Ethics in Research involving

Human Subjects
 Justification for Human Research

It is impossible to reach the important conclusions without studying in

humans
Human physiology and animal physiological responses are often not
the same.
Agents for treating humans because animal experiments don’t always
predict results
If you are going to treat humans you must study humans
Prior to 1906, when the Pure Food and Drug Act was passed, there
were no regulations regarding the ethical use of human subjects in
research. There were no consumer regulations, no Food and Drug
Administration (FDA), no Common Rule, and no Institutional Review
Board (IRB).
 Nazi Medical War Crimes (1939–1945)
• A well-known chapter in the history of research with human subjects
opened on December 9, 1946, when an American military tribunal
opened criminal proceedings against 23 leading German physicians
and administrators for their willing participation in war crimes and
crimes against humanity. Among the charges were that German
physicians conducted medical experiments on thousands of
concentration camp prisoners without their consent. Most of the
subjects of these experiments died or were permanently crippled as
a result.
• The Nazi War crimes have been one of the first large scale known
violations against human subjects.
 Nazi Medical War Crimes (1939–1945)

Medical Research involving human beings have

created a lot of potential pitfalls that led to tragedies
in the last century.
A photo for a burn induced in one of the prisoners , in a
study for treatment of burns.
 Tuskegee Syphilis Study - Alabama

• Tuskegee Syphilis Study (1932-1972). An equally well

known chapter in history occurred during a research
project conducted by the U.S. Public Health Service. Six
hundred low-income African-American males, 400 of whom
were infected with syphilis, were monitored for 40 years.
Free medical examinations were given; however, subjects
were not told about their disease. Even though a proven
cure (penicillin) became available in the 1950s, the study
continued until 1972 with participants being denied
treatment. In some cases, when subjects were diagnosed
as having syphilis by other physicians, researchers
intervened to prevent treatment. Many subjects died of
syphilis during the study.
 Tuskegee Syphilis Study - Alabama

• The study was stopped in 1973 by the U.S. Department of

Health, Education, and Welfare only after its existence was
publicized and it became a political embarrassment. In 1997,
under mounting pressure, President Clinton apologized to the
study subjects and their families.
 :Willowbrook

From 1963 to 1966, the Willowbrook Study involved a group of children

diagnosed with mental retardation, who lived at the Willowbrook State
.Hospital in Staten Island, New York
These innocent children were deliberately infected with the hepatitis
virus; early subjects were fed extracts of stools from infected
individuals and later subjects received injections of more purified virus
.preparations
Investigators defended the injections by pointing out that the vast
majority of them acquired the infection anyway while at Willowbrook,
and it would be better for them to be infected under carefully controlled
.research conditions
The study's purpose was to study the history of the disease
when left untreated and later to assess the effects of
.gamma globulin as a therapeutic intervention
This study generated a variety of concerns, such as the
deliberate infection of the children and the attempts to
convince the parents to enroll them in the study in
exchange for admission to the hospital (which was
.deliberately short of space)
 :Fernald School Study
The Fernald School was the site of the 1946–53 joint
experiments by Harvard University and MIT that exposed
.young male children to tracer doses of radioactive isotopes
The experiment was conducted in part by a research fellow
sponsored by the Quaker Oats Company. MIT Professor of
Nutrition Robert S. Harris led the experiment, which studied
.the absorption of calcium and iron
The boys were encouraged to join a "Science Club", which
offered larger portions of food, parties, and trips to Boston
Red Sox baseball games. The 57 club members ate iron-
.enriched cereals and calcium-enriched milk for breakfast
In order to track absorption, several radioactive
calcium tracers were given orally or
intravenously. Radiation levels in stool and
blood samples would serve as dependent
.variables
Neither the children nor their parents ever gave
adequate informed consent for participation in a
.scientific study
 Brooklyn - Jewish -- 1963
Chronic Diseases Hospital
• Cancer cells were injected into debilitated elderly
patients to see if they would immunologically reject the
cells.
 History of Ethical Code
• It is clear that Various cultures
such as ancient Egypt , Persia,
Babylonia and Greece have
attempted to regulate medicine
and protect patient rights.
• One of the earliest written
provisions in the field is that .
comes about 1750 BC is the
Code of Hammurabi.
• Polished Black Diorite Steel
1792 – 1750 BC WITH CODE
OF Hammurabi inscribed and
bas-relief at top of showing king
receiving laws from Sun God
 The Nuremberg Code -1948
– Voluntary informed consent
– Likelihood of some good resulting
– Based on prior research (animal models)
– Avoidance of physical or psychological injury or harm
– Benefits should outweigh risks
– Proper experience of researcher
– Right to withdraw consent
– Research must stop if harm is resulting

