Transcript Slide 1

Pediatric Clinical Research
A Regulatory and Everyday Perspective
Linda DiMeglio, MD, MPH; Lucy Miller, RN, BSN, CCRP; Jody Harland, MS, CIP
Department of Pediatrics, IU School of Medicine
Shawn Axe, CIP
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Research Compliance Administration, IUPUI
Objectives
• To understand:
– federal regulations related to the involvement of
children in research
– the IRB’s and investigator’s responsibilities in
reviewing pediatric clinical research
– the assent process in clinical research with
children
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Relevant Regulatory Citations
• DHHS: The Common Rule at 45 CFR 46, Subpart D
• FDA: 21 CFR 50, Subpart D
– Regulations largely mirror each other; however, FDA does not allow for a
waiver of parental permission.
– DHHS regulations do not require written documentation of assent (they give
IRBs the latitude to make this determination); however, FDA guidance states
that written documentation (via “separately designed, written assent form or
the written informed consent) should be obtained.
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How do the federal regulations define
“children?”
“Persons who have not attained the legal age
for consent to treatments or procedures
involved in the research, under the applicable
law of the jurisdiction in which research will
be conducted” (45 CFR 46, Subpart D) (21 CFR 50, Subpart D)
– Children/adolescents = less than 18 years of age
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Special vulnerability of children
• Children are considered a “vulnerable
population”
– Children have not reached their full physical or
emotional capacities
– Children are unable to provide legally-valid
consent for themselves (with a few exceptions)
– Children are particularly vulnerable to potential
coercion
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Why is pediatric clinical research
important?
• National Institutes of Health (NIH) policy on
inclusion of children (1998)
• Best Pharmaceuticals for Children Act (2002)
– Involving children can extend the length of the
patent
• Pediatric Research Equity Act (2003)
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IRB responsibilities in reviewing pediatric
clinical research
• Review all research in which children are the
target population or may make up some of
the population
• Have members with expertise in pediatrics
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IRB responsibilities in reviewing pediatric
clinical research
• Designate a “category” of research involving
children
– Risk/benefit ratio
– Adequate plan for obtaining parental consent and child
assent (if applicable)?
• One parent/guardian or both?
• Child’s agreement to participate needed or not?
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Category 1 Research
• (§46.404): Not involving greater than minimal risk
to children.
– Adequate plan for soliciting the assent of the children and
the permission (parental/guardian informed consent) of
each parent or guardian
• Justification if permission from only one parent or guardian will be
solicited.
– IRB can determine that permission (e.g., informed
consent) of one parent/guardian is sufficient.
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Category 2 Research
• (§46.405): Involving greater than minimal risk but
presenting the prospect of direct benefit to the
individual child.
– Adequate plan for soliciting the assent of the children and
the permission (parental/guardian informed consent) of
each parent or guardian
• Justification if permission from only one parent or guardian will be
solicited.
– IRB can determine that permission (e.g., informed
consent) of one parent/guardian is sufficient.
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Category 3 Research
• (§46.406): Involving greater than minimal risk and
no prospect of direct benefit to the individual child,
but likely to yield generalizable knowledge about the
child’s disorder or condition.
– Adequate plan for soliciting the assent of the children and
the permission (parental/guardian informed consent) of
each parent or guardian
• Permission of both parents/guardians must be obtained (unless
one is not reasonably available, etc.)
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Category 4 Research
• (§46.407): Research not otherwise approvable under one of
the above categories, which presents an opportunity to
understand, prevent, or alleviate a serious problem affecting
the health or welfare of children.
– Adequate plan for soliciting the assent of the children and the
permission (parental/guardian informed consent) of each parent or
guardian
– Permission of both parents/guardians must be obtained (unless one
is not reasonably available, etc.)
– The Secretary of HHS must approve, after consultation with a panel
of experts following publication and public comment.
