Every CCRC study needs to address inclusion of children as part of the "Protection of Human Subjects" section of the “Application to Use the CCRC.”

NIH definition: Children <21 years of age

NIH mandate: Children should be included in research unless there are scientific and ethical reasons for exclusion.

1. For studies excluding children, the Principal Investigator must specify why children are excluded. The NIH lists the following as acceptable justifications for the exclusion of children in research. The Principal Investigator should specify which justification is relevant for the study and explain why.
   
   
   1. The research topic to be studied is irrelevant to children.
   2. There are laws or regulations barring the inclusion of children in the research.
   3. The knowledge being sought in the research is already available for children or will be obtained from another ongoing study, and an additional study will be redundant. Documentation of other studies justifying the exclusions should be provided.
   4. A separate, age-specific study in children is warranted and preferable. Examples include:
      1. The relative rarity of the condition in children, as compared to adults
      2. The number of children is limited because the majority are already accessed by a nationwide pediatric disease research network
      3. Issues of study design preclude direct applicability of hypotheses and/or interventions to both adults and children (including different cognitive, developmental, or disease stages or different age-related metabolic processes). While this situation may represent a justification for excluding children in some instances, consideration should be given to taking these differences into account in the study design and expanding the hypotheses tested or the interventions to allow children to be included rather than excluding them.
   5. Insufficient data are available in adults to judge potential risk in children
   6. Study designs aimed at collecting additional data on pre-enrolled adult study participants (e.g., longitudinal follow-up studies that did not include data on children).
   7. Other special cases justified by the investigator and found acceptable to the GAC.
   
   
2. For studies including minors (i.e., subjects under 18 years of age), the Principal Investigator must specify:
   
   
   1. Under what section of the Code of Federal Regulations (45 CFR Part 46 is the part of the code that pertains to research in children) is this study IRB approvable?
      • § 46.404 Research not involving greater than minimal risk.
        HHS will conduct or fund research, in which the IRB finds that no greater than minimal risk to children is presented, only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in §46.408.
      • § 46.405 Research involving greater than minimal risk, but presenting the prospect of direct benefit to the individual subjects.
        HHS will conduct or fund 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, only if the IRB finds 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 approaches; and
        3. Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth in §46.408.
      • § 46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition.
        HHS will conduct or fund 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, only if the IRB finds 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 assent of the children and permission of their parents or guardians, as set forth in §46.408.
   2. A list of all procedures to be performed on subjects.
   3. For studies approvable under § 46.404, the PI must assure that all procedure pose no more than minimal risk.
   4. For studies approvable under Under § 46.405, the PI must:
      1. For each procedure that poses greater than minimal risk, demonstrate why the risk of that procedure is justified by the anticipated benefit of that procedure to the subjects; and
      2. Demonstrate that the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches
   5. For studies approvable under Under § 46.406, the PI must:
      1. Assure that the risk of each procedure represents no more than a minor increase over minimal risk;
      2. Discuss how each 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. Clearly articulate the subjects' disorder or condition;
      4. Explain how each intervention or procedure is likely to yield generalizable knowledge about the subjects' disorder or condition; and
      5. Explain why such knowledge is of vital importance for the understanding or amelioration of the subjects' disorder or condition
      
      Note: In rare circumstances, research on children that is not approvable under subparts §46.404-46.406 may be approved under provisions of §46.407 (see Section C below).
      
      
3. CCRC Advisory Committee (GAC) Actions regarding inclusion of children:
   
   1. For each CCRC study, the GAC will carefully review the inclusion/exclusion of children. The answers that each investigator provides to the specific questions listed above will guide the committee. The CCRC RSA and Pediatric Ethicist specifically will evaluate the risk level for children and make a recommendation to the GAC.
   2. For studies that do not plan to enroll children but where the GAC feels that this would be appropriate, the committee will table the study pending clarification from the principal investigator and/or an amendment to the protocol.
   3. All studies that specifically involve children will be evaluated by a pediatrician for the GAC to determine the need for direct coverage by a pediatrician during the study.
   4. Children >15 years of age, that do not have a significant medical condition requiring on-site oversight of a pediatrician, can be seen at the CCRC. For these studies, the PI will be asked to identify a study-specific pediatrician who can be available should any medical emergency arise.
   5. Children
   6. The CCRC will ensure that the nursing staff and the VA Code team have adequate education in PALS (Pediatric Advanced Life Support). All studies involving children
   
   
4. Research in children that is not approvable under 404, 405, 406
   
   THE CODE OF FEDERAL REGULATIONS 45 CFR 46 allows for pediatric research subject participation under an additional category:
   § 46.407 Research not otherwise approvable, which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. This research requires the review of the federal government.
   HHS will conduct or fund research that the IRB does not believe meets the requirements of §46.404, §46.405, or §46.406, only if:
   1. 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, and
   2. The Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law), and following opportunity for public review and comment, has determined either:
      1. That the research in fact satisfies the conditions of §46.404, §46.405, or §46.406, as applicable, or
      2. The following: (i) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (ii) the research will be conducted in accordance with sound ethical principles; (iii) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in §46.408.
         Weblink to §46.408:
         http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.408