SOP #33 Research Involving Children and Investigator/Reviewer Checklist

Owner: Vice President of Academic Affairs
Author: CSS IRB
Contact: irb@css.edu
Policy Number: 33
Effective Date: 10/8/2021

Policy

The following applies to all research involving children, regardless of funding source. The requirements in this section are consistent with Subpart D of 45 CFR 46, which applies to DHHS-funded research and Subpart D of 21 CFR 50, which applies to FDA-regulated research involving children.

Purpose

The purpose of this SOP is to describe the special regulatory requirements that the researcher and the IRB must take into consideration when a proposed research study involves children, a vulnerable population, to provide additional protection for children involved in research.

Definitions

The human subject research regulations (45 CFR 46.402) definitions include:

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.

Assent means a child's affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent.

Permission means the agreement of parent(s) or guardian to the participation of their child or ward in research.

Parent means a child's biological or adoptive parent.

Guardian means an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care. No guardian may give consent for experimental treatment of any kind unless the procedure is first approved by an order of the court.  (Minn. Stat. §524.5-207 Subd 2 (c).)

Allowable Categories

In addition to the IRB’s normal duties, research involving children must be reviewed by the IRB to determine if it fits within and is permissible under one or more federally defined categories (OHRP/FDA). Each procedure or intervention that the child will undergo for the research must be taken into consideration, and, if the research includes more than one study group assignment (e.g., placebo vs. active, investigational agent vs. comparator) the category determination must be made for each group assignment. In other words, a component analysis must be conducted by the IRB. The categories are as follows:

  1. Research/Clinical Investigations not involving greater than minimal risk. [45 CFR 46.404/21 CFR 50.51] Research determined to not involve greater than minimal risk to child subjects may be approved by the IRB only if the IRB finds and documents that adequate provisions are made for soliciting the assent of the children and the permission of either one or both parents or guardians (45 CFR § 46.408).
  2. Research/Clinical Investigations involving greater than minimal risk but presenting the prospect ofdirect benefit to the individual subjects. [45 CFR 46.405/21 CFR 50.52] 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, may be approved by the IRB only if the IRB finds and documents that:
    1. The risk is justified by the anticipated benefit to the subjects;
    2. The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative options; and
    3. Adequate provisions are made for soliciting the assent of children and the permission of either one or both parents or guardians (45 CFR § 46.408).
  3. Research/Clinical Investigations involving greater than minimal risk and no prospect of directbenefit to the individual subject, but likely to yield generalizable knowledge about the subject's disorder or condition. [45 CFR 46.406/21 CFR 50.53] Research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well-being of the subject, may be approved by the IRB only if the IRB finds and documents that:
    1. The risk represents a minor increase over minimal risk;
    2. 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;
    3. 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
    4. Adequate provisions are made for soliciting the assent of children and the permission of both parents or guardians (45 CFR § 46.408).
  4. Research not otherwise approvable which presents an opportunity to understand, prevent, oralleviate serious problems affecting the health or welfare of children. [45 CFR 46.407/21 CFR 50.54] When the IRB does not believe that the research meets the requirements of any of the above categories, and the IRB finds and documents 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, the IRB shall refer the research for further review as follows:
    1. DHHS conducted or supported research in this category will be referred for review by the Secretary of Health and Human Services. However, before doing so the IRB must determine that the proposed research also meets all of the requirements of the Common Rule.
    2. FDA-regulated research in this category will be referred for review by the Commissioner of Food and Drugs.
    3. For research in this category that is not DHHS conducted or supported and is not FDA-regulated, the IRB will consult with a panel of experts in pertinent disciplines (for example: science, medicine, ethics, law). Based on the recommendation of the panel, the IRB may approve the research based on either:
      1. That the research in fact satisfies the conditions of the previous categories, 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 accord with sound ethical principles; and
        3. Adequate provisions are made for soliciting the assent of children and the permission of both parents or guardians (45 CFR § 46.408).

Parental Permission and Assent

Parental Permission

The IRB must determine that adequate provisions have been made for soliciting the permission of each child’s parent or guardian.  Parents or guardians must be provided with the basic elements of consent and any additional elements the IRB deems necessary.

The IRB may find that the permission of one parent is sufficient for research to be conducted under Categories 1 [45 CFR 46.404/21 CFR 50.51] & 2 [45 CFR 46.405/21 CFR 50.52] above. The IRB’s determination of whether permission must be obtained from one or both parents will be documented in the reviewer’s notes when a study receives expedited review, and in meeting minutes when reviewed by the convened committee.

Permission from both parents is required for research to be conducted under Categories 3[45CFR 46.406/21 CFR 50.53] & 4[45 CFR 46.407/21 CFR 50.54] above unless:

1. One parent is deceased, unknown, incompetent, or not reasonably available; or

2. When only one parent has legal responsibility for the care and custody of the child.

Permission from both parents is also required for research involving care or treatment to a child in connection with an abortion. For research not covered by the FDA regulation, the IRB may waive the requirement for obtaining permission from a parent or legal guardian if:

  1. The research meets the provisions for waiver; or
  2. If the IRB determines that the research is designed to study conditions in children or a subject population for which parental or guardian permission is not a reasonable requirement to protect the subjects (for example, neglected or abused children) provided that an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and that the waiver is not inconsistent with Federal, State, or local law. The choice of an appropriate mechanism would depend upon the nature and purpose of the activities described in the protocol/research plan, the risk and anticipated benefit to the research subjects, and the child’s age, maturity, status, and condition.

Parental permission may not be waived for research covered by the FDA regulations.

