Vulnerable Subjects - Children / Minors
The legal mandate of the IRB is to protect the rights and welfare of human subjects. This task becomes more difficult when considering children as research subjects. OHRP provides an FAQ on this topic. The Federal regulations provide for “Additional Protections for Children Involved as Subjects of Research.” Subpart D of 45 CFR 46. "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 (45CFR46.402(a). In the state of Virginia the legal age is 18 however some exceptions may apply.
The definition of “children” also takes into account the particular treatments or procedures involved in the proposed research; for example, in some places individuals who are sixteen years of age may legally consent to certain medical treatments, and so if the involvement of human subjects in a proposed research activity consists of these treatments, then they may be considered as adults for that purpose. If a proposed activity includes something for which the subject has not yet reached the legal age of consent, however, that person must be considered a child.
An FAQ from OHRP states
If by law a child is able to consent to treatment without parental permission, can they also consent to participate in research related to that treatment?
HHS regulations at 45 CFR 46.402(a) define “children” as “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.” If research on a specific treatment involves solely treatments or procedures for which minors can give consent outside the research context (under applicable state and local laws, for example, research on sexually transmitted diseases or pregnancy), such individuals would not meet the definition of children as defined at 45 CFR 46.402(a). Thus, subpart D would not apply to the research and parental permission (or waiver thereof) is not a consideration for these minors. Under these circumstances, minors may provide their own informed consent.
Issues to consider when proposing to involve children in research
- Is the participation of children as research subjects justified in this particular instance?
- If this research question can be addressed initially in adults, has this research been conducted?
- Have results from any adult research indicated that the proposed research would benefit, or at least not be harmful, to children?
- Has every effort been made to ensure that a parent is present when the research intervention is conducted? This will not only comfort the child but will enable the parent to exercise the right to end the child's participation in the research project at any time. Investigators should note that in some cases (e.g., research into sensitive personal matters, physical examinations of adolescents, research into abuse, etc.) it may not be appropriate to have a parent present. If a parent will not be present during the course of the project, has the investigator clearly stated why in the protocol form?
- Are the personnel involved in the research, and the facility in which the research will be conducted, knowledgeable about and sensitive to the physical and psychological needs of the children and their families?
- Have the investigators taken into account the child's previous experience with illness and medical interventions? Some children may be able to cope with the stress of research better than others as a result of previous experience with medicine. Younger, "less experienced" children may be unprepared for participation in medical research.
- How has the investigator determined the number of children to be enrolled for the study? Investigators should justify the number of subjects they propose to study. Investigators should always plan to involve the fewest number of children necessary to obtain statistically significant data from which valid conclusions can be drawn.
- Whether the proposed techniques are the least invasive (physically and psychologically) in order to obtain the research information.
- Have the investigators clearly defined how the assent of the child-subjects will be obtained?
- For research involving medical interventions, the IRB will consider previous research with animals. The investigator should indicate whether the animal research is completed and the results to date.
- All research involving children as subjects must be reviewed by the full IRB unless the research is exempt from review. All personnel working with children should be familiar with the State laws requiring the reporting of suspected abuse. The IRB cannot approve research that exposes children as subjects to more than minimal risk and does not satisfy the conditions outlined above. The Federal regulations, however, provide a process for seeking approval for such research from the DHHS secretary.
Permitted Categories for Research with Children
Federal regulations classify permissible research involving children into four categories based on degree of risk and type of individual subjects. These categories are described in relation to " minimal risk ":
- Research not involving greater than minimal risk (45 CFR 46.404 and 21 CFR 50.51)
- Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects (45 CFR 46.405 and 21 CFR 50.52):
- Research that involves more than minimal risk and presents the prospect of no direct benefit to individual subjects, but generalizable knowledge (societal benefit) (45 CFR 46.406 and 21 CFR 50.53):
- Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children (45 CFR 46.407 and 21 CFR 50.54):
Because children cannot legally provide consent for research on their own behalf, permission by at least one parent or legal guardian is required prior to enrollment of a minor in a research study.
- Research involving no more than minimal risk requires permission from at least one parent (or guardian).
- Research that involves more than minimal risk but presents the prospect of direct benefit to individual subjects requires permission from at least one parent (or guardian).
- Research that involves more than minimal risk and presents the prospect of no direct benefit to individual subjects, but generalizable knowledge (societal benefit) requires permission from both parents .*
- Research that presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children, does NOT provide direct benefit to the subject or societal (indirect) benefit requires permission from both parents .*
NOTE: If there are two parents available to give permission but they disagree about allowing their child to participate in the study, the child should not be enrolled unless that disagreement can be resolved. This policy applies to all permissible categories of research involving children.
*Unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child. If these circumstances are present, the researcher should document this in the subject's research record.
Process of Obtaining Parental Permission
Unless the IRB has granted a “Waiver of Documentation of Consent” the answer is NO. It is true that verbal permission from the parent/guardian is allowed in the clinical setting, however this is not allowed in research.
