Ethical Principles for
Biomedical Research
Involving Human Subjects:
Overview of International Guidelines
Maria Fidelis C. Manalo, MD,
MSc Epidemiology
Department of Community &
Family Medicine
Far Eastern UniversityNRMF Medical Center
Philippines
Public Concern for
Vulnerable Subjects
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Nazi Experiments and the Nuremberg Trials
Tuskegee Syphilis Study-involvement of black
males
Willowbrook Study-hepatitis study among
children in New York State institution for
mentally defective persons
Jewish Chronic Disease Hospital Studyinjection of live cancer cells into patients to
study transplant rejection process
San Antonio Contraceptive Study-study of side
effects of contraceptives on Mexican American
women
In research using human subjects, several
categories of persons maybe involved:
 Normal healthy adults, including the
investigator,
and elderly persons
 Sick adults, including the acutely and terminally ill
 People living in highly controlled situations, such
as, prisoners, soldiers, and students
 Children, both healthy and ill
 Mentally incompetent persons, whether adults or
children
 Unborn fetuses or still living aborted fetuses
Use of Vulnerable Persons
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Not forbidden by ethical codes or
regulations
Need for justification for their inclusion
 Unsuitability
of less vulnerable
populations
 Use of mitigation to address
vulnerability
NUREMBERG CODE:
INFORMED CONSENT
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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 . . . able to exercise free power of
choice, without the intervention of any
element of force, fraud, deceit, duress, . . . or
coercion;
Should have sufficient knowledge and
comprehension . . . .
NUREMBERG CODE:
INFORMED CONSENT
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The duty and responsibility for
ascertaining the quality of consent
rests upon . . .each individual who
initiates, directs, or engages in the
experiment.
It is a personal duty that may not be
delegated
ELEMENTS OF INFORMED
CONSENT
(1) DISCLOSURE
In general necessary items to disclose include:
a) the patient’s current medical status including
the likely course if no treatment is provided.
b) the contemplated procedure or medication
c) alternative available procedures or medication
d) anticipated risks and benefits of both
e) a statement offering an opportunity to ask
further questions
f) in case of research, his right to withdraw any
time
g) a professional opinion about the alternatives
ELEMENTS OF INFORMED
CONSENT
(2) COMPREHENSION
 7th grade level (US Standard)
 Language understood by the subject
 Oral or written quizzes to assess
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comprehension
Use of educational intervention prior to getting
consent
Allowed into research environment to
experience routine and procedures
ELEMENTS OF INFORMED
CONSENT
(3) VOLUNTARINESS - The patient must of his
own free will make a choice without being
unduly pressured by anyone else.
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Being free in making a decision means
that the patient owns the decision, that
the decision is the patient’s alone, that
the patient has chosen the option based
on the information disclosed to him/her.
ELEMENTS OF INFORMED
CONSENT
(4) COMPETENCE - patient’s capacity for
decision making. One is considered competent
when
(a) one has made a decision (i.e. one can
choose between alternatives)
(b) one has the capacity to justify one’s choice
(i.e, give reasons for one’s choice)
(c) one justifies one’s choice in a reasonable
manner
HUMAN SUBJECTS
OVER SCIENCE AND SOCIETY
. . . considerations related to
the well-being of the human
subject should take
precedence over the interests
of science and society.
(Helsinki Declaration, par. 5)
Protection of Special
Populations

Embryos And Human Fetuses
 Since
the human individual, in the
prenatal stage, must be given the dignity
of a human person, research and
experimentation on human embryos and
fetuses is subject to the ethical norms
valid for the child already born and for
every human subject.
Protection of Special
Populations
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Pregnant Women, Embryos And Human
Fetuses
 Research
in particular, that is the
observation of a given phenomenon
during pregnancy, can be allowed only
when “there is moral certainty that there
will be no harm either to the life or the
integrity of the expected child and the
mother, and on the condition that the
parents have given their consent.”
THERAPEUTIC CRITERIA
ONLY
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Experimentation is possible only for
clearly therapeutic purposes, when no
other possible remedy is available.
“No finality, even if itself noble, such as
the foreseeing of a usefulness for
science, for other human beings or for
society, can in any way justify
experimentation on live human embryos
and fetuses, whether viable or not, in the
maternal womb or outside of it.
Protection of Special
Populations
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Experimentation of embryos or
fetuses has the risk, indeed in most
cases the certain foreknowledge, of
damaging their physical integrity or
even causing their death.
