Vulnerable populations include groups who may have impaired ability to provide fully informed consent to participate in clinical trials. These include children, pregnant women, prisoners, students/employees, and those with cognitive impairments. Additional protections are required when including such groups in research. For children, assent from the child and permission from parents/guardians is needed. Research involving pregnant women or fetuses generally requires the mother's consent and may require the father's consent depending on the study's risks and benefits. Prisoners can only be in research related to their incarceration or behavior with minimal risk. Cognitively impaired individuals may require consent from a legally authorized representative. Researchers must consider risks unique to vulnerable populations and implement safeguards to

1. Vulnerable Populations
Presented By
Tejinder Kaur Marwaha

2. Who are vulnerable populations?
In Clinical Trials, people who need special protection to be included as subjects

3. Vulnerable Subjects (ICH GCP)
Clinical 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. Examples
are members of a group with a hierarchical structure, such as medical,
pharmacy, dental and nursing students, subordinate hospital and
laboratory personnel, employees of the pharmaceutical industry,
members of the armed forces, and persons kept in detention. Other
vulnerable subjects include patients with incurable diseases, persons in
nursing homes, unemployed or impoverished persons, patients in
emergency situations, ethnic minority groups, homeless persons,
nomads, refugees, minors, and those incapable of giving consent.

4. •When study includes such subjects additional care has to be taken to
protect their rights.
• It is the investigator and his research team’s responsibility to ensure that
these subjects are not exploited in the name of research.
• The study design team, sponsor, investigator must be aware of the special
requirements needed for vulnerable subjects and they should develop the
study protocol, informed consent form and the confidentiality agreement
keeping the vulnerable subjects’ needs in mind.

5. The different types of vulnerable subjects included in clinical trials are
classified on basis of their vulnerability. Some examples are as follows:
1. Cognitive and Communicative vulnerability:
This includes children and adolescents.
Patient’s suffering from mental retardation, dementia and other kinds of
mental illness.
Enrolment of people with educational deficits and unfamiliarity with language.
Stressful emergency: conditions that do not permit otherwise capable adults to
implement their capabilities efficiently.

6. 2. Juridical or institutional vulnerability:
Person who is under the official authority of others (egs. Parents, guardians,
warders, officers and judges) who may have their own benefits in whether the
individual agrees to enrol in the study.
3. Deferential vulnerability:
Influence of other people in subjects life, determine their decision to enter the
trial. Existence of an informal hierarchy (egs. Relatives, friends, masters,
physician)

7. 4. Medical vulnerability:
Prospective patients who have a severe medical condition, for which there are
no existing efficient or satisfactory regular cure (examples: very aggressive and
malignant forms of cancer, last stage AIDS and some uncommon ailments)
owing to their unusual medically tricky state, misuse of these patients
throughout their hope for remission or improvement is not unusual.
5. Social vulnerability:
Refers to individuals belonging to undervalued social groups or
communities.(sex workers)

8. 6. Economic vulnerability:
Prospective subjects with low economic background may join trial with hope of
getting income, housing and healthcare facilities.
Payment for participation or free access to healthcare services might constitute
unfair inducements to enrol through exploitation of these subjects.
7. Infrastructural vulnerability:
Patient is tempted to enrol in trials, as they pre-suppose the availability to
them of resources or facilities (egs. a rapid communication system, a reliable
dietary intake, skilled healthcare professionals)

9. •Review by an ethics committee, written standard operating procedures
(including those pertaining to vulnerable subjects), and maintenance of ERC
records are all routine required activities for all studies and research subjects
regardless of whether they involve vulnerable subjects.
•There are many additional protections for vulnerable subjects that can be
considered depending on the reasons for the vulnerability and the
circumstances of the study. For example, for subjects who are unemployed or
impoverished, the ethics review committee may ensure that incentives offered
to subjects for participating in the study (e.g., payment to subjects) is not so
high as to unduly influence the subjects to enrol, or the ethics review
committee may include a member with experience working with
unemployed/impoverished subjects, or the ethics review committee may
ensure that the informed consent document be written using simple language if
the subjects are also educationally deprived.

