This document discusses guidelines for obtaining assent from children participating in research. It provides an overview of the history of regulations protecting human subjects, including the Belmont Report and Common Rule. For research with children, federal regulations require assessing their capacity to provide assent or waiving assent. The document recommends a flexible approach to assent that respects children's autonomy, involves them in decisions to an appropriate degree, and integrates their perspective into family decision making about research participation.

1. Guidelines for Assent for
Research with Children:
History, Practice, and Arriving at a Consensus
on Assent
Catherine L. Woodman, MD
University of Iowa
Iowa City, IA

2. Oncology Research and Children
• COG Ethics Committee Task Force
– Steven Joffe, MD, MPH Dana Farber, Boston, MA
– Conrad Fernandez, MD Halifax, NS
– Rebecca D. Pentz, PhD Emory, Atlanta, GA
– David R. Ungar, MD Hershey, PA
– N. Ajoy Mathew, JD COG, Anahiem, CA
– Angela J. Alessandri, MD Vancouver, BC
– Catherine L. Woodman, MD Iowa City, IA
– Dale A. Singer, MD Phoenix, AZ
– Eric Kodish, MD Case, Cleveland, OH
– Missy Layfield Cedar Falls, IA
– Winnie Kittiko, RN Children’s, Atlanta

3. Outline
• Children and Oncology
• Research and Humans
• Research and Children
• Assent, Research, and Children
• Assent, Oncology Research, and
Children

4. Children and Oncology
• The ethical ideal
– Respect the developing autonomy of
children in decisions about participation in
research
– When possible, seek assent prior to
enrollment in research

5. Children and Oncology
• 12,500 children diagnosed with cancer
annually
– 31% Leukemias
– 24% CNS tumors
– 15% Lymphomas
– 14% Sarcomas
– 6% Renal Tumors
• ~70% participate in a clinical trial at some
point in their treatment

6. Children and Oncology
• High rate of clinical trial participation:
– Increased cure rates in childhood cancer
(~20% in the 1970’s to ~75%)
– Decreased toxicity
– Development of chemotherapy regimens
with more than one agent
– Development of more successful adult
treatment regimens

7. Children and Oncology
• Complicating factors:
– Integration of research and care
– Medical and emotional acuity
– Both standard treatment plans and research
protocols are complex
– Considerable contextual variability (newly dx’d
ALL very different from relapsed ALL looking at a
Phase I protocol)
– The norm is that treatment decisions need to be
made within days

8. Children and Oncology
• Know very little about soliciting assent,
including:
– How IRB’s determine whether assent is
required
– How often and in what way assent is
solicited
– What children understand when they
assent
– The optimal way to obtain assent

9. Research and Humans
• Prior to 1906, when the Pure Food and
Drug Act was passed, there were no
regulations regarding the ethical use of
human subjects in research. There were
no consumer regulations, no Food and
Drug Administration (FDA), no Common
Rule, and no Institutional Review Board
(IRB).

10. Research and Humans
• Nuremberg Code.
– A well-known chapter in the history of research with
human subjects opened on December 9, 1946, with
criminal proceedings against 23 leading German
physicians and administrators for their willing
participation in war crimes and crimes against
humanity.
– As a direct result of the trial, the Nuremberg Code
was established in 1948, stating that "The voluntary
consent of the human subject is absolutely essential“
– Although it did not carry the force of law, the
Nuremberg Code was the first international
document which advocated voluntary participation
and informed consent.

11. Research and Humans
• Declaration of Helsinki. In 1964, the World Medical
Association established recommendations guiding
biomedical research involving human subjects. Issues
addressed include:
– Research with humans should be based on the
results from laboratory and animal experimentation
– Research protocols should be reviewed by an
independent committee prior to initiation
– Informed consent from research participants is
necessary
– Research should be conducted by
medically/scientifically qualified individuals
– Risks should not exceed benefits

12. Research and Humans
• National Research Act (1974 ).
– Due to the publicity from the Tuskegee Syphilis
Study, the National Research Act of 1974 was
passed.
– Created the National Commission for the Protection
of Human Subjects of Biomedical and Behavioral
Research, which was charged to:
• identify the basic ethical principles that should underlie
the conduct of biomedical and behavioral research
involving human subjects and
• develop guidelines which should be followed to assure
that such research is conducted in accordance with
those principles.

13. Belmont Report (1979)
Principle Application
• Respect for • Informed consent
persons – Subjects, to the
degree that they are
– Individuals should be capable, must be
treated as given the opportunity
autonomous agents to choose what shall
– Persons with or shall not happen to
diminished autonomy them
are entitled to – The consent process
protection. must include three
elements:
• information,
• comprehension, and
• voluntariness.