(no specific mention of children, unconscious people, or others who may not
be competent to give consent)

As a direct result of the trial, the Nuremberg Code was established in 1948,
stating that "The voluntary consent of the human subject is absolutely
essential," making it clear that subjects should give consent and that the
benefits of research must outweigh the risks. Although it did not carry the
force of law, the Nuremberg Code was the first international document
which advocated voluntary participation and informed consent.
National Commission for the Protection of Human Subjects of Biomedical
.and Behavioral Research in 1974

•Respect for persons

•Beneficence
•Justice
 The Belmont Report
• The National Research Act codified the requirement that
human subjects in research must be protected and set
the stage for the issuance of the Belmont Report.
• THE BELMONT REPORT
• Carrying out its charge, the National Commission for the
Protection of Human Subjects of Biomedical and
Behavioral Research prepared the Belmont Report in
1979. The Belmont Report attempts to summarize the
basic ethical principles identified by the Commission in
the course of its deliberations. The Report is a statement
of basic ethical principles and guidelines that should
assist in resolving the ethical problems that surround the
conduct of research with human subjects.
 Helsinki Declaration
1. Ethical Principles for Medical Research Involving
Human Subjects Adopted by the 18th WMA General
Assembly, Helsinki, Finland, June 1964;
2. amended by the 29th WMA General Assembly,
Tokyo, Japan, October 1975;
3. 35th WMA General Assembly, Venice, Italy, October
1983;
4. 41st WMA General Assembly, Hong Kong,
September 1989;
5. 48th WMA General Assembly, Somerset West,
Republic of South Africa, October 1996, and
6. the 52nd WMA General Assembly, Edinburgh,
Scotland, October 2000
 Helsinki Declaration

The World Medical Association (WMA) has

developed the Declaration of Helsinki as a
statement of ethical principles for medical
research involving human subjects, including
research on identifiable human material and
data. The first version was adopted in 1964
and has been amended six times since, most
recently at the General Assembly in October
2008. The current (2008) version is the only
official one.
• The Declaration governs international research ethics and
defines rules for "research combined with clinical care" and
"non-therapeutic research."
• Revised Declaration of Helsinki is the basis for Good Clinical
Practices used today.
• Issues addressed in the Declaration of Helsinki include:
1. Research with humans should be based on the results from laboratory
and animal experimentation
2. Research protocols should be reviewed by an independent committee
prior to initiation
3. Informed consent from research participants is necessary
4. Research should be conducted by medically/scientifically qualified
individuals
5. Risks should not exceed benefits
 Introduction