10. Vulnerable subjects include
1. Children
2. Pregnant women
3. Handicapped and mentally disabled persons
Persons with acute or severe mental illness
4. Prisoners

11. Requirements for Involvement of
Children as Subjects

12. Children are considered a vulnerable research population
because their intellectual and emotional capacities are limited
and therefore, they are legally incompetent to give valid
informed consent. Research involving children can be
approved by the IRB if it satisfies the following requirements
of federal regulations:

13. •Research that involves no more than minimal risk can
be approved with adequate provisions for obtaining
the assent of the child and permission from their
parents/guardians.
•1 parent + child assent

14. •Assent Research that involves more than minimal risk
but presents the prospect of direct benefit to
individual subjects:
•The risks must be justified by the anticipated benefits;
•The risk to benefit ratio must be at least the as favorable as
alternative treatments or approaches; and
•Assent of the child and permission from their parents/guardians
are required.
•1 Parent consent + child

15. •Research that involves more than minimal risk and presents the prospect
of no direct benefit to individual subjects, but generalizable knowledge
(societal benefit):
•The risks represent a small increase over minimal risk;
•The interventions or procedures are commensurate with those
associated with the subjects' actual or expected medical, dental,
psychological, social or education situations;
•The interventions or procedures are likely to yield generalizable
information about the subjects' disorder, condition, situation, which is
of vital importance to understand or ameliorate; and
•Assent of the child and permission from their parents/guardians are
required.
•2 Parent consent + child assent

16. •The combination of assent by the minor subject and permission
(consent) from the parents is deemed appropriate to enrol the
child subject in the trial.
•In case of life threatening events only consent from parents
would suffice, as there is expectation of direct benefit. However
the child must be given full explanation of the trial.

17. •*Unless one parent is deceased, unknown,
incompetent, or not reasonably available, or when
only one parent has legal responsibility for the care
and custody of the child.
•When parents of the child are deceased, unknown
or incompetent then the legal guardian must give is
consent.
• If these circumstances are present, the
investigator should document this in the subject's
research record.

18. Who may consent a child to research?
•Natural or adoptive parents
•Legal custodians or legal guardians
•Individuals who possess a power of attorney or court
order authorizing consent to participate in research
•Minors emancipated by marriage or court order

19. Who may not consent a child to
research?
•Stepparents
•Grandparents
•Adult Siblings
•Adult Aunts or Uncles
•Minors emancipated by pregnancy outside of
marriage or by adjudication as an adult

20. Child Assent
Federal regulation and state statute require that minors
assent to participate in research.
Assent is defined as a minor's affirmative agreement to
participate in research.
In most cases, this must be documented in writing if the subjects
are at least seven years old.
The IRB has authority to require assent from children younger
than seven if they are likely to comprehend and appreciate what
it would mean to volunteer to participate in a given protocol.

21. Written Assent Requirements
Assent forms should be written at the appropriate educational and
maturity level of the youngest prospective subject in the age range.
Techniques such as the use of larger type, simple schema, and
pictures may help boost a child's understanding of the text.
Depending on the age range of the minors to be involved, the
Lead Researcher may be required to develop 2 different assent
forms at different reading comprehension levels (e.g., one assent
form written for young children ages 7-12 years old, and one
assent form written for minors ages 13-17 years old).
Alternatively, for children 13-17 years of age, the researcher may
develop a joint assent/permission consent form and obtain the
signatures of the minor and parent(s) or guardian(s) on one
document.

22. Assent Elements
Assent should cover the following points:
what the study is about,
why the child is eligible to participate for the study,
what procedures will be performed,
potential risks and discomforts to the child,
potential benefits to the child or society,
for non-therapeutic research, a statement that the child can
choose whether to participate and may withdraw at any time
without negative consequences,
an invitation to ask questions any time, and
names and phone numbers of whom to contact with questions.

23. IRB CONSIDERATIONS
National Commission for the Protection of
Human Subjects recommended that, as a
matter of social justice, there should be an
order of preference in the selection of classes of
subjects: adults before children.

24. What happens if a child reaches the legal
age of consent while enrolled in a study?
Unless the Institutional Review Board (IRB) determines
that the requirements for obtaining informed consent
can be waived, the investigators must seek and obtain
the legally effective informed consent, for the now-
adult subject for any ongoing interactions or
interventions with the subjects.

25. Pregnant Women, Fetuses and Neonates

26. Need for research for treatment
of problems during pregnancies
• Few prescription drugs
are specifically labelled
for use during
pregnancy
• Most women take at
least one prescription
drug during a
pregnancy
• Pregnant women react
differently to drugs than
non-pregnant women
• Unknown effects on
foetus
Why is it different?
• Changes in absorption, distribution,
metabolism and elimination of drug
during pregnancy
• Foetus and placenta also active
‘management’ of the drug
• Foetal susceptibility to the drug varies
based on gestational age

27. The foetus as a subject
• Only two circumstances when this is ethical
• 1. to promote life or health of foetus
• 2. to give the mother information regarding the health of
the foetus so she can make decisions regarding treatment
and or termination of pregnancy

28. Research studies involving pregnant women or fetuses can be
approved by the IRB if the following requirements of federal
regulations are satisfied:
Preclinical studies have been conducted, including studies on
pregnant animals; clinical studies, that include non-pregnant
women and provide data for assessing potential risks to
pregnant women and fetuses
Risk to fetus is caused solely by interventions or procedures that
hold prospect of direct benefit for the woman or the fetus or,
If no benefit, risk to the fetus is not greater than minimal and
the research develops important biomedical knowledge not
obtainable by any other means.

