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Guidelines for Assent for Research with Children - The University of

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

				
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