1. Statement of ethical principles to provide guidance to

physicians and other participants in medical research
involving human subjects. Medical research involving
human subjects includes research on identifiable
human material or identifiable data.
2. It is the duty of the physician to promote and
safeguard the health of the people. The physician’s
knowledge and conscience are dedicated to the
fulfillment of this duty.
 Introduction
3. The Declaration of Geneva of the World Medical
Association binds the physician with the words, ‘‘The
health of my patient will be my first consideration,’’
and the International Code of Medical Ethics declares
that, ‘‘A physician shall act only in the patient’s
interest when providing medical care which might
have the effect of weakening the physical and mental
condition of the patient.’’
4. Medical progress is based on research which
ultimately must rest in part on experimentation
involving human subjects.
 Introduction
5. In medical research on human subjects,
considerations related to the well-being of the human
subject should take precedence over the interests of
science and society.
6. The primary purpose of medical research involving
human subjects is to improve prophylactic, diagnostic
and therapeutic procedures and the understanding of
the aetiology and pathogenesis of disease. Even the
best proven prophylactic, diagnostic, and therapeutic
methods must continuously be challenged through
research for their effectiveness, efficiency,
accessibility and quality.
7. In current medical practice and in medical research,
most prophylactic, diagnostic and therapeutic
procedures involve risks and burdens.
 Introduction
8. Medical research is subject to ethical standards that
promote respect for all human beings and protect their
health and rights. Some research populations are
vulnerable and need special protection. The particular
needs of the economically and medically
disadvantaged must be recognized. Special attention
is also required for those who cannot give or refuse
consent for themselves, for those who may be subject
to giving consent under duress, for those who will not
benefit personally from the research and for those for
whom the research is combined with care.
 Introduction
9. Research Investigators should be aware of the
ethical, legal and regulatory requirements for research
on human subjects in their own countries as well as
applicable international requirements. No national
ethical, legal or regulatory requirement should be
allowed to reduce or eliminate any of the protections
for human subjects set forth in this Declaration.
Basic principles for all medical research
1. It is the duty of the physician in medical research to
protect the life, health, privacy, and dignity of the
human subject.
2. Medical research involving human subjects must
conform to generally accepted scientific principles, be
based on a thorough knowledge of the scientific
literature, other relevant sources of information, and
on adequate laboratory and, where appropriate,
animal experimentation.
3. Appropriate caution must be exercised in the conduct
of research which may affect the environment, and
the welfare of animals used for research must be
respected.
 Basic principles for all medical research
4. The design and performance of each experimental procedure involving
human subjects should be clearly formulated in an experimental
protocol.
• This protocol should be submitted for consideration, comment,
guidance, and where appropriate, approval to a specially appointed
ethical review committee, which must be independent of the
investigator, the sponsor or any other kind of undue influence.
• This independent committee should be in conformity with the laws and
regulations of the country in which the research experiment is
performed.
• The committee has the right to monitor ongoing trials.
• The researcher has the obligation to provide monitoring information to
the committee, especially any serious adverse events.
• The researcher should also submit to the committee, for review,
information regarding funding, sponsors, institutional affiliations, other
potential conflicts of interest and incentives for subjects.
Basic principles for all medical research
5. The research protocol should always contain a
statement of the ethical considerations involved and
should indicate that there is compliance with the
principles enunciated in this Declaration.
6. Medical research involving human subjects should be
conducted only by scientifically qualified persons and
under the supervision of a clinically competent
medical person. The responsibility for the human
subject must always rest with a medically qualified
person and never rest on the subject of the research,
even though the subject has given consent.
Basic principles for all medical research
7. Every medical research project involving human
subjects should be preceded by careful assessment
of predictable risks and burdens in comparison with
foreseeable benefits to the subject or to others. This
does not preclude the participation of healthy
volunteers in medical research. The design of all
studies should be publicly available.
8. Physicians should abstain from engaging in research
projects involving human subjects unless they are
confident that the risks involved have been
adequately assessed and can be satisfactorily
managed. Physicians should cease any investigation
if the risks are found to outweigh the potential benefits
or if there is conclusive proof of positive and beneficial
results.
Basic principles for all medical research
9. Medical research involving human subjects should
only be conducted if the importance of the objective
outweighs the inherent risks and burdens to the
subject. This is especially important when the human
subjects are healthy volunteers.
10. 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.
11. The subjects must be volunteers and informed
participants in the research project.
Basic principles for all medical research
12. The right of research subjects to safeguard their
integrity must always be respected. Every precaution
should be taken to respect the privacy of the subject,
the confidentiality of the patient’s information and to
minimize the impact of the study on the subject’s
physical and mental integrity and on the personality of
the subject.
Basic principles for all medical research
13. In any research on human beings, each potential subject
must be adequately informed of the aims, methods,
sources of funding, any possible conflicts of interest,
institutional affiliations of the researcher, the anticipated
benefits and potential risks of the study and the discomfort
it may entail.
• The subject should be informed of the right to abstain from
participation in the study or to withdraw consent to
participate at any time without reprisal.
• After ensuring that the subject has understood the
information, the physician should then obtain the subject’s
freely-given informed consent, preferably in writing.
• If the consent cannot be obtained in writing, the non-written
consent must be formally documented and witnessed.
Basic principles for all medical research
14. When obtaining informed consent for the research project
the physician should be particularly cautious if the subject is
in a dependent relationship with the physician or may
consent under duress. In that case the informed consent
should be obtained by a well-informed physician who is not
engaged in the investigation and who is completely
independent of this relationship.
15. For a research subject who is legally incompetent,
physically or mentally incapable of giving consent or is a
legally incompetent minor, the investigator must obtain
informed consent from the legally authorized representative
in accordance with applicable law. These groups should not
be included in research unless the research is necessary to
promote the health of the population represented and this
research cannot instead be performed on legally competent
persons.
 Basic principles for all medical research
16. When a subject deemed legally incompetent, such as a minor child,
is able to give assent to decisions about participation in research, the
investigator must obtain that assent in addition to the consent of the
legally authorized representative.
17. Research on individuals from whom it is not possible to obtain
consent, including proxy or advance consent, should be done only if
the physical/mental condition that prevents obtaining informed
consent is a necessary characteristic of the research population.
• The specific reasons for involving research subjects with a condition
that renders them unable to give informed consent should be stated
in the experimental protocol for consideration and approval of the
review committee.
• The protocol should state that consent to remain in the research
should be obtained as soon as possible from the individual or a
legally authorized surrogate.
Basic principles for all medical research
18. Both authors and publishers have ethical obligations.
• In publication of the results of research, the
investigators are obliged to preserve the accuracy of
the results.
• Negative as well as positive results should be
published or otherwise publicly available.
• Sources of funding, institutional affiliations and any
possible conflicts of interest should be declared in the
publication.
• Reports of experimentation not in accordance with the
principles laid down in this Declaration should not be
accepted for publication.
 Additional principles for medical
research combined with medical care
1. The physician may combine medical research with
medical care, only to the extent that the research is
justified by its potential prophylactic, diagnostic or
therapeutic value. When medical research is
combined with medical care, additional standards
apply to protect the patients who are research
subjects.
2. The benefits, risks, burdens and effectiveness of a
new method should be tested against those of the
best current prophylactic, diagnostic, and therapeutic
methods. This does not exclude the use of placebo, or
no treatment, in studies where no proven prophylactic,
diagnostic or therapeutic method exists.
 Additional principles for medical
research combined with medical care
3. At the conclusion of the study, every patient
entered into the study should be assured of
access to the best proven prophylactic,
diagnostic and therapeutic methods identified
by the study.
4. The physician should fully inform the patient
which aspects of the care are related to the
research. The refusal of a patient to
participate in a study must never interfere with
the patient–physician relationship.
 Additional principles for medical
research combined with medical care
5. In the treatment of a patient, where proven
prophylactic, diagnostic and therapeutic methods do
not exist or have been ineffective, the physician, with
informed consent from the patient, must be free to
use unproven or new prophylactic, diagnostic and
therapeutic measures, if in the physician’s judgement
it offers hope of saving life, reestablishing health or
alleviating suffering. Where possible, these measures
should be made the object of research, designed to
evaluate their safety and efficacy. In all cases, new
information should be recorded and, where
appropriate, published. The other relevant guidelines
of this Declaration should be followed.
 Other International Guidelines