Permission from parents or legal guardians must be documented in accordance with 45 CFR § 46.117 of Subpart A (Documentation of Informed Consent).

Assent from Children

The IRB is responsible for determining 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. This judgment may be made for all children to be involved in the study, or for each child, as the IRB deems appropriate (45 CFR §46.408.)

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 when consent may be waived in accordance with the applicable regulations. (See, CSS IRB SOP # 18, Waiver of Documentation of Consent.)

It is important to note that the FDA regulations do permit the IRB to waive the assent requirement if it finds and documents that:

  1. The clinical investigation involves no more than minimal risk to the subjects;
  2. The waiver will not adversely affect the rights and welfare of the subjects;
  3. The clinical investigation could not practicably be carried out without the waiver; and
  4. Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

Because “assent” means a child’s affirmative agreement to participate in research, the child must actively show his or her willingness to participate in the research, rather than just complying with directions to participate and not resisting in any way.

The IRB should consider the nature of the proposed research activity and the ages, maturity, and psychological state of the children involved when reviewing the proposed assent procedure and the form and content of the information conveyed to the prospective subjects. For research activities involving adolescents whose capacity to understand resembles that of adults, the assent procedure should likewise include information similar to what would be provided for informed consent by adults or for parental permission. For children whose age and maturity level limits their ability to fully comprehend the nature of the research activity, but who are still capable of being consulted about participation in research, it may be appropriate to focus on conveying an accurate picture of what the actual experience of participation in research is likely to be (for example, what the experience will be, how long it will take, whether it might involve any pain or discomfort). The assent procedure should reflect a reasonable effort to enable the child to understand, to the degree they are capable, what their participation in research would involve.  (See, CSS IRB SOP # 16 Informed Consent w/ Checklist and Templates.)

Parents and children will not always agree on whether the child should participate in research. Where the IRB has indicated that the assent of the child is required in order for him or her to be enrolled in the study, dissent from the child overrides permission from a parent. Similarly, a child typically cannot decide to be in research over the objections of a parent. There are individual exceptions to these guidelines but in general, children should not be forced to be research subjects, even when permission has been given by their parents.

Documentation of Assent

When the IRB determines that assent is required, it also is responsible for determining whether and how assent must be documented. (See, CSS IRB SOP #16 Informed Consent w/ Checklist and Templates.)

When the research targets the very young child or children unable or with limited capacity to read or write, an oral presentation accompanied perhaps by some pictures with documentation of assent by the person obtaining assent in a research note is likely more appropriate than providing the child a form to sign. In this case, the investigator should provide the IRB with a proposed script and any materials that they intend to use in explaining the research.

When the research targets children who are likely able to read and write, investigators should propose a process and form that is age appropriate and study specific, taking into account the typical child's experience and level of understanding, and composing a document that treats the child respectfully and conveys the essential information about the study. The assent form should:

  1. Tell why the research is being conducted;
  2. Describe what will happen and for how long or how often;
  3. Say it is up to the child to participate and that it is okay to say no;
  4. Explain if it will hurt and if so for how long and how often;
  5. Say what the child's other choices are;
  6. Describe any good things that might happen;
  7. Say whether there is any compensation for participating; and
  8. Ask for questions.

Whenever possible, the document should be limited to one page. Illustrations might be helpful, and larger type and other age appropriate improvements are encouraged when they have the potential to enhance comprehension. Studies involving older children or adolescents should include more information and may use more complex language.  (See again, CSS IRB SOP #16.)

Children Who are Wards

Children who are wards of the State or any other agency, institution, or entity can be included in research approved under 45 CFR 46.406/21 CFR 50.53 (no direct benefit) or 45 CFR 46.407/21 CFR 50.54 (research not otherwise approvable), only if such research is:

  1. Related to their status as wards; or
  2. Conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards.

If the research meets the condition(s) above, an advocate must be appointed for each child who is a ward (one individual may serve as advocate for more than one child), in addition to any other individual acting on behalf of the child as legal guardian or in loco parentis or as a Legally Authorized Representative (LAR). (See, CSS IRB SOP #16 Informed Consent w/ Checklist and Templates.)

The advocate must be an individual who has the background and experience to act in, and agrees to act in, the best interests of the child for the duration of the child's participation in the research and who is not associated in any way (except in the role as advocate or member of the IRB) with the research, the investigator(s), or the guardian organization.

NOTE WELL MINNESOTA LAW: No consent may be given for experimental treatment of such a child or children unless it is first approved by an order of the court as set forth in Minnesota Statute 524.5-207 No guardian may give consent for psychosurgery, electroshock, sterilization, or experimental treatment of any kind unless the procedure is first approved by the order of the court, after a hearing as prescribed by section 524.5-313, paragraph (c), clause (4) (https://www.revisor.mn.gov/statutes/cite/524.5-207).

Resources

Allina Health HRPP/IRB SOP Version 04/20/2020 -

https://www.allinahealth.org/-/media/allina-health/files/for-medical-professionals/research/allina-resea rch-administration-home/hrpp-irb-sop-manual.pdf

Children’s Hospital of Philadelphia (CHOP) SOP Research Involving Children https://irb.research.chop.edu/sites/default/files/documents/irbsop504.pdf OHRP FAQS Children Involved in Research https://www.hhs.gov/ohrp/regulations-and-policy/guidance/faq/children-research/index.html

IRB EasyEd Parental Permission Waivers of Parental Permission, and Child Assent. Volume 3 number 3 © 2017 Apex Ethical

This is a new policy per the 2018 Common Rule Requirements.

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