Protection of Vulnerable

Subjects
Cristina E. Torres, PhD
FERCAP Coordinator
 Learning Objective

• To define vulnerability and provide

protection for vulnerable participants in
protocol development and review
 Outline
• Definition of vulnerable groups
• Ethical issues concerning vulnerable
groups
• Mechanisms of protection

3
 Background
• Human participation in research is
inherently risky, however, such research is
required in order to move from showing
the efficacy and safety of unproven
medical therapies.
• Research becomes more complicated
when the participants are members of
“vulnerable populations”.
Public Perception of
Research
 Public Concern for Vulnerable
Subjects
• 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 Study – injection 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
 Vulnerable and Less Advantaged
Persons
• Persons who are absolutely or relatively incapable of
protecting their interests
• Insufficient power, intelligence, resources, strength or
other needed attributes to protect their own interests
through informed consent
• Each person when measured against the highest
standards of capability is relatively vulnerable

– Robert Levine, The Ethics and Regulation of

Clinical Research, 1986
 Involvement of Vulnerable
Subjects
“The proposed involvement of hospitalized
patients, other institutionalized persons, or
disproportionate numbers of racial or
ethnic minorities or persons of low
socioeconomic status should be justified.”
US National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research: Institutional Review Boards:
Report and Recommendation, 1978
 WHAT is vulnerable ?

Individuals whose willingness to volunteer in a clinical

trial may be unduly influenced by the expectation,
whether justified or not, of benefits associated with
participation, or of a retaliatory response from
senior members of a hierarchy in case of refusal to
participate.
ICH 1.61
 Special Populations
• Fetuses, pregnant women and human in
vitro fertilization
• Prisoners
• Children
US Department of Health and Human Services Rules and Regulations 45
CFR 46
 Age groups and levels of maturity
• ICH E11: Children (2 to 11 years); Adolescents
(12-18 years)
• Age ranges redefined to provide guidance
regarding the proper involvement of minors in
the informed consent process
• EU: redefined (to emphasize need to
take children seriously) into Pre-
schoolers (2-5 years), Schoolers (6-9
years) and Adolescents (10-18
years).
• WHO definition of adolescence
starting at the age of 10 years
 Chronological age –
used to delineate groups

Maturity -
starting point
Physiology/ for discussing
metabolism- research
used to information
define dose & with minors
outcomes
Research in children and adolescents

• Children and adolescents must be included in

health-related research unless a good scientific
reason justifies their exclusion
• They merit special consideration by virtue of
their distinctive physiologies and health
needs
• May not be able to protect their own interests
and may be at risk of additional harm
• Need special protection
• Evidence that the protocol
Information
and information material have sheet for
been designed with and
reviewed by parents and children
patients
• Provide age-appropriate
information and
assent/agreement forms
• Separate material should be
used for children, using
language and communication
tools (visuals, cartoons,
videos etc.) appropriate to the
participants’ age and maturity
Assent
• Assent – process of meaningful discussion
with the child or adolescent
• Not merely absence of dissent
• Takes into account their age, individual
circumstances, life experiences, emotional and
psychological maturity, intellectual capabilities
and their family situation
 Waiver of parental permission
• May be waived by RECs in cases when permission of a
parent is not feasible or is undesirable
– “emancipated” or “mature” minors (married,
pregnant or parents themselves, or living
independently)
– Studies about adolescents’ beliefs and behavior
(sexuality, use of recreational drugs, domestic
violence, sexually transmitted diseases, pregnancy,
abortion, or child abuse)
• Cases when parental knowledge of the research topic
may place the children or adolescents at risk of
intimidation or physical harm by their parents.
 Involvement of
Independent child
advocates

• A relative, trusted friend, or family physician not involved

in the research project may represent the child.
• Independent psychological and medical support for the
participating children and adolescents is another special
protection
• In some communities, the study personnel may be
sufficiently qualified to help children and adolescents
who need medical and psychological support.
 Order of
involvement in
research
• Studies may be done in adults first before
children to minimize risks to children unless
research addresses an important health need or
priority among children
• RECs must be convinced of the special
relevance of research to children
• Older children must be selected before younger
children or infants, unless there are sound
scientific reasons
 Pediatric
expertise

• Defined as a combination of education, training

and experience on various aspects of ethics,
child development and psychosocial aspects
• Goes beyond having professionally worked with
children
• Needed to assess clinical trial applications
• Methodological expertise needed to prevent
unnecessary risks to children
Women as Research Participants
CIOMS Guideline 18
•Women must be included in health-related research
unless a good scientific reason justifies their exclusion.
Women have been excluded from much health-related
research because of their childbearing potential.

