The IRB can approve research involving children as research subjects only when it determines the research satisfies the conditions of one or more of the categories outlined below.

Category 404 Research not involving greater than minimal risk

Research which the IRB finds to present no more than minimal risk to the children; and adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.

Category 405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects

Research which the IRB finds presents more than minimal risk to children 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, and,

• the risk is justified by the anticipated benefits to the subjects
• the relation of the anticipated benefit to the risk presented by the study is at least as favorable to the subjects as that provided by available alternative approaches, and
• adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.

Category 406 Research involving greater than minimal risk and no prospect of direct benefit to the individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition

Research which the IRB finds presents a minor increase over minimal risk by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is not likely to contribute to the well-being of the subject, and:

• the intervention or procedure presents experiences to the subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations;
• 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
• adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.

Category 407 Research not otherwise approvable

The IRB may approve research which does not meet the requirements of the categories listed above if the IRB finds 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.

For federally-funded research which meets this criteria, the DHHS Secretary or his/her designee, after consulting with a panel of experts in pertinent disciplines (e.g., science, medicine, education, ethics, law) and following an opportunity for public review and comment, must determine either

• that the research in fact satisfies the conditions above; or
• 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 research will be conducted in accordance with sound ethical principles; and adequate provisions are made for soliciting the assent of children and the permission of their parents or legal guardians.

The IRB may find that all children, some children, or no children are capable of assenting. When the IRB finds children are capable of providing assent, the IRB must also find that adequate provisions are made for soliciting the assent of the children, and determine that the plan for soliciting the assent of the children is appropriate.

The assent of the children is not required if the IRB finds any of the following is true:

• The children are not capable of providing assent based on their age, maturity, or psychological state.
• The capability 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.

The IRB may waive the assent requirement for some or all children when the IRB determines all of the following criteria are met:

• The research does not involve more than minimal risk to subjects.
• The research could not be practicably carried out without the waiver.
• If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable manner.
• The waiver will not adversely affect the rights and welfare of the subjects.
• When appropriate, subjects will be provided with additional pertinent information after participation.

Research personnel may only approach a child-subject to obtain his/her assent to participate in the research after the parents/guardian have given written permission (unless waived).

When the IRB finds that assent is required, it shall also approve a plan for whether assent will be documented and, if so, the mechanism for documentation.

The IRB must find that adequate provisions are made for soliciting the permission of each child's parents or guardian, when required, and determine that the plan for soliciting the permission of the parent/guardian is appropriate.

• For Categories 404 or 405, the IRB may find that the permission of one parent or guardian is sufficient.
• For Categories 406 and 407, both parents must give their permission 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.
• Permission by parents or guardians shall be documented in accordance with the IU HRPP Policy on Informed Consent.
• Pursuant to Indiana law IC 16-36-1-5, the IRB may approve, on a case-by-case basis, that one of the following may consent in lieu of a parent or guardian:
  • An adult sibling if there is no parent or guardian or the parent or guardian is not reasonably available
  • A grandparent of the child if there is no parent or guardian or the parent or guardian is not reasonably available

The IRB may waive the requirement for obtaining parental or guardian permission if:

• The IRB determines all of the following criteria are met:
  • The research does not involve more than minimal risk to subjects.
  • The research could not be practicably carried out without the waiver.
  • The waiver will not adversely affect the rights and welfare of the subjects.
  • If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable manner
  • When appropriate, subjects will be provided with additional pertinent information after participation.
• The IRB determines that a research study is designed for conditions or for a subject population for which parental or guardian permission is not a reasonable requirement to protect the subjects, provided an appropriate mechanism is in place to protect the children, and the waiver is not inconsistent with federal, state, or local law. The choice of an appropriate substitute mechanism (for example, appointing a child advocate or an assent monitor) for protecting children participating in research would depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity, status, and condition.

Children who are wards of the state or any other agency, institution, or entity can be included in research approved under Categories 406 or 407 only if the IRB finds the research is either:

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

For research with wards approved under Categories 406 or 407, the IRB must require appointment of an advocate for each child who is a ward.

• The advocate serves in addition to any other individual acting on behalf of the child as guardian or in loco parentis.
• One individual may serve as advocate for more than one child.
• 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.
• The advocate must not be associated in any way (except in the role as advocate or member of the IRB) with the research, research personnel, or the guardian organization.

Research involving children must be reviewed carefully by the IRB for its relevance to the VA and must not be greater than minimal risk. The VA medical facility Director must approve participation in proposed research that includes children.

VA research involving biospecimens or data obtained from children is considered to be research involving children even if de-identified. If the biospecimens or data were previously collected, they must have been collected under applicable policies and ethical guidelines.

VA research personnel cannot conduct interventions in research that enrolls newborns within four weeks of birth while on official duty, at VA facilities, or at VA-approved offsite facilities. Prospective observational and retrospective record review studies that involve neonates or neonatal outcomes are permitted.

For studies proposing to enroll children, the study team completes the IRB application and provides protocol-specific information related to research with children. The study team makes the initial determination regarding the appropriate categories of research involving children in which the research falls, including justification as to why the categories were selected. In addition, the study team provides an explanation regarding how adequate provisions are made for soliciting the assent of the children and the permission (parental/guardian informed consent) of each parent or guardian. The IRB considers the information in the IRB application and documents its determinations, as appropriate.

In deciding whether children are capable of assenting, the IRB shall take into account the ages, maturity, psychological status, and health condition of the children involved. The IRB's findings may apply to all or some of the children involved in the research.

When the IRB finds that written assent is required, the child must personally sign the assent statement.

When the IRB finds that assent is required and a child expresses a wish to decline participation in research, the child's decision prevails, even if his/her parents or guardian have granted permission.

If permission from both parents/guardians is required but an exception applies, the study team must document the exception. A study team can find that a parent/guardian is not reasonably available after the study team has made and documented repeated attempts to contact the parent/guardian over a reasonable time period with no response. The expectation is that study teams will make at least 3 attempts over at least 48 hours, unless the IRB has reviewed and approved a protocol-specific standard for finding that parents/guardians are not reasonably available.

If a parent or guardian is not reasonably available to provide consent for a potential subject, and the study team believes that allowing an adult sibling and/or grandparent would provide reasonable protections for that potential subject, the study team may submit a subject-specific request to the IRB that the sibling or grandparent provide consent for the particular subject and provide appropriate justification.

When a child who was enrolled in research with parental or guardian permission subsequently reaches the legal age of consent, the subject's participation in the research is no longer covered by this policy, and the permission granted by the parent/guardian for the minor to participate is no longer valid for continued participation.

• All research procedures with the now-adult subject, including interactions and interventions and collection of identifiable private information, must immediately cease.
• Research personnel must seek and obtain informed consent for the now-adult subject's continued participation in the research, or request a waiver of informed consent, per the IU HRPP Policy on Informed Consent.
• Research personnel must seek and obtain HIPAA authorization for the now-adult subject's continued participation in the research, or request a waiver of authorization, per the IU HRPP Policy on Use of PHI in Research.

In Indiana, pregnant minors cannot, by virtue of their pregnant status alone, consent on their own behalf to participate in research. Please note that although pregnant minors cannot consent for their own participation in research, once the child is born, the mother, even if she is still a minor, is the appropriate person to consent for her child to participate in research.