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To use a human embryo or the fetus
as an object or instrument of
experimentation is a crime against
their dignity as human beings.
Protection of Special Populations
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“The practice of keeping human
embryos alive, actually or in vitro, for
experimental or commercial reasons,”
is especially and “altogether contrary
to human dignity.”
The informed consent, normally
required for clinical experimentation
on an adult, cannot be given by the
parents, who may not dispose of the
physical integrity or the life of the
expected child.
PROPORTIONALITY OF
RISKS TO BENEFITS
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Degree of risk to be taken should never
exceed . . . humanitarian importance of
the problem to be solved . . . .
(Nuremberg, #6)
Medical research . . . should only be
conducted if the importance of the
objective outweighs the inherent risks
and burdens to the subject. (Helsinki,
#18)
Right to refusal or withdrawal
of treatment
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“the patient has the right to refuse or withdraw
from treatment to the extent permitted by law
and to be informed of the medical
consequences of his action.”- Patient’s Bill of
Rights
a patient may refuse or withdraw from medical
treatment because their religious convictions
prohibit them from doing so (e.g., a patient
who is a member of a particular religious sect
may refuse to undergo blood transfusions)
PLACEBO MAY BE USED:
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When there is no established effective
intervention;
When withholding an established effective
intervention would expose subjects to, at
most, temporary discomfort or delay in
relief of symptoms;
When use of an established effective
intervention as comparator would not
yield scientifically reliable results and use
of placebo would not add any risk of
serious or irreversible harm to the
subjects (CIOMS #11)
Are there ethical issues in social
science or behavioral research?
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Most common methodology used
involves interviewing people and asking
questions
 “We
would just like to ask some
questions…”
 “We would just like to observe…”
 “We would just like to share your life…”
 Focus Group discussion (FGDs), Survey
 Does not involve invasive procedures
Ethical Issues in Social Science
& Behavioral Research
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Privacy
Confidentiality
Linking behavior
with medical
procedure
DO NO HARM
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Experiment should . . . avoid all
unnecessary physical and mental
suffering and injury. (Nuremberg, #4)
Forms of Harm to Human
Subjects in Behavioral Research
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Psychological harm – recalling a
traumatic event
Social stigma – loss of reputation
Cultural effects – going against existing
cultural norms
Political effects – disturbing existing
power relationships
Economic repercussions – loss of jobs
HOW TO AVOID HARM
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The experiment should be
conducted only by scientifically
qualified persons. (Nuremberg #8)
. . . human subject should be at
liberty to bring the experiment to an
end . . . (#9)
. . . terminate the experiment at any
stage, if . . . continuation of the
experiment is likely to result in
injury, disability, or death (#10)
HOW TO AVOID HARM
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[Ensure that] risks involved have been
adequately assessed and can be
satisfactorily managed.
Cease . . . investigation if:
1.
2.
the risks are found to outweigh the
potential benefits, or
there is conclusive proof of positive and
beneficial results (Helsinki #17)
Mitigating harm to human
subjects
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Research design- community inputs
Adequate research preparationfamiliarization with local culture,
sociopolitical structures, traditions and
cultural norms
Good reason to conduct research in a
particular community
Ethical Consideration Section in the
protocol
NBAC Guideline
“ Whenever possible, preceding the start
of research, agreements should be
negotiated by the relevant parties to
make effective intervention or other
research benefits available to the host
country after the study is completed.”
Mitigating harm to human
subjects
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Research methodologies should avoid
harm
 Mechanisms
for protection of privacy and
confidentiality
 Avoidance of social stigmatization
 Process of data storage
 Adequate infrastructure to protect privacy
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Research methodologies should provide
opportunities for empowerment-reflexivity
Mitigating harm to human
subjects-Reviewing the protocol
Technical
review
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Risk-benefit analysis
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Benefits should be defined in the protocol
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Provisions for support mechanisms
Consent process should be as strict as
requirements in clinical trials
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 Recruitment procedures
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Full disclosure of information
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Reconsenting mechanisms
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Feedback to community
Mitigating harm to human
subjects- Reviewing the protocol
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Culturally competent consent form
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Individual consent
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Family consent-secondary subjects
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Community consent
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Mechanisms for protection of privacy and
confidentiality defined in the consent form of
information sheet
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Provision of support/coping mechanism
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Need to take precaution to protect identity
of host community
Informed consent:
Community Context - CIOMS
“When it is not possible to request
informed consent from every
individual to be studied, the
agreement of a representative of a
community or group should be
sought, but the representative should
be chosen according to the nature,
traditions and political philosophy of
the community or group.”
