Children are considered a vulnerable population in the research context. The Common Rule (45 CFR 46) and FDA regulations (21 CFR 50) include Subpart D: Additional Protections for Children as Research Subjects. Subpart D establishes risk-benefit categories for research involving children. Only research that fits into one of the first three categories may be approved by an IRB; a fourth category requires the approval of the Secretary of the Department of Health and Human Services. Subpart D also specifies requirements for obtaining the permission of parents for the child’s participation in research and establishes expectations for obtaining the assent of children who are deemed capable of providing assent.

Who is a Child?

In order to decide whether or not the additional protections of Subpart D apply, the IRB must first determine if any of the subjects will be children. The definition of who is a child is determined by state laws. In Tennessee, as in most states, the age of majority is 18 years. In most cases this means that research enrolling persons in Tennessee who are under the age of 18 must comply with all of the requirements of Subpart D.

However, there are some situations where minors may consent to their own treatment prior to turning 18. If a minor can consent to a clinical treatment or evaluation under State law without parental permission, and the research closely relates to the care for which they have provided clinical consent, the IRB may determine that the minor can provide informed consent for the research without requiring parental permission, and that Subpart D does not apply to the research.

Subpart D Risk/Benefit Categories

Federal regulations require the IRB to classify research involving children into one of four categories and to document discussion of the risks and benefits of the research study. Those four categories of research are as follows:

• Category1:

  Research not involving greater than minimal risk (45 CFR 46.404). Parental permission of one parent and child assent are required, unless waived by the IRB.
• Category 2:

  Research involving greater than minimal risk when there is a possibility that participants will directly benefit from the research procedures or interventions, based on prior research, pre-clinical data, or the expertise of the investigators and the IRB. This includes potential benefits from study monitoring and diagnostic procedures that may contribute to the subject’s care or well-being (45 CFR 46.405). The relation of the anticipated benefits to the risk must be at least as favorable to the children as presented by available alternatives. Parental permission of one parent and child assent are required and cannot be waived.
• Category 3:

  Research involving greater than minimal risk without prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition (45 CFR 46.406). If the research procedures are for research purposes only and not for the childrens' direct benefit, the regulations require the following additional protections:

  • The risk represents a minor increase over minimal risk.
  • The intervention or procedure presents experiences to participants that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situation.
  • The intervention or procedure is likely to yield generalizable knowledge about the participants' disorder or condition which is of vital importance for the understanding or amelioration of the participants' disorder, or condition.

  This category of research is limited to children participants that have a disorder or condition, so healthy controls cannot be studied under this category. Parental permission from both parents and child assent are required and cannot be waived. If one parent is not reasonably available, consent of one parent may suffice.

  Children who are wards of the state or other agency/institution can be included if the research is related to their status as wards or is conducted in a setting in which the majority of children involved are not wards, such as schools or hospitals. If wards are included, the IRB must appoint a child advocate for each ward in addition to any other individual acting on behalf of the child as legal guardian.

• Category 4:

  Research not otherwise approvable under categories 1-3, which presents an opportunity research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children. If the IRB determines that a study may be approved under this category, the only way for the research to proceed is if the Secretary of Health and Human Services determines that it meets the criteria of §46.407. Referrals for a 407 determination are quite rare. Research under this category would require documentation of parental permission from both parents.

Minors as Parents

Unless parental permission is waived, any minor parent can give permission for their child to participate in research, but the parent/guardian of the minor parent must give permission for the minor parent to participate in research (if it does not fall within one of the categories above for which minors can consent as an adult).

Assent Requirements

The IRB must determine that adequate provisions are made for obtaining and documenting 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 assent, the IRB shall take into account the age, maturity, and psychological state of the children involved. This judgment may be made for all children to be involved in the research under a particular protocol, or for each child, as the IRB deems appropriate.

When the IRB determines that assent is required, it will also determine whether and how assent must be documented such as:

• Assent is required for each child who is capable of providing assent based on age, maturity, and psychological state.
• Assent is not required because the capability of some or all of the children is so limited (i.e., based on age or maturity) that they cannot reasonably be consulted.
• Assent is not required because the research provides direct, therapeutic benefit to the children that is only available in the context of the research, or the circumstances of the study meet the waiver criteria.

The abilities and needs of children vary. Investigators should describe the study and obtain assent in a manner appropriate for the individual child. As with obtaining consent from adult subjects, obtaining assent should be a discussion. The child’s assent must be affirmative. Acquiescence is not evidence of assent.

The IRB usually recommends documenting assent for subjects ages 7-12 through the use of a simple language assent form and documenting the assent for subjects ages 13-17 by asking the subjects to sign the consent
form signed by their parent(s)/guardian(s), which should be in language at an 8th grade reading level anyway. Hospital policies may also require that assent be documented in the electronic medical record.

An assent form need not include all the elements of consent. It should be written using simple, age appropriate wording. The assent form must be understandable to the children that will be asked to read it. The assent form should state clearly that the child can choose to be in the study or not. The assent form should summarize the purpose of the research and the procedures, explain whether any of the study procedures will hurt, and explain whether the child may benefit from being in the study. The assent should also state that if the child decides to participate, they can change their mind later.

Parental Permission

The regulations at 45 CFR 46.408 and 21 CFR 50.55 include requirements for obtaining or waiving parental (or legal guardian) permission for research involving children. Parental permission is typically documented using the ETSU Informed Consent Document template, as the documentation requirements for adults consenting for themselves are the same as for parental permission.

For research that is minimal risk to children, the regulations allow that parental permission only be obtained from one parent or guardian, unless otherwise determined by the IRB. For research greater than minimal risk to children, it is generally expected that permission of both parents or guardians be documented, unless one parent is unavailable (such as deceased, unknown, incompetent, or when one parent has sole custody).

The regulations allow the IRB to waive parental permission for minimal risk research if the requirements for waiver are met. There are also allowances for waiver of parental permission when it would not be in the best interest of the child participant to obtain parental permission such as research involving child abuse, neglect, or other confidential situations for minors, as long as there is an appropriate alternative mechanism in place to protect the rights and welfare of the child participants. In such a case, it would be necessary to obtain child assent and possibly include an independent child advocate in the process.