•Women have distinctive physiologies and health needs,

they merit special consideration by researchers and
research ethics committees
CIOMS 2017
 Women as Research Participants
• Women of childbearing potential must be informed in
advance of the possibility of risks to the fetus should
they become pregnant during their research
participation.
• When participation in research might be hazardous to
a fetus or if she becomes pregnant, sponsors and
researchers must guarantee access to pregnancy
tests, effective contraceptive methods before and
during the research and to safe, legal abortion.
Thalidomide 1950-1960’S
 Pregnant and Breastfeeding Women as
Research Participants
GUIDELINE 19
•Research in pregnant women must be initiated
only after careful consideration of the best
available relevant data
•Source of data: preclinical research in pregnant
animal models, research in non-pregnant women,
retrospective observational studies, and pregnancy
registries
Pregnant and Breastfeeding Women as
Research Participants
• Requirement of individual informed consent by
the pregnant or breastfeeding woman
• Some research involving women may be
directed at the health of the fetus. The
woman remains the decision-maker for any
interventions that affect her. This does not
exclude the possibility of the woman
consulting the father of the fetus, if she
wishes
 Other Vulnerable Groups
Uncomprehending Subjects
• Persons unable to understand and cooperate may defeat
purpose of the research or harm themselves
• Includes
– Mentally retarded
– Uneducated
– Senile
– Linguistically disadvantaged
– Inebriated
– Unconscious
– Dying
 Other Vulnerable Groups
Mentally disabled

• Problems with capacity, continuous or

fluctuating
• Often institutionalized or hospitalized
• Potential for control or manipulation
• May suffer from incurable diseases
 Other Vulnerable Groups:
Sick Subjects
• Illness is indicative of the disturbance of the capacity to
perform roles and tasks effectively
• Types
– Persons with prolonged chronic illness – more prone
to take risks to gain relief, even if remote
– Depressed persons
– Suffering persons
– Emergency cases
– Dying
 Other Vulnerable Subjects
Emergency Situation
• Possible problems with capacity
• Limits on voluntariness due to time
constraints
• Institutional setting
• Potential for control, coercion and
undue influence or manipulation
 Other Vulnerable
Groups
Economically
disadvantaged
• Limited access to
health care
• May enroll in research for
treatment or compensation
• Often educationally disadvantaged
• Potential for undue influence or
manipulation
 Other Vulnerable Groups
Dependent Subjects
• Dependence by virtue of relationship with investigator
• Types of dependence
– Administrative availability – patients, students,
employees, prisoners, etc.
– Threatened relationships – fear of jeopardizing
relationships if they refuse to participate
– Poor subjects – unable to secure money by ordinary
means
 Other Vulnerable Groups
Minority Groups
• Determined by age, race, sex, ethnicity,
etc.
• Culturally different – indigenous peoples
• Gays
• Elderly
– Ageism - deep and profound prejudice against
the elderly
 Other Vulnerable Groups
Subjects in Unusual
Circumstances

• Sexual abuse / rape victims

• Domestic violence victims
• HIV-AIDS / STD cases
• Victims of war
 Use of vulnerable persons
• Not forbidden by ethical codes or
regulations
• Need for justification for their inclusion
– Unsuitability of less vulnerable populations
– Use of mitigation to address vulnerability
 General Principles
• Need to minimize the potential harms of
research and balance any harms with
commensurable benefits.
• Valid informed consent including disclosure of
conflicts of interest
• Ensuring independent review and oversight of
research
• In case of persons with impaired decisional
capacity and children – assent should be sought
 Ethical issues
• Research should be protective? …or
inclusive of vulnerable groups?
– Vulnerable groups need extra protection from
potential harms of research
– It is important to be especially careful to
include at least some of these groups in
research so they can benefit from the
knowledge gained
 Need for Informed Consent
• Upholds autonomy or respect for persons
• Requires
– Legal capacity to give consent
– Free power of choice, without undue force,
fraud, deceit, duress, constraint or coercion
• Fiduciary relationship (duty to protect)
between investigator and subject