Definitions

Subpart D: This term refers to the regulations which apply to research involving children as subjects.  Subpart D is found in both 45 CFR 46 (DHHS) and 21 CFR 50 (FDA).

Children: By regulatory definition, “children” are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under applicable law of the jurisdiction in which the research will be conducted, according to DHHS and FDA regulations.

In Utah, individuals under the age of 18 are considered children as defined in federal regulations unless one of the exceptions listed below applies.  In Utah, a person under the age of 18 is no longer considered a child as defined above and Subpart D of 45 CFR 46 and 21 CFR 50 does not apply if he or she is:

• Married;
• A member of the armed forces of the United States;
• “Emancipated,” a finding typically made by a court;
• Receiving care or treatment for one of the following conditions (provided that the research is directly connected to one of these conditions):
  1. A sexually transmitted disease (Utah Code 26-6-18);
  2. Pregnancy or childbirth (Utah Code 78B-3-406).

For research conducted outside of Utah, the IRB will contact General Counsel for assistance in understanding applicable law in order to determine whether Subpart D must be applied.

Federal Research Regulations

Federal regulations require additional safeguards when approving research involving children. These special protections are found in Subpart D. The IRB may approve research involving children only if the research falls under one of the three categories found in Subpart D (see description of categories below) provided that the research also meets the general criteria for approval.

Guidance

The IRB must consider the general criteria for IRB approval for all studies, including those that involve children. In determining whether the general criteria for approval are met, the IRB may have additional considerations for the research that would generally not be of concern in an adult population.

Risks

Risks that may be considered minimal when dealing with adults (e.g., blood draw) may be riskier when applied to a child population. Efforts should be made to minimize any potential harm.

Equitable selection of subjects

Children may be particularly vulnerable to undue influence and coercion due to the significant influence that parents and other authority figures (e.g., teachers, doctors) have over this population. It is extremely challenging (if not impossible) to eliminate all the influential elements in a research study involving children; however, with special consideration to alternatives to participation, setting(s) of the research and other factors that have great importance to children, elements of coercion and undue influence can be alleviated. Children should be included in research only when their participation is necessary to answer the research question and not out of convenience.

Privacy

Efforts made to protect privacy may differ depending on whether research participants are children, adolescents, or adults. For example, a small child may prefer to have a parent present during a physical examination while adolescents may prefer to have no parent present during a physical examination.

Additional Protections for the Inclusion of Children in Research

The IRB must consider the degree of risk and discomfort involved in the research in relation to the direct benefits it offers to the child to determine whether the study is approvable under the federal regulations. The standard of review is conducted consistently, regardless of full board or expedited review. The IRB may approve studies involving children only if the research falls into one of the three following categories:

1. Research involving no greater than minimal risk. ^{[45 CFR 46.404; 21 CFR 50.51]}

   If the IRB determines the interventions or procedures present no more than minimal risk to the child, the research is approvable under this category regardless of whether there is a prospect of direct benefit to the child.

2. Research involving interventions or procedures that present greater than minimal risk but offers the prospect of direct benefit or may contribute to the well-being of the individual child. [45 CFR 46.405; 21 CFR 50.52]

   Most therapeutic medical trials that hold out the prospect of direct benefit to the child may be approvable under this category. Phase I trials and placebo-controlled trials often do not hold out the prospect for direct benefit to participants and may not be approvable under this category.  Any submissions that include children in such research practices should include a thorough justification for the involvement of children.

3. Research involving interventions or procedures that present a minor increase over minimal risk and no prospect of direct benefit to individual children, but likely to yield generalizable knowledge about the child’s disorder or condition. ^[45 CFR 46.406; 21 CFR 50.53]

   The risk involved with each procedure must represent minimal risk or a minor increase over minimal risk. It is up to the board to determine the risk level presented by each procedure associated with the study to determine if the research can be approved under this category.

If a proposal involving children cannot be adequately justified in one of these three categories, the IRB must either disapprove the research or refer it to the Secretary of the DHHS and/or the FDA Commissioner. This category of research is considered category (4). Before the IRB refers a project for federal review, the IRB must first find that “the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children”. ^{[45 CFR 46.407; 21 CFR 50.54]}

Permission from a parent or guardian and a child’s assent is required. Requirements for parental permission are described in the Investigator Guidance Series: Parental Permission (see links at end of this document).

Additional Considerations

Wards of State: Special considerations and requirements are associated with the inclusion of wards in research. Requirements are outlined in the Investigator Guidance Series: Research Involving Wards of State.

VA Research:  The VASLCHCS is authorized to care for veterans and to conduct research that supports the mission of the Veterans Health Administration (VHA) and that enhances the quality of health care delivery to veterans. Therefore, research involving children should be reviewed carefully by the IRB for its relevance to VA and cannot present greater than minimal risk to the children. Research involving biological specimens or data obtained from children is considered to be research involving children even if de-identified. The VA’s facility Director should approve the research before initiation. See the ORD Guidance on Conducting Research Involving Children.

Child Abuse and Neglect: In cases where the nature or procedures of the research may reveal cases of child abuse and/or neglect, researchers must inform participants and their parents whether their confidentiality in this regard is limited by State laws. See the Supplemental Elements tab on the Consent Document Checklist found on the IRB website for sample consent language. Sexual Activity of Adolescent Subjects: When the proposed participants are adolescents, additional sensitivity is required in discussions of the participant’s sexual activity. If the consent, parental permission, and/or assent document stipulates that pregnant women must not participate in the research and must have a negative pregnancy test prior to participation in research, investigators must clarify who will receive the results of the pregnancy test.

Individuals Under 18 Who are Not Considered Children:  As indicated in the Definitions section above, in certain circumstances Utah law authorizes an individual under the age of 18 to function as an adult when seeking or receiving health care. In such circumstances, parental permission is not required as part of the research consent process.  When an individual under the age of 18 is authorized to consent for care or treatment because the care or treatment is connected to a sexually transmitted disease or pregnancy/childbirth, the individual may only consent for himself/herself in connection with that treatment or care and the individual may only provide full informed consent for research that is directly connected to that treatment or care.

Researchers are required to conduct a full consent process in a way that is understandable to the individual under 18.  The IRB may require parental permission or other methods to ensure comprehension of the study prior to enrollment.

Documents and References

Additional Protections for the Inclusion of Children in Research (OHRP): 45 CFR 46, Subpart D http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd  

Additional Protections for the Inclusion of Children in Research (FDA): 21 CFR 50 http://www.ecfr.gov/cgi-bin/text-idx?SID=73aec6d4923eb29d3ef60696c0d1b662&mc=true&node=pt21.1.50&rgn=div5

Investigator Guidance Series: Parental Permission and Child Assent: https://irb.utah.edu/guidance-series/parental-permission-and-child-assent/

Investigator Guidance Series: Research Involving Wards of State: https://irb.utah.edu/guidance-series/research-involving-wards-of-state/

Model Parental Permission and Model Assent: https://irb.utah.edu/informed-consent/consent-document-models/

VHA ORD Guidance on Conducting Research Involving Children: https://www.research.va.gov/resources/policies/human_research.cfm

Points to Consider