Section XV:

Children as Research Participants

WPP #: XV-1

Title 1:

Permissible Categories

Effective Date:

09-24-14

Revision History:

06-20-00; 07-26-00; 06-07-04; 6-21-06; 11-01-06; 10-15-07; 05-22-14

Policy Statement

The VCU IRB adheres to both state and federal regulatory requirements when reviewing research involving children as participants. When submitting to the IRB, the principal investigator should request a specific children’s category, and the IRB will determine the appropriateness of the category and document the required findings/conditions under each category.

Description and Procedures

Note: Text that is boxed or in quotation marks is from federal regulations. Text effects are added.

According to the Code of Virginia§.1-207, “child; juvenile; minor; infant or any combination thereof means a person less than 18 years of age” who is not legally emancipated. Such an individual requires permission from parent(s), guardian, or legally authorized representative to participate in research, even if the research comprises activities for which a child or minor may ordinarily consent to treatment under statutory exceptions. For purposes of the VCU IRB Written Policies and Procedures, a ‘child’ refers to an individual under the age of 18, unless legally emancipated. Note that in Virginia, an individual below the age of 18 years of age who is legally emancipated (with legal documentation to verify such status) is permitted to make all decisions concerning research participation as would someone 18 and older who is also decisionally capable. In such cases, the ‘legal age for consent,’ as described in both HHS and FDA definitions, has been attained. The individual is no longer considered a ‘child’ under Virginia law or federal definitions.

For research conducted outside of Virginia, relevant law for the jurisdiction in which the research is being conducted will determine whether an individual is considered a child to whom DHHS or FDA regulations apply for the conduct of research. Note that different states may have varying definitions for who may serve as a legally authorized representative (LAR) on behalf of a prospective child participant. The criteria for emancipated minor and legal authorization may also differ between states.

  1. Applicability:
    VCU applies Subpart D (the portion of 45 CFR 46 which describes the special protections for children as research participants) and Subpart D of FDA regulations at 21CFR 50.50-56 to research involving children.
    • The exemption at 45 CFR 46.101(b)(2), for research involving survey or interview procedures or observation of public behavior, does not apply to research with children, except for research involving observations of public behavior when the investigator(s) do not participate in the activities being observed. For FDA-regulated research, children may participate in the permissible exemptions from IRB requirement listed at 21CFR56.104.
    • The VCU IRB has the authority to require that additional protections be applied to any research project (even if determined to be exempt). In doing so, the VCU IRB may apply 45CFR46 Subpart D to FDA-regulated research as it deems appropriate.

    The VCU IRB recognizes the applicability of other Virginia State law requirements (also applicable within the research setting) including (but not limited to) mandatory reporting of suspected child and adult abuse or neglect, HIV testing consent requirements, and mandatory disease reporting. Mandatory reporting requirements should appear in parental permission and assent forms, as applicable to the protocol.

  2. Definitions:
    Federal definitions pertaining to children’s participation in research are found in Subpart D in the DHHS regulations found at 45CFR46.402. FDA regulations pertaining to additional safeguards for children in clinical investigations are found in Subpart D at 21.CFR.50.50. Definitions are at 21CFR50.3.
    1. Definition of "Child":
      1. DHHS - "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.”
      2. FDA – “Children means persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations, under the applicable law of the jurisdiction in which the clinical investigation will be conducted.”

      For information and IRB review criteria regarding children in state or court-appointed custody (“wards of the state”) and emancipated minors, please see VCU IRB WPP XV-3: Children in Court-Appointed or State Custody and Emancipated Minors.

      Note that the designation of ‘child’ is determined by the jurisdiction in which the research is being conducted. Therefore, for research conducted outside of Virginia, the PI is to provide information pertaining to how the designation of the legal age of majority is determined.

    2. Definition of "Assent':
      1. DHHS - "Assent means a child's affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent.”
      2. FDA – Same definition as above

      The giving of assent should not be assumed by the investigator. Unless waiver of assent is specifically approved, the child may withhold assent, in which case the child may not be enrolled as a research participant. For information regarding assent and the assent process, please see VCU IRB WPP#: XV-2: Assent / Informed Consent Considerations.

