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Guidelines for Assent for Research with Children:History, Practice, and Arriving at a

Consensus on Assent

Catherine L. Woodman, MDUniversity 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


• 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


• 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


• 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


• 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

• Respect for persons – Individuals should be

treated as autonomous agents

– Persons with diminished autonomy are entitled to protection.

Application• Informed consent

– Subjects, to the degree that they are capable, must be given the opportunity to choose what shall or shall not happen to them

– The consent process must include three elements:

• information, • comprehension, and • voluntariness.

Belmont Report (1979)

Principle• Beneficence

– Human subjects should not be harmed

– Research should maximize possible benefits and minimize possible harms.

Application• Assessment of

risks and benefits – The nature and

scope of risks and benefits must be assessed in a systematic manner

Belmont Report (1979)

Principle• Justice

– The benefits and risks of research must be distributed fairly.

Application• Selection of

subjects – There must be fair

procedures and 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


• 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


• 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


• 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


• 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


• 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


• 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


• 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


• Specific Recommendations:– Determining Capacity to Assent:

• Age• Maturity• Physiological and psychological state• Reasons a child gives for preferences


• 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


• 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


• 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


• 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


• 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


• 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


• NCI Pediatric CIRB:– 94/230 institutions – Adopted these guidelines March 2005– Require a written information sheet

for each new protocol as of November 2005


• 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


Education

C wchildassent