29. Any risk is the least possible for achieving the objectives
of the research.
Individuals engaged in the research will have no part in:
1) any decisions as to the timing, method, or procedures
used to terminate a pregnancy, and 2) determining the
viability of the fetus at the termination of the pregnancy;
and
No inducements, monetary or otherwise, will be offered
to terminate the pregnancy.

30. Direct
benefit to
mother
only
Direct
benefit
to
mother
and
fetus
Direct
benefit to
fetus only
No direct benefit
or societal
benefits only
Risk is
more
than
minimal
Mother's
consent
Mother's
consent
Mother and
father's
consent
NOT
APPROVABLE
BY IRB
Risk is no
more
than
minimal
Mother's
consent
Mother's
consent
Mother and
father's
consent Mother's consent

31. Definition of Prisoner:
“prisoner” is defined as “any individual
involuntarily confined or detained in a penal
institution.
This definition includes individuals in county jails
awaiting arraignment or trial, and individuals in a
variety of alternative correctional programs,
including commitment to mental health facilities.
PRISONERS

32. SPECIAL CONSIDERATIONS FOR PRISONERS
•The voluntary choice of the prisoners must not influenced by any
potential advantages entailed to them due to the study, which
outweighs the risks. For example, Parole decisions must not be
affected for prisoners participating in the trial.
•The study is ethical, when the risk of participation is acceptable
even to a non prisoner subject.
•Selections of subjects are carried out in a fair manner. When spoilt
for choice, randomization techniques must be used.
•If necessary, adequate follow-up care must be provided to the
volunteers.

33. Studies of the possible causes, effects, and processes of
incarceration, and of criminal behavior, provided that
the study presents no more than minimal risk and no
more than inconvenience to the subjects.
Studies of prisons as institutional structures or of
prisoners as incarcerated persons, provided that the
study presents no more than minimal risk and no more
than inconvenience to the subjects.

34. Prisoners are considered as vulnerable research
population because the very fact of incarceration may
make it difficult for them to give truly voluntary informed
consent.
To protect this study population, federal regulations
stipulate that the only studies that may use prisoners
are those with an independent and valid reason for
involving them. Specifically:

35. Clearly, it may not be obvious to researchers if an
individual in any of these programs enrolls in research.
However, enrolling a subject who meets the definition of
prisoner in a research protocol that has not been
approved in accordance with guidelines is considered a
protocol deviation and must be reported to the IRB. If a
researcher becomes aware of this situation, there are
three (3) options available:

36. Option 1
The researcher may allow the subject to continue to
participate in the research, after taking the steps
listed below.
All study interventions and interactions with, and data collection
on, the subject must cease until the IRB re-reviews the
protocol .
The researcher must promptly notify the IRB of the protocol
deviation.
The IRB must promptly re-review the protocol.

37. Option 2
The researcher may continue the study interactions or
interventions if it is in the subject’s best interest to do so,
after taking the steps listed below.
The researcher must promptly notify the IRB of the protocol
deviation.
The IRB Chairperson may determine that the subject can
continue to participate in the research until the protocol
is reviewed
The IRB must promptly re-review the protocol.

38. Option 3
The researcher may remove the subject from
the protocol, provided it is not in the best
interest of the subject to remain in the
protocol, and promptly notify the IRB of the
protocol deviation.

39. Students, Employees and faculty
the Investigator should provide and the IRB
should consider the scientific and ethical
justification for their inclusion in the study and
describe any additional safeguards that may be
needed to minimize risks unique to each
population.

40. SPECIAL CONSIDERATIONS FOR DECISIONALLY
IMPAIRED
A combination of assent from the subject and permission from
the concerned legal authorities constitute for the informed
consent.
The risk of participation would be agreeable to general volunteers
too.
Selection is fair and unbiased
Adequate follow up is provided

41. Cognitively Impaired
Cognitively impaired
persons are considered as
vulnerable research
population because their
mental disability may
compromise their capacity
to make a reasoned
decision about
participation in a study.

42. People with Alzheimer's disease, dementia, mental
illness and developmental disabilities may be considered
cognitively impaired and may not be able to provide
informed consent for participation in research. In certain
circumstances, when it is determined that a potential
research participant is cognitively impaired, federal
regulations and state statute permit researchers to
obtain consent from a legally-authorized representative
(surrogate consent).

43. Regulations
•ICH GCP 1.61
• International Ethical Guidelines for Biomedical Research
Involving Human Subjects
Guidelines 13-17