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Investigator responsibilities when conducting
pediatric research
• Obtain approval from IRB before enrolling
children into a study
• Make initial determination as to the
appropriate “category” of research involving
children
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Investigator responsibilities when conducting
pediatric research
• Present the IRB with parental informed consent
statement or rationale for requested waiver of
informed consent
• Ensure the protocol/submission describes if and
how assent will be obtained and documented (or
rationale for requested waiver of assent)
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Investigator responsibilities when conducting
pediatric research
• Waiver of informed consent for parents
– Certain types of research involving minimal risk
– Where permission of parents is not reasonable
• This may require involvement of a court-appointed
guardian.
– Not an option for FDA-regulated research.
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Investigator responsibilities when conducting
pediatric research
• Assent of child subjects
– A child’s affirmative agreement to participate
– Present a plan to the IRB for whether and how
assent will be obtained
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Investigator responsibilities when conducting
pediatric research
• Assent
– Typically required of children ages 7 and above
• Could use an oral script (for very young)
• Could create a separate written document
• Could use the Informed consent itself (with appropriate language
and additional signature lines – often appropriate for older
adolescents)
– Should be in a language appropriate to child’s
age/developmental level
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Investigator responsibilities when conducting
pediatric research
• Waiver of assent
– May be requested by PI when believes that
obtaining assent is unreasonable due to subject
condition (e.g., presence of a ventilator or serious
psychiatric disorders).
– When a waiver is granted, this means that the
child does not have to provide assent to
participate in the research.
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Investigator responsibilities when conducting
pediatric research
• Waiver of assent
– Must be requested prospectively and granted by the IRB
• Can be done as a “blanket” (e.g., for all participants) or on a
“case-by-case” basis
– PI cannot make this determination alone
– If waiver is granted by IRB, an age-appropriate
Information Sheet shall be provided to the child
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Regulatory summary:
• Individuals less than 18 years old are considered “children”
from a regulatory perspective.
– Before children are enrolled on a study, IRB must approve their
inclusion.
• IRBs must consider carefully the involvement of children in
research and make specific determinations about their
involvement in research.
• When conducting pediatric research, PIs must provide
detailed information to the IRB on whether and how parental
permission and child assent will be obtained.
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Frequently Asked Questions (FAQs) re:
children in research
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FAQs
Q1: When can a “minor” consent for
himself/herself to participate in a research
study?
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FAQs
A1: A minor can consent for himself/herself if any of the following are
true:
– By law the minor is considered emancipated;
– The minor is at least fourteen (14) years old, not dependent on a parent for
support, is living apart from parents or from an individual in loco parentis
(e.g., someone who acts in the place of a parent), AND is managing his/her
own affairs;
– The minor is or has been married;
– The minor is in the military service of the United States; OR
– The minor is authorized to consent to the health care by any other statute.
– If none of the above are true, and informed consent has not been waived
prospectively by the IRB, parent(s)/guardian(s) must provide permission for
the participation of their child or ward in research.
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FAQs
Q2: What are the different ways in which
assent can be obtained from children?
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FAQs
• A2: Assent should be conducted in a manner that is
developmentally appropriate and which takes into account
the ages, maturity, and psychological state of the children
involved. Typical recommendations are as follows:
– For younger children (e.g., less than 7 years old), an oral conversation/script
in very simple language might be appropriate.
– For children ages 7-12 years old, a separate assent document written simply
and at an appropriate developmental level would be acceptable.
– For children (adolescents) ages 13-17 years old, a separate assent
document may be used or the parent(s)/guardian(s)’ informed consent may
be used if it contains appropriate signature lines (e.g., a signature line for the
parent(s)/guardian(s) and adolescent) and is written in “you/your child or
adolescent” language.
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FAQs
Q3: How much information should be included
in an assent form? Couldn’t too much
information be scary?
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FAQs
• A3: See an Assent Template at:
http://www.iupui.edu/%7Eresgrad/irbpacket/assent0
3-03.rtf
– The study should be described in enough detail to
appropriately convey to the subject what will happen
during the study, but not be so detailed that the subject
cannot comprehend it.