• 1982 - International Ethical Guidelines for

Biomedical Research Involving Human Subjects
by World Health Organization (WHO) and
Council for International Organizations of
Medical Sciences (CIOMS)

• This 2002 text supersedes the 1993 Guidelines. It is the

third in the series of biomedical-research ethical
guidelines issued by CIOMS since 1982. Its core
consists of 21 guidelines with commentaries.
 The Four Principles of Ethics

1 - Autonomy (Respect for the person)

2 - Beneficence (Do Good)
3 - Non-malfeasance (Do No Harm)
4 - Justice
Institutional Review Board (IRB)
• Also known as an Independent Ethics
Committee (IEC) or Ethical Review Board
(ERB) is a committee that has been
formally designated to approve, monitor,
and review biomedical and behavioral
research involving humans with the aim to
protect the rights and welfare of the
research subjects .
– The IRB must have at least seven members.

– The members must have enough

experience, expertise, and diversity

– If the IRB works with studies that include

vulnerable populations, the IRB should have
members who are familiar with these groups.
– The IRB should include both men and
women.

– The members of the IRB must not be

all of the same profession.

– The IRB must include at least one

scientist and at least one non-scientist.
These terms are not defined in the
regulations.
– The IRB must include at least one person who
is not affiliated with the institution or in the
immediate family of a person affiliated with
the institution. These are commonly called
"Community Members.”

– IRB members may not vote on their own

projects.

– The IRB may include consultants in their

discussions to meet requirements for
expertise or diversity, but only actual IRB
members may vote.
 Responsibilities of IRB
– Risks to study participants are minimized
– Risks are reasonable in relation to anticipated
benefits
– Selection of study participants is equitable
– Informed consent is obtained and
appropriately documented for each participant
– Adequate provisions for monitoring data
collection to ensure safety of the study
participants
– Participant privacy and confidentiality is
protected
• The chief objectives of every IRB protocol review
are
– to assess the scientific merit of the research and its
methods,
– to promote fully informed and voluntary participation
by prospective subjects who are themselves capable
of making such choices (or, if that is not possible,
informed permission given by a suitable proxy) and
– to maximize the safety of subjects once they are
enrolled in the project
 The IRB/IEC should obtain the
following documents

– Trial protocol(s)/amendment(s),
– Written informed consent form(s)
– Consent form updates that the investigator
proposes for use in the trial
– subject recruitment procedures (e.g.,
advertisements), written information to be
provided to subjects, Investigator's Brochure
(IB),
– Available safety information,
– Information about payments and
compensation available to subjects,
the investigator's current curriculum
vitae and/or other documentation
evidencing qualifications,
– Any other documents that the
IRB/IEC may need to fulfill its
responsibilities.
• The IRB/IEC should review within a reasonable time and
document its views in writing, clearly identifying the trial, the
documents reviewed and the dates for the following:
• approval/favourable opinion;
• modifications required prior to its approval/favourable opinion;
• disapproval/negative opinion; and
• termination/suspension of any prior approval/favourable
opinion.
• According to ICH GCP the IRB/IEC should conduct continuing
review of each ongoing trial at intervals appropriate to the
degree of risk to human subjects, but at least once per year.
Thank You