Research Ethics

Copyright @ 2018 University of Washington

• The atrocities committed by Nazi physicians on
Jewish prisoners during World War II prompted an
international tribunal, convened in the city of
Nuremberg, Germany between 1945-1946, to
elaborate 10 principles, called the Nuremberg
Code, by which research involving human
subjects should be governed.
• Publication of the Nuremburg Code in 1947
ushered in the modern era of research ethics,
which mandated balancing the advancement of
science with the rights and welfare of humans
who serve as research subjects.
• Since Nuremburg, a multitude of regulations and policy
statements have been developed by domestic and
international bodies.
• These regulatory guidance documents, including the World
Medical Association Declaration of Helskinki (World Medical
Association); the Belmont Report and the Federal
Regulations at 45 CFR 46 and 21 CFR 50 share a common
purpose: to protect the autonomy, safety, privacy, and
welfare of human research subjects.
• Within institutions where clinical research is conducted,
responsibility for the interpretation and application of these
ethical principles and regulations rests with committees
comprised of scientist and non-scientists, called Institutional
Review Boards for the Protection of Human Subjects (IRBs).
 What are the general ethical principles
applied to research with human subjects?

• The Belmont Report, which provides the

ethical foundation for research
regulations and guides IRB deliberations,
was generated by a federally
commissioned group of scientists,
physicians, ethicists, and philosophers
and published in 1979.
• The three primary ethical principles cited
in Belmont are: autonomy, beneficence,
and justice.
• Autonomy refers to the right of an individual to determine what
activities they will or will not participate in. Implicitly, full autonomy
requires that an individual be able to understand what they are being
asked to do, make a reasoned judgment about the effect participation
will have on them, and make a choice to participate free from coercive
influence.
• The cornerstone of protecting autonomy is the informed consent
process, whereby an investigator provides a potential research
participant with full disclosure about the nature of the study, the risks,
benefits and alternatives, and an extended opportunity to ask
questions before deciding whether or not to participate.
• Populations presumed to have diminished autonomy, by virtue of
impaired cognition (for example, children, cognitively-impaired elderly,
or mentally ill subjects) or of circumstance (for example prisoners or
seriously ill people) are considered to be vulnerable populations.
• In some of these cases (children and prisoners) special safeguards to
protect their autonomy are required by regulation.
• Beneficence refers to the obligation on the part
of the investigator to maximize benefits for the
individual participant and/or society, while
minimizing risk of harm to the individual.
• Maximizing potential benefits is predicated on
sound experimental design, thus research
proposals must undergo rigorous scientific review
before proceeding to the IRB for ethical review.
• An honest enumeration of reasonably anticipated
risks must be followed by a thorough risk/benefit
calculation.
• Justice demands equitable selection of
participants, i.e., avoiding participant
populations that may be unfairly coerced
into participating, such as prisoners and
institutionalized children.
• The principle of justice requires that those
who undertake the burdens of research must
be likely to benefit from the research, and is
a principle often violated by the export of
clinical trials to underdeveloped countries.
 How do you design ethical
research studies?
• The primary concern of the investigator should
be the safety of the research participant.
• Protecting subject safety requires the
investigator to use all available information to
identify potential risks to the subject, to
establish means of minimizing those risks, and
to continually monitor the ongoing research
for adverse events experienced by subjects.
• The investigator must be prepared to stop the
study if serious unanticipated risks are
manifest.
• The scientific investigator must obtain informed consent
from each research participant.
• This should be obtained in writing (although oral consents
are sometimes acceptable) after the participant has had
the opportunity to carefully consider the risks and benefits
and to ask any pertinent questions.
• Informed consent should be seen as an ongoing process,
not a single event or a mere formality.
• There are regulations and guidance documents that
govern exceptions to the requirement to obtain informed
consent, for example in cases of emergency or if the
subject is unconscious and thereby unable to give
consent.
• The investigator must protect the subjects’
privacy and confidentiality. Researchers must
have mechanisms in place to prevent the
disclosure of, or unauthorized access to, data
that can be linked to a subject’s individual
identity.
• The investigator must consider how adverse
events will be handled. In particular, it must
be established a priori who will provide care
for a participant injured in a study and who
will pay for that care.
• The investigator must strive for
clinical equipoise. A true null
hypothesis should exist at the onset
regarding the outcome of the trial,
that is, if a new intervention is being
tested against the currently accepted
treatment, the investigator should be
genuinely uncertain which approach
is superior.
 What are the components of ethically
valid informed consent for research?