– Keep in mind the target audience; use different versions
for different ages of children/adolescents.
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FAQs
A3 (cont.): Think carefully about how to convey risks.
EX: Don’t have to describe the myriad potential risks of each study drug
which the child might receive, but child should know that:
• he/she will be participating in a research study (like a science experiment)
• that doctors don’t know if the medicines will help the child or not
• that the child will have to come to the hospital for treatments over the next several
weeks
• that the child may feel some discomforts (like nausea, etc.) during that time
• For anxious child who will worry about complex plans, use a “staged” assent
process – this breaks up the protocol into more manageable pieces of information
(e.g., one assent document to cover the first cycle/phase of treatment, a second
document to be presented when the child enters the second cycle/phase, etc.).
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FAQs
Q4: How do I request a waiver of assent
from the IRB?
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FAQs
• A5: For new study submissions, you can request a
“blanket” waiver of assent.
– A “blanket” waiver would be applied to all children to be
enrolled in the study.
• Requested in Section III, Part A.1. of the SSS when responding to
the statement regarding provisions for soliciting assent of the
children.
• Provide as much detail as possible when explaining why obtaining
assent from that subject population is not reasonable.
• Note: “because the information may scare the subject” is not
sufficient justification for requesting a waiver of assent.
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FAQs
• A5 (cont.): If you are conducting a study and it is thought
that a particular potential subject cannot appropriately give
assent, a request for a waiver of assent for that particular
subject can be made (e.g., on a “case-by-case basis”).
– Request should be submitted as a memo to the Board.
– Memo should be very detailed regarding the specific circumstances
and why it is thought that the subject cannot provide assent.
– An Information Sheet (that would be presented to the child) should
also be submitted to the IRB detailing what will happen during the
study in language appropriate for the subject population.
– If the Board approves the waiver of assent for the particular subject,
the Information Sheet must then be given to the subject.
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FAQs
Q6: I have a child that will qualify to participate
in a research study, but the child is currently
placed in foster care. Who can provide
informed consent for the child’s participation
in the research study?
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FAQs
A6: Typically, consent for the child who is in foster care would
be provided for by the judicially-appointed guardian;
however, the identity of that individual may not always be
immediately evident.
As such, the investigator should contact the Research
Compliance Administration office (317/274-8289) for
guidance. Because such arrangements are often
complicated and can differ from situation to situation, RCA
may need to contact University Counsel for an appropriate,
case-specific legal opinion and recommendation.
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FAQs
Q7: When you have a child whose parents are
divorced, and there is no proof available
regarding who has custody/ability to consent
to healthcare, how do you know who can sign
the informed consent statement?
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FAQs
A7: IRB’s SOP on Children in Research describes who is authorized to
consent for children for healthcare purposes (per Indiana Code 16-35-15). Section is extrapolated to research. Consent to health care for a
minor may be given by any of the following individuals:
•
•
A judicially appointed guardian of the person or a representative appointed.
A parent or an individual in loco parentis if:
–
–
–
•
There is no guardian or other representative described in the first bullet point above;
The guardian or other representative is not reasonably available or declines to act; or
The existence of the guardian or other representative is unknown to the health care provider.
An adult sibling of the minor if:
–
–
–
There is no guardian or other representative described in 4.14.1 above;
A parent or an individual in loco parentis is not reasonably available or declines to act; or
The existence of the parent or individual in loco parentis is unknown to the health care provider.
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FAQs
A7 (cont.): In this situation, without evidence of who has the
authority to consent to healthcare, the investigator should
contact the Research Compliance Administration office (2748289) for guidance before approaching anyone for obtaining
informed consent.
Because custody arrangements are often complicated and
can differ from situation to situation, RCA may need to
contact University Counsel for an appropriate, case-specific
legal opinion and recommendation.
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Everyday experiences with an assent
process
• Comments from a pediatric faculty researcher
• Comments from a pediatric research nurse
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Questions or Comments?
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Thank You!
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