g., due to
adverse reaction
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Pressure re prestiege, publication, tenure
Other Conflicts of Interest
at the Site
Use of a class of drug in a study-e.g., Quinolones,
that you might not use otherwise
 Access to care for indigent patients
 Access to novel drug (pt may lie)
 Adverse event classification

Yet more COI

IRB related
Voluntary, unpaid
 Lack of training
 Paid by drug company
 Pressure from administration
 Personal competition/conflict
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Mrs. G?
Evaluating a Study

Does the study ask an important/valuable
question?
Is the study design reasonable?
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Would I be willing to be in this trial?

Evaluating a Potential Volunteer
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Level of understanding based on
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Motivation
Financial need
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vs. ethics of lack of universal health care
What will happen to the pt when the study ends?
Stage of illness
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Education, life experience
Risk vs. Benefit
What do they have to lose?
Would I take this drug or give it to my family member?
Politics of Research: Women
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Viewed as vulnerable population
Paternalism
Woman vs. fetus
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e.g. AIDs clinical trials
Religion

Exclusion of women from participation due to
restrictions about contraceptive use
Politics of Research: Race

one-fourth of the U.S. population is made up of
“people of color”

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Only 5% of trial participants
Legacy of distrust
Tuskeegee
 HIV-foster children study (despite evidence)
 Nigerian Pfizer meningitis trial => resistance to
polio vacciination

Politics of Research:
Race and Gender Overlap
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1980 and 1983, fully one-fifth of contraceptive
research was conducted in developing countries
Oral contraceptive research in Puerto Rico
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Adverse events analysis was inadequate
Quinacrine
The effect of power inequities between men and
women
 Lack of social support for many women
 Coercion by medical providers or government
agencies

Quinacrine-Belmont Principles
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Beneficence
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Distributive Justice
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No safety or toxicity studies of intrauterine
installation
Almost all the women were low income, poorly
educated women of color in developing countries.
Respect for Persons, autonomy, selfdetermination

No explanation of experimental nature of
quinacrine and no informed consent or offer of
Shifting Research
to Developing Countries
United States accounts for ~ 4 percent of the
world’s population vs. 84% for dev. Countries
 90 percent of $ is spent on the illnesses of the
wealthiest countries,
leaving 10 % of monies to care for 84 % of the
global population

Vulnerable international populations
• Limited economic development
• Inadequate protection of human rights
• Inadequate community and cultural experience
with, or understanding of, scientific research
• Limited availability of healthcare and treatment
options
• Limited ability of individuals in the community
to provide informed consent due to illiteracy
and language, educational, or cultural barriers
Vulnerable international populations
What standards should apply?
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Meningitis trial
Maternal-fetal HIV transmission trials
Absolute standard of care vs. local standard?
What if the local standard is to do nothing?
International consensus is that it is ethical if:
it is based on a valid scientific purpose for using a lesser
standard, provides social benefits for the local host
community, and shows a favorable risk-benefit ratio for
the individual research participants
Vulnerable international populations
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Distributive justice is violated
the local study populations will not significantly
benefit from the research if the new therapies
will not be affordable to them, although they are
taking a higher proportion of the risk.