14. Belmont Report (1979)
Principle Application
• Beneficence • Assessment of
– Human subjects risks and
should not be benefits
harmed – The nature and
– Research should scope of risks and
maximize possible benefits must be
benefits and assessed in a
minimize possible systematic
harms. manner

15. Belmont Report (1979)
Principle Application
• Justice • Selection of
– The benefits and subjects
risks of research – There must be fair
must be procedures and
distributed fairly. outcomes in the
selection of
research subjects

16. Research and Humans
• CURRENT REGULATIONS
– In 1981, the Department of Health and
Human Services (DHHS) and the Food and
Drug Administration (FDA) issued
regulations based on the Belmont Report.
DHHS issued Code of Federal Regulations
(CFR) Title 45 (public welfare), Part 46
(protection of human subjects). The FDA
issued CFR Title 21 (food and drugs), Parts
50 (protection of human subjects) and 56
(Institutional Review Boards).

17. Research and Humans
• CURRENT REGULATIONS
– In 1991, the core DHHS regulations
(45 CFR Part 46, Subpart A) were
formally adopted by more than a
dozen other Departments and
Agencies that conduct or fund
research involving human subjects as
the Federal Policy for the Protection
of Human Subjects, or "Common
Rule."

18. Research and Humans
• The main elements of the Common
Rule include :
– requirements for assuring compliance by
research institutions;
– requirements for researchers obtaining and
documenting informed consent;
– requirements for Institutional Review Board
(IRB) membership, function, operations,
review of research, and record keeping.
– additional protections for certain vulnerable
research subjects-- pregnant women,
prisoners, and children (45 CFR 46)

19. Research and Children (45 CFR 46)
• §46.402 Definitions.
• The definitions in §46.102 of subpart A
shall be applicable to this subpart as well.
In addition, as used in this subpart:
– (a) Children are 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 the
research will be conducted.
– (b) Assent means a child's affirmative
agreement to participate in research. Mere
failure to object should not, absent affirmative
agreement, be construed as assent.

20. Research and Children (45 CFR 46)
• §46.402 Definitions.
• The definitions in §46.102 of subpart A shall be
applicable to this subpart as well. In addition, as
used in this subpart:
– (c) Permission means the agreement of parent(s) or
guardian to the participation of their child or ward in
research.
– (d) Parent means a child's biological or adoptive
parent.
– (e) Guardian means an individual who is authorized
under applicable State or local law to consent on
behalf of a child to general medical care.

21. Research and Children
• §46.404 Research not involving greater than minimal risk.
– HHS will conduct or fund research in which the IRB finds
that no greater than minimal risk to children is presented,
only if the IRB finds that adequat46.405 Research involving
greater than minimal risk but presenting the prospect of
direct benefit to the individual subjects.
• (a) The risk is justified by the anticipated benefit to the
subjects;
• (b) The relation of the anticipated benefit to the risk is at least
as favorable to the subjects as that presented by available
alternative approaches; and
• (c) Adequate provisions are made for soliciting the assent of
the children and permission of their parents or guardians, as
set forth in §46.408.
• (d) provisions are made for soliciting the assent of the children
and the permission of their parents or guardians, as set forth in
§46.408.

22. Research and Children
• §46.405 Research involving greater than minimal risk
but presenting the prospect of direct benefit to the
individual subjects.
HHS will conduct or fund research in which the IRB finds that
more than minimal risk to children is presented by an
intervention or procedure that holds out the prospect of
direct benefit for the individual subject, or by a monitoring
procedure that is likely to contribute to the subject's well-
being, only if the IRB finds that:
– (a) The risk is justified by the anticipated benefit to the
subjects;
– (b) The relation of the anticipated benefit to the risk is at
least as favorable to the subjects as that presented by
available alternative approaches; and
– (c) Adequate provisions are made for soliciting the assent
of the children and permission of their parents or
guardians, as set forth in §46.408.

23. Research and Children
• §46.406 Research involving greater than minimal risk
and no prospect of direct benefit to individual subjects,
but likely to yield generalizable knowledge about the
subject's disorder or condition.
– (a) The risk represents a minor increase over minimal risk;
– (b) The intervention or procedure presents experiences to
subjects that are reasonably commensurate with those
inherent in their actual or expected medical, dental,
psychological, social, or educational situations;
– (c) The intervention or procedure is likely to yield
generalizable knowledge about the subjects' disorder or
condition which is of vital importance for the understanding
or amelioration of the subjects' disorder or condition; and
– (d) Adequate provisions are made for soliciting assent of
the children and permission of their parents or guardians,
as set forth in §46.408.

24. Research and Children
• §46.408 Requirements for permission by parents or guardians
and for assent by children.
– (a) In addition to the determinations required under other
applicable sections of this subpart, the IRB shall determine that
adequate provisions are made for soliciting the assent of the
children, when in the judgment of the IRB the children are capable
of providing assent. In determining whether children are capable of
assenting, the IRB shall take into account the ages, maturity, and
psychological state of the children involved. This judgment may be
made for all children to be involved in research under a particular
protocol, or for each child, as the IRB deems appropriate. If the IRB
determines that the capability of some or all of the children is so
limited that they cannot reasonably be consulted or that the
intervention or procedure involved in the research holds out a
prospect of direct benefit that is important to the health or well-
being of the children and is available only in the context of the
research, the assent of the children is not a necessary condition for
proceeding with the research. Even where the IRB determines that
the subjects are capable of assenting, the IRB may still waive the
assent requirement under circumstances in which consent may be
waived in accord with §46.116 of Subpart A.

