Pediatric Clinical Research A Regulatory and Everyday Perspective

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Pediatric Clinical ResearchA 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
• Research Compliance Administration, IUPUI

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Objectives

• To understand
• federal regulations related to the involvement of
  children in research
• the IRBs and investigators 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?
• Childs 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 childs
  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 childs 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 childs
  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? Couldnt too much information
  be scary?

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FAQs

• A3 See an Assent Template at
  http//www.iupui.edu/7Eresgrad/irbpacket/assent03
  -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/adolescent
  s.

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FAQs

• A3 (cont.) Think carefully about how to convey
  risks.
• EX Dont 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 dont 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 childs 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 IRBs SOP on Children in Research describes
  who is authorized to consent for children for
  healthcare purposes (per Indiana Code 16-35-1-5).
  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
  (274-8289) 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!