FDA Guidance contains the following information:
May informed consent be obtained by telephone from a legally authorized representative?
A verbal approval does not satisfy the 21 CFR 56.109(c) requirement for a signed consent document, as outlined in 21 CFR 50.27(a). However, it is acceptable to send the informed consent document to the legally authorized representative (LAR) by facsimile and conduct the consent interview by telephone when the LAR can read the consent as it is discussed. If the LAR agrees, he/she can sign the consent and return the signed document to the clinical investigator by facsimile.
OHRP Guidance contains the following information:
How should parental permission for research involving children be documented?
Permission by parents or guardians shall be documented in accordance with and to the extent required by 46.117 of subpart A of 45 CFR part 46. Essentially, parental permission should be documented in a manner similar to that used to document informed consent. An Institutional Review Board (IRB) may find that waiver of documentation of informed consent is appropriate under the HHS regulations at 46.117.
45CFR46.117 Documentation of informed consent.
(a) Except as provided in paragraph (c) of this section, informed consent shall be documented by the use of a written consent form approved by the IRB and signed by the subject or the subject's legally authorized representative. A copy shall be given to the person signing the form.
Wards of State
This information is from the OHRP website.
Children who are wards of the state or any other agency can be involved in research that is:
- no more than minimal risk with permission from a guardian;
- more than minimal risk but presents the prospect of direct benefit to individual subjects with permission from a guardian;
- more than minimal risk and presents the prospect of no direct benefit to individual subjects, but generalizable knowledge (societal benefit) ONLY if the research is
- related to their status as wards, or
- conducted in schools camps, hospitals, institutions, or similar settings in which the majority of children involved are not wards.
The IRB must require appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis.
- Research not otherwise approvable that presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children, but does NOT provide direct benefit to the subject or societal (indirect) benefit. The research cannot be approved unless the criteria in #3 are met and HHS Secretary approval is granted.
NOTE: The foster parent is usually not the legal guardian of a child in foster care. The social services department usually has legal authority for the child.
In addition to parental permission, federal regulations require that research studies involving children include adequate provisions for soliciting the assent of a child to participate in research when the child is capable of providing assent. Assent is defined as “a child’s affirmative agreement to participate in research.” However, the mere absence of an objection by the child should not be construed as assent.
The IRB must find that adequate provisions are made for soliciting the assent of 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 will take into account the ages, maturity, and psychological state of the children involved. When a child’s assent is required, the child should be given an explanation of the proposed research procedures in a language that is appropriate to the child’s age, experience, maturity and condition.
The requirement for documenting informed consent by use of a written consent/assent form approved by the IRB and signed by the participant or the participant’s legally authorized representative applies when children are the subjects of research, unless this requirement is waived by the IRB (see below). A parent (one or both) or, in some cases, a guardian must document permission for his/her child to participate in research.
If verbal consent/assent will be obtained, the IRB must review a written description of the information (i.e. consent/assent) that will be provided to the children during the assent process. As with written consent/assent, a parent (one or both) or, in some cases, a guardian must document permission for his/her child to participate in research.
The regulations do not specify an age at which assent is required. The UVA IRB-HSR requires either verbal or written documentation of assent for participation of subject's ages 7 – 17 (when determined to be appropriate) unless waived as explained below.
If an investigator chooses not to use the stand alone assent form for children ages 7-14 or the written documentation on the main consent from the minor ages 15-17, the investigators should seek verbal assent from children as appropriate to their age, maturity and psychological state. The protocol should detail the process of obtaining assent. In this case, the main consent will document the person obtaining verbal assent from the minor.
The IRB may waive assent under the following circumstances:
- The capability of some or all of the children is so limited that they cannot reasonably be consulted;
- 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; or
- Even where the IRB determines that the children are capable of assenting, the IRB may waive the requirement for obtaining assent under circumstances under 45CFR46.116(d) in which consent may be waived.
Difficult Issues/Sensitive Matters involving Children
Discovery and Disclosure of Sensitive Information
In the course of research with children, especially adolescents, researchers may discover sensitive information about subjects that is not related to the study itself. For example, such information as sexual activity, STDs, use of illegal substances, and child abuse.
- Confidentiality : Researchers need to consider how they will handle such situations should they arise. The permission and/or assent form should describe plans for disclosure—or non-disclosure—of such information to parents, legal authorities, and the subjects themselves. In some situations it may be appropriate to obtain a NIH Certificate of Confidentiality.
- Child Abuse Reporting : Additional Information.
Enrolling Children in Long-Term Studies
Long-term research studies may involve subjects who are children at the time of enrollment but reach the age of consenting for themselves (in Virginia, usually 18 years old) while study procedures or follow-up are still ongoing. The IRB will consider on a protocol-by-protocol basis whether obtaining new consent from such subjects is required.
If there is continued interaction with subjects who were first enrolled as children, "re-consenting" when a subject's legal status changes will usually be required. If the only continuing study procedures are follow-up activities such as review of records or examination of biological specimens, the original consent may suffice. OHRP Guidance