Feedback to the Community
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Reporting results to the community
A
good means to highlight good practices:
positive reinforcement
 Suggestions for improvement should be
presented as constructive recommendations
 Public forum: a means to get public
commitment from public officials
 Opportunities for researchers to connect
community to larger community
RELEVANCE &
RESPONSIVENESS OF RESEARCH
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Medical research is only justified
if there is a reasonable likelihood
that the populations in which the
research is carried out stand to
benefit from the results of the
research. (Helsinki #19)
CIOMS
RELEVANCE AND
RESPONSIVENESS
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The sponsor and the investigator must
make every effort to ensure that:
1.
2.
the research is responsive to the health
needs and the priorities of the
population . . . ; and
any intervention or product developed,
or knowledge generated, will be made
reasonably available for the benefit of
that population. (CIOMS #10)
GENETIC RESEARCH:
Privacy, Confidentiality and
Integrity
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Respect the privacy of the subject,
the confidentiality of the patient's
information and minimize the
impact
of the study on the subject's
physical and mental integrity
(Helsinki #21)
MEDICAL RECORDS &
BIOLOGICAL SPECIMENS
Exempted from individual consent requirement
only if an ethical review committee has
determined that:
 Research
poses minimal risk
 Rights or interests of the patients will not
be violated
 privacy and confidentiality or anonymity are
ensured
 Research is designed to answer an
important question
 Impracticable if the requirement for
informed consent were to be imposed
(CIOMS)
HUMAN GENETIC DATA
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Clear, balanced, adequate and
appropriate information shall be
provided to the person whose prior, free,
informed and express consent is sought.
Information shall . . . specify the purpose
for which human genetic data . . . are
being derived, . . . used and stored
(International Declaration on Human Genetic
DataAdopted by the UNESCO General Assembly on 16 October
2003)
WITHDRAWAL OF CONSENT
(a) . . . Consent may be withdrawn by the
person concerned unless such data are
irretrievably unlinked to an identifiable person.
(b) When a person withdraws consent, the
person’s genetic data, proteomic data and
biological samples should no longer be used
unless they are irretrievably unlinked to the
person concerned.
(c) If the person’s wishes cannot be determined
or are not feasible or are unsafe, the data and
biological samples should either be
irretrievably unlinked or destroyed.
UNESCO Int’l Declaration, Art. 9
RIGHT TO BE, OR NOT TO
BE INFORMED OF RESULTS
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The person concerned
has the right to decide
whether or not to be
informed of the results
UNESCO Int’l Declaration, Art. 10
GENETIC COUNSELLING
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. . . When genetic testing . . . is being
considered, genetic counselling should
be made available . . . .
Genetic counselling should be nondirective, culturally adapted and
consistent with the best interest of the
person concerned.
UNESCO Int’l Declaration, Art. 11
CLINICAL TRIAL REGISTRATION
A Requirement for Publication
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Trials must register at or before the
onset of patient enrollment.
Selective reporting . . . distorts the
body of evidence available for
clinical decision-making.
Trial results that place financial
interests at risk are particularly likely
to remain unpublished and hidden
from public view.
Anyone should be able to learn of
any trial's existence and its
important characteristics.
BIBLIOGRAPHY
1. Ethical Review of Research: Overview of
International Guidelines and Principles by Prof.
Leonardo de Castro, Ph.D, Department of
Philosophy, University of the Philippines, Diliman
2. Ethical Issues in Social Science Research: by Prof.
Cristina E. Torres, Ph.D, College of Arts and
Sciences, University of the Philippines, Manila &
National Institute of Health
3. Protection of Vulnerable Subjects by Prof. Cristina E.
Torres, Ph.D, College of Arts and Sciences, UP
Manila & National Institute of Health
4. World Medical Association (WMA): Declaration of
Helsinki, Tokyo, 2004
5. The Nuremberg Code 1947
BIBLIOGRAPHY
6. The CIOMS Guidelines Nov 2000, International
Ethical Guidelines for Biomedical Research Involving
Human Subjects
7. The NBAC Report Aug 2001, Ethical and Policy
Issues in Research Involving Human Participants
8. International Declaration on Human Genetic Data,
UNESCO, October 16, 2003
9. The Belmont Report, 1979, Ethical Principles and
Guidelines for the Protection of Human Subjects of
Research
10. Fifth Global Forum for Health Research, Paris, 2004