    3. Definition of "Permission":
      1. DHHS - "Permission means the agreement of parent(s) or guardian to the participation of their child or ward in research.”
      2. FDA – “Permission means means the agreement of parent(s) or guardian to the participation of their child or ward in a clinical investigation. Permission must be obtained in compliance with Subpart B of this part and must include the elements of informed consent described in 50.25.”
  3. Definitions of "Parent," "Guardian," and "LAR":
    1. DHHS & FDA - "Parent means a child's biological or adoptive parent.”
    2. DHHS - "Guardian means an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care.
    3. FDA - “Guardian means an individual who is authorized under applicable state or local law to consent on behalf of a child to general medical care when general medical care includes participation in research. For purposes of Subpart D of this part [21CFR50.50], a guardian also means an individual who is authorized to consent on behalf of a child to participate in research.”
    4. Legally Authorized Representative (LAR): For research being conducted in Virginia, investigators are expected to ascertain parental or guardian status and consequent ability to provide permission prior to the child’s enrollment in the study. If a question of status exists, investigators should request documentation from the parent or legal guardian. For research conducted outside Virginia, the PI is to indicate how parental or guardian status will be ascertained according to state laws applicable to the jurisdiction in which the research is being conducted.

    Virginia law broadly views all individuals described in the prioritized LAR list, at Virginia Code 32.1-162.16, to be Legally Authorized Representatives (see WPP XI-3 Legally Authorized Representatives). As such, an individual designated as an LAR provides consent on behalf of the research subject who is not otherwise able to do so on his or her own behalf. For purposes of research with unemancipated minors, individuals who may serve as ‘LARs” for children/unemancipated minors are: 1) “the parent or parents having custody of a prospective subject who is a minor, 2) ‘the legal guardian of a prospective subject,’ or 3) ‘any person or judicial or other body authorized by law or regulation to consent on behalf of a prospective subject to such subject’s participation in the particular human research.’ Examples of individuals who may have designation as legal guardian for a child include: an adult family member of the child, an adult friend of the family. Note that in the case of a legal guardian, the child usually, but not always, lives with the guardian. Additionally, not every sibling in a family may have the same legal guardian.

  4. Additional Duties of the VCU IRB:
    The VCU IRB will make the determination that research involving children fits into one of the following 4 categories of research (described in detail below) and will document (as part of the official review record) the required findings for each:
    • Category 404 - Minimal Risk
    • Category 405 - Greater than Minimal Risk (with Prospect of Direct Benefit)
    • Category 406 - Greater than Minimal Risk (with No Prospect of Direct Benefit)
    • Category 407 - Not Otherwise Approvable (w/ potential to understand, prevent, pain mgmt.)

    For FDA-regulated research involving children, the categories address ‘clinical investigations’ in 50.51, 50.52, 50.53, and 50.54 which respectively reflect the DHHS categories above.

  5. Categories 404 and 405:
    1. Category 404 - Minimal Risk:
      The VCU IRB must find and document that the following 3 conditions have been met:
      1. The research is not greater than minimal risk;
      2. Adequate provisions for permission are in place (from parents or guardians) 45 CFR 46.408; and,
      3. Adequate provisions for assent are in place.
    2. Category 405 - Greater than Minimal Risk (with Prospect of Direct Benefit):
      The VCU IRB must find and document that the following 4 conditions have been met:
      1. Research greater than minimal risk is presented by a procedure that holds out the prospect of direct benefit for the individual child;
      2. The risk is justified by the benefits to the children;
      3. Adequate provisions for permission are in place (from parents or guardians) 45 CFR 46.408; and,
      4. Adequate provisions for assent are in place.

      At VCU, Categories 404 or 405 are most common for research involving children.  For all research determined by the IRB to involve children under categories 404 or 405, all 5 of the following additional conditions must be met:

      1. The research was approved by the VCU IRB under children’s category 46.404 or 46.405.
      2. The VCU IRB has determined that the research is therapeutic or if non-therapeutic, represents no more than minimal risk to the subject.
      3. For children in court-appointed or state custody (as vulnerable research subjects), the VCU IRB has determined that the research does not pose additional risks to and/or could not reasonably be accomplished without their inclusion.
      4. For children in court-appointed or state custody (as vulnerable research subjects), the LAR does not over-ride known or reasonably known religious or value restrictions of the child in court-appointed or state custody (or parents or guardians) and otherwise acts in accordance with the laws of the Commonwealth (noted above).
      5. Assent is requested of the child, as appropriate given the age and maturity level of the child.
  6. Categories 406 and 407:
    1. Category 406 - Greater than Minimal Risk (with NO Prospect of Direct Benefit): The VCU IRB must find and document that the following 6 conditions have been met:
      1. Research risk is a minor increase over minimal risk;
      2. There is no prospect of direct benefit to the individual child;
      3. The research is likely to yield generalizable knowledge about the participant's disorder or condition;
      4. The research procedures/intervention is reasonably commensurate with experiences that the research participant is exposed to (during actual or expected medical, dental, psychological, social, or educational situations);
      5. Adequate provisions for permission are in place (from parents or guardians) 45 CFR 46.408; and,
      6. Adequate provisions for assent are in place.
    2. Category 407 - Not Otherwise Approvable (Understand, Prevent, or Alleviate): If following findings and actions must occur:
      1. The IRB finds that the research does not meet the requirements of 45 CFR 46.404, 46.405, or 46.406;
      2. The IRB finds that the research presents a reasonable opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children; and
      3. The HHS Secretary (after consultation with a panel of experts in pertinent disciplines and following opportunity for public review and comment) has determined either:
        1. that the research, in fact, is found to satisfy the conditions of 45 CFR 46.404, 46.405, or 46.406, as applicable, or
        2. the following:
          1. the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children;
          2. the research will be conducted in accordance with sound ethical principles;
          3. adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in 46.408.

      In the case of the above category’s required reporting to DHHS or FDA, such reporting is initiated by correspondence to DHHS or FDA, from the VCU IRB chairperson or designee, who will report directly to the Office for Human Research Protections (OHRP) or the Commissioner of Food and Drugs on this matter. The OHRP Guidance Document: Special Protections for Children as Research Subjects (45 CFR 46.407 Process) will be followed by the VCU IRB and OHRP, if FDA regulations do not apply. Not until the appropriate official has issued determinations in writing back to the IRB (as documented in the official record) will the IRB be able to fully review the research and consider its approval status.

      For all research determined by the IRB to involve children under categories 406 or 407, all 9 of the following conditions must be met:

      1. The research was approved by the VCU IRB under children’s category 46.406 or 46.407.
      2. The research was approved by the VCU IRB as a study focused on evaluating the status of wards OR conducted in a setting where the majority of children involved as subjects are NOT in court-appointed or state custody.
      3. The VCU IRB has determined that the research is therapeutic or if non-therapeutic, represents no more than minimal risk to the subject.
      4. The VCU IRB has determined that the research does not pose additional risks to children in court-appointed custody (as vulnerable research subjects) and/or could not reasonably be accomplished without their inclusion.
      5. The LAR does not over-ride known or reasonably know religious or value restrictions of the child in state custody and otherwise acts in accordance with the laws of the Commonwealth.
      6. An advocate is appointed for each child who is in court-appointed or state custody (the advocate may serve on behalf of more than one child at a time and must be prepared to document appropriate background and experience to act in the best interests of the child for the duration of the research, document their willingness accept the role of advocate for the child, document that they have no other association with the research/investigator(s)/guardian organization, except as the role of advocate or member of the IRB.
      7. The IRB will be involved in determining whether the parents of a child in court-appointed custody are to be informed of the child's possible involvement in research and whether parental refusal may be considered.
      8. Assent is requested of the child, as appropriate given the age and maturity level of the child.
      9. If the research is underway, yet was not "approved by the IRB to involve children in court-appointed or state custody", and the investigator learns that a subject is eligible for enrollment and is in the custody of the state, the investigator should communicate with the IRB regarding how to proceed BEFORE the child is enrolled in the study. Further direction may include submission of written request, rationale, and process to allow such children as participants in the research (using the VCU IRB Change in Research form).

References

45 CFR 46, Subpart D
21 CFR 50.3 and 21 CFR 50.50, Subpart D
Special Protections for Children as Research Subjects (45 CF 46.407 Process)
Special Protections for Children as Research Subjects (General Guidance)
OHRP FAQs - Children as Research Subjects
VCU WPP XV-2: Assent / Informed Consent Considerations
VCU WPP XV-3: Children in Court-Appointed or State Custody and Emancipated Minors
VCU WPP XI-3: Legally Authorized Representatives