• Given the appreciation that informed

consent is at the crux of human
subjects protection, it is not
surprising that the regulations reflect
extensively upon the necessary
elements of the consent document
itself as well as on the informed
consent process. For an
informed consent to be ethically
valid, the following components must
• Disclosure: The informed consent document must make
clear that the study is a research study, and not clinical
therapy. The potential participant must be informed as fully
as possible of the nature and purpose of the research, the
procedures to be used, the expected benefits to the
participant and/or society, the potential of reasonably
foreseeable risks, stresses, and discomforts, and alternatives
to participating in the research. There should also be a
statement that describes procedures in place to ensure the
confidentiality of data and anonymity of the participant. The
informed consent document must also disclose what
compensation and medical treatment are available in the
case of a research-related injury. The document should make
it clear whom to contact with questions about the research
study, research subjects' rights, and in case of injury.
• Understanding: The participant must understand
what has been explained and must be given the
opportunity to ask questions and have them
answered by someone fully conversant in the
study particulars. The informed consent document
must be written in lay language, avoiding any
technical jargon. The potential participant must be
able to read and/or understand the language in
which the consent form is written. Consent forms
for multinational research must be translated into
the respective language for each participating
country and back-translated to verify accuracy.
• Voluntariness: The participant's consent to
participate in the research must be voluntary,
free of any coercion or inflated promise of
benefits from participation. Care should be
taken that the consent form is administered
by someone who does not hold authority over
the participant. Ideally, the potential
participant is given the opportunity to discuss
their participation in the study with family,
trusted friends, or their physician before
reaching a decision.
• Competence: The participant must be
competent to give consent. If the participant is
not competent due to mental status, disease,
or emergency, a designated surrogate may
provide consent if it is in the participant's best
interest to participate. In certain emergency
cases, consent may be waived due to the lack
of competence of the participant and absence
of an appropriate surrogate. In the event that
there is a question about competence, mental
status exams may be administered.
• Consent: The potential human subject must
authorize his/her participation in the research
study, preferably in writing. If there is no need
to collect personally identifiable information,
and a signature on the consent form would be
the only thing linking the subject to the
study, an oral or implicit consent may be more
appropriate. Children who cannot read or write
should still signal their willingness to participate
by an affirmative act (for example, nodding their
head). Consent by minors is referred to as
assent.
• Exculpatory language: No
informed consent may contain any
exculpatory language by which the
participant waives any legal rights or
releases the investigator or sponsor
from liability for negligence.
What are the regulatory requirements to
administer informed consent?

• According to the regulations at 45

CFR 46.116: "no investigator may
involve a human being as a subject
in research covered by this policy
unless the investigator has obtained
the legally effective informed
consent of the subject or the
subject's legally authorized
representative."
 What does IRB review of research entail:
full-board, expedited, and exempt reviews?

• Full board: Clinical trials that expose subjects to

more than minimal risk must be reviewed by the IRB
at a convened meeting of the full Board. Minimal
risk is defined as those risks and discomforts to
which a person is commonly exposed in the ordinary
course of daily life, including routine visits to
physicians. It is important to remember that loss of
privacy, i.e unauthorized disclosure of personal
information, is considered to be a risk of research.
As technology and social media strip away more and
more of our privacy, ethicists debate what
constitutes a reasonable expectation of privacy.
• Expedited: Studies that qualify for
expedited review are those that present no
more than minimal risk to subjects, and
involve only procedures commonly done in
clinical settings, such as taking hair, saliva,
excreta or small amounts of blood. A study
that qualifies for expedited review is held to
the same ethical standards of autonomy,
beneficence and justice that are used in full
board review, but the approval process may
take less time.
• Exempt: Some research with humans can
be designated as exempt from IRB review.
Research that is part of a routine
educational experience, or in which
participants will be anonymous or
effectively de-identified falls into this
category and may be granted a certificate
of exemption. The proposal must still be
reviewed by a member of the IRB to assign
exempt status, but the application process
may be considerably shorter.
Is deception of subjects allowed
when doing research?
• As a general rule, deception is not acceptable when doing
research with humans. Using deception jeopardizes the
integrity of the informed consent process and could harm
participants, as well as eroding trust between the public and
researchers. In some instances deception is necessary to
conduct the research: for example, a study of how the
decision-making practices of physicians affect their practice
of medicine might be presented as a study of
"communication behaviors.” The IRB will carefully review
any proposal that suggests using deception or
misrepresentation. They will require an in-depth justification
of why deception is necessary for the study and the steps
that will be taken to safeguard participants, including a plan
to debrief subjects at the end of the research.
• A form of deception of subjects can occur if the
terms of the informed consent are violated by
the investigator or other scientists. For example,
if a subject consents to have their blood sample
evaluated for markers of diabetes and the
investigator or other scientists use the blood
sample for purposes unrelated to diabetes
research, the subject has effectively been
deceived about the nature of their research
participation and they have been denied
autonomous agency over their own actions.
 Case 1
• Mrs. Franklin, an 81-year-old Alzheimer's patient
hospitalized under your care has been asked to
participate in a clinical trial testing a new drug
designed to help improve memory. You were
present when the clinical investigator obtained a
signed informed consent from Mrs. Franklin a
few days ago. However, when you visit Mrs.
Franklin today and ask her if she is ready to
begin the study tomorrow, she looks at you
blankly and seems to have no idea what you are
talking about.
• What should you do?
 Case Discussion
• The competence of Mrs. Franklin to give an ethically
valid informed consent is in doubt. You should
contact the primary investigator to discuss Mrs.
Franklin's participation in the trial. There may be a
surrogate who can give consent for her
participation if it is deemed to be in her best
interests. Although she may be considered a
vulnerable research subject because of her mental
status, Mrs. Franklin does belong to the population
the intervention is designed to assist, and the study
may lead to beneficial interventions for Alzheimer's
patients in the future. However, a careful balancing
of risks and benefits should occur.
 Case 2
• During the conduct of a large clinical trial of an
investigational drug, preliminary analysis of
results show that there were three times as
many participants in the experimental group
who experienced severe nausea and vomiting
compared to the control group. Two of the cases
were severe enough to require that the
participants be hospitalized. This is despite the
fact that the preliminary analysis shows that
there may be a moderate benefit with the drug.
• What should be done?
 Case Discussion
• All adverse events are reported to the Data Safety
Monitoring Board, and serious adverse events must
be reported to the IRB. Investigators should consider
reevaluating the balance of risks versus benefits.
While these adverse events are probably not serious
enough to suggest that the trial be terminated,
these adverse events should be balanced by
significant benefits. These findings may relate to
each participant’s willingness to continue in the
trial, and according to 45 CFR 46.116(b)(5) the
findings should be provided to all current and future
participants as part of the informed consent
process.