25. Children, Research and Assent
• IRB’s may waive the requirement for
assent (capacity-based waiver)
– Insufficient capacity to participate in the
decision
– Direct benefit to the child
• IRB’s determine how assent should be
documented (benefit-based waiver)

26. Children, Research, and Assent
• Problems with the Regulatory
Framework
– All-or-nothing approach to children’s role in
decision-making
• Either accorded decision-making power or no
role
• Not required to provide developmentally
appropriate information
• Inconsistent w/ cognitive and moral
development

27. Children, Research, and Assent
• Problems with the Regulatory
Framework
– Offer no guidelines as to what constitutes
“meaningful” assent
• Do the required elements of consent need to be
addressed
• AAP and IOM suggest that central elements of
assent are purpose, risks, and benefits

28. Children, Research, and Assent
• Problems with the Regulatory
Framework
– Ignores the fact that clinical research exits
along a spectrum of complexity
– Ignores the interconnected nature of
decision making in most families

29. Children, Oncology Research, and
Assent
• Principles Governing Children’s Participation
in Research Decisions
– Investigators should respect children as persons.
In particular, honor children’s developing
autonomy in decisions about research
participation
– Respect parents’ roles in assessing their children’s
best interests.
– Policies regarding assent should be sufficiently
flexible to accommodate a wide range of medical,
psychological, and contextual circumstances.

30. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Provide information to children
• Diagnosis
• Treatment
• Proposed research participation
• Procedures that are for research
• Risks and benefits
• Often appropriate to use written information
sheet

31. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Inclusion of the child in the decision-
making process
• Invite a decision only if you intend to honor that
decision
• Solicit the child’s perspective—allows parents
and investigators to arrive at a decision with
this in mind
• Don’t promise to follow the child’s wishes if you
can’t follow through

32. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Integration of Family Decision-making
• Rather than seeing the child and the parents as
separate entities, seek to help the family arrive
at a decision about research participation
• In cases where there is conflict, work to
minimize inappropriate pressure on the child,
and consider independent mediation if
disagreement persists

33. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Assent as a Process over Time
• View it as a process rather than an event
• Continuing education of the family throughout—
particularly in light of the psychological
challenges inherent in the initial consent and
assent process
• Revisit the child and family’s agreement to
participation

34. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Benefit-based Waivers of Assent:
• Only appropriate when intervention is
unavailable outside the research context
• Must justify why the study intervention is likely
to be more effective than other treatments
available outside the trial
• Should apply only to components of the trial
that fit this definition and should seek assent for
the non-therapeutic aspects of the trial

35. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Capacity-based Waivers of Assent:
• Recognizing the considerable complexity and
heterogeneity of pediatric oncology research,
investigators and IRB’s should permit
considerable flexibility in determining when
children have the capacity to assent
• Ethics consultation when there are divergences
of opinion

36. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Determining Capacity to Assent:
• Age
• Maturity
• Physiological and psychological state
• Reasons a child gives for preferences

37. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Documentation of Assent:
• Describe the child’s role in decision-making
process in a note
– Whether assent was sought
– If sought, was it granted
• Preferable to a signed assent
– Allows flexibility and adaptation to circumstances

38. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Role of Older Adolescents in Decisions
about Research:
• Under optimal circumstances, can make
decisions about research participation
• Should co-sign consent form with parents

39. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Resolving Disagreements with Children
about Research Participation:
• Rare
• Need to have fair procedure in place locally to
deal with these circumstances
• Options include appointing an advocare for the
child, asking an IRB member/other individual to
serve as a neutral consent advocate, or an
ethics consult

40. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Defining, Understanding, and Improving
Assent :
• Support empiric research in important aspects
of the assent process
– Children’s and parent’s views
– Children’s capacity
– Nature of optimal and actual consent and assent
practice
– Conflict resolution

41. Children, Oncology Research, and
Assent
• Specific Recommendations:
– Training Research Staff in Soliciting
Assent:
• Need to know the rules
• Need to have the practical skills to educate
children about treatment and research

42. Children, Oncology Research, and
Assent
• Current Status:
– Presented to Children’s Oncology Group:
• Executive Committee February 2004
• General membership March 2004
– Presented to NCI:
• CTEP August 2004
– Presented to OHRP:
November 2004

43. Children, Oncology Research, and
Assent
• NCI Pediatric CIRB:
– 94/230 institutions
– Adopted these guidelines March 2005
– Require a written information sheet for
each new protocol as of November 2005

44. Children, Oncology Research, and
Assent
• Current Research:
– Query COG institutions IRB’s about the
current use of assent forms
– Practice of assent
– Skills-based curriculum for staff who
describe research to children
– Assessing benefit to subjects from
research participation

45. Children, Oncology Research, and
Assent