SUBPART D: ADDITIONAL DHHS PROTECTIONS FOR CHILDREN INVOLVED AS SUBJECTS IN RESEARCH


	º46.401 To what do these regulations apply?
46.401(a) To all DHHS supported research on children	(a) This subpart applies to all research involving children as subjects, conducted or supported by the Department of Health and Human Services.
46.401(a)(1) Includes research conducted by DHHS employees	(1) This includes research conducted by Department employees, except that each head of an Operating Division of the Department may adopt such nonsubstantive, procedural modifications as may be appropriate from an administrative standpoint.
46.401(a)(2) Includes foreign research. Provisions in subpart A may be applied	(2) It also includes research conducted or supported by the Department of Health and Human Services outside the United States, but in appropriate circumstances, the Secretary may, under paragraph (i) of º46.101 of Subpart A, waive the applicability of some or all of the requirements of these regulations for research of this type.
46.401(b) Research exemptions apply except for the exemption for survey, interview or observation research	(b) Exemptions at º46.101(b)(1) and (b)(3) through (b)(6) are applicable to this subpart. The exemption at º46.101(b)(2) regarding educational tests is also applicable to this subpart. However, the exemption at º46.101(b)(2) for research involving survey or interview procedures or observations of public behavior does not apply to research covered by this subpart, except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed.
46.401(c) Other provisions of Subpart A section 101 also apply	(c) The exceptions, additions, and provisions for waiver as they appear in paragraphs (c) through (i) of º46.101 of Subpart A are applicable to this subpart.

	º46.402 Definitions.
46.402 Definitions from subpart A apply. Additional definitions for this subpart:	The definitions in º46.102 of Subpart A shall be applicable to this subpart as well. In addition, as used in this subpart:
46.402(a) Children	(a) "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.
46.402(b) Assent	(b) "Assent" means a child's affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent
46.402(c) Permission	(c) "Permission" means the agreement of parent(s) or guardian to the participation of their child or ward in research.
46.402(d) Parent	(d) "Parent" means a child's biological or adoptive parent
46.402(e) Guardian	(e) "Guardian" means an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care.

	º46.403 IRB duties.
46.403 IRB may approve covered research only if it meets the conditions of this subpart	In addition to other responsibilities assigned to IRBs under this part, each IRB shall review research covered by this subpart and approve only research which satisfies the conditions of all applicable sections of this subpart.

	º46.404 Research not involving greater than minimal risk.
46.404 Minimal risk research may be conducted if appropriate assent and permission will be obtained	DHHS 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 º46.408.

	º46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects.
46.405 Research involving greater than minimal risk but with the prospect of benefit to the subject may be conducted if the IRB finds:	DHHS 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:
46.405(a) Risk is justified by the benefit	(a) the risk is justified by the anticipated benefit to the subjects;
46.405(b) Risk/benefit ratio is at least as favorable as with alternative approaches, and	(b) 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
46.405(c) Appropriate permission and assent will be obtained	(c) adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth in º46.408.

	º46.406 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.
46.406 Research with greater than minimal risk and no prospect of benefit to subjects may be conducted only if the IRB finds that:	DHHS 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:
46.406(a) Risk is a minor increase over minimal	(a) the risk represents a minor increase over minimal risk;
46.406(b) Experiences of subjects will be commensurate with their actual situations	(b) 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;
46.406(c) Generalizable knowledge of vital importance is likely to be gained	(c) 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
46.406(d) Appropriate permission and assent will be obtained	(d) adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in º46.408.

	º46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.
46.407 Research that cannot be approved under the previous sections may be conducted if:	DHHS will conduct or fund research that the IRB does not believe meets the requirements of º46.404, º46.405, or º46.406 only if:
46.407(a) The IRB finds the research may further understanding of a serious problem, and	(a) 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
46.407(b) The Secretary has determined either:	(b) 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:
46.407(b)(1) That the research is permissible under the conditions of previous sections, or	(1) that the research in fact satisfies the conditions º46.404, º46.405, or º46.406, as applicable, or
46.407(b)(2) The following are true;	(2) the following:
46.407(b)(2)(i) The research may further understanding of a serious problem	(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;
46.407(b)(2)(ii) Sound ethical principles will apply	(ii) the research will be conducted in accordance with sound ethical principles;
46.407(b)(2)(iii) Appropriate permission and assent will be obtained	(iii) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in º46.408.

	º46.408 Requirements for permission by parents or guardians and for assent by children.
46.408(a) The IRB will determine that provisions for obtaining the child’s assent are adequate. Factors to consider in requiring assent. Assent requirement may be waived under some circumstances.	(a) In addition to the determinations required under other applicable sections of this subpart, the IRB shall determine 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. In determining whether children are capable of assenting, the IRB shall take into account the ages, maturity, and psychological state of the children involved. This judgment may be made for all children to be involved in research under a particular protocol, or for each child, as the IRB deems appropriate. 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 under circumstances in which consent may be waived in accord with º46.116 of Subpart A.
46.408(b) The IRB will determine that adequate provisions are made for soliciting the permission of each child's parents or guardian	(b) In addition to the determinations required under other applicable sections of this subpart, the IRB shall determine, in accordance with and to the extent that consent is required by º46.116 of Subpart A, that adequate provisions are made for soliciting the permission of each child's parents or guardian. Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient for research to be conducted under º46.404 or º46.405. Where research is covered by º46.406 and º46.407 and permission is to be obtained from parents, 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.
46.408(c) The IRB may waive requirement for parental permission under certain circumstances	(c) In addition to the provisions for waiver contained in º46.116 of Subpart A., if the IRB determines that a research protocol is designed for conditions or for a subject population for which parental or guardian permission is not a reasonable requirement to protect the subjects (for example, neglected or abused children), it may waive the consent requirements in Subpart A of this part and paragraph (b) of this section, provided an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and provided further 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, the risk and anticipated benefit to the research subjects, and their age, maturity, status, and condition.
46.408(d) Parental permission must be appropriately documented	(d) Permission by parents or guardians shall be documented in accordance with and to the extent required by º46.117 of Subpart A.
46.408(e) When assent is required, the IRB will determine how it will be documented	(e) When the IRB determines that assent is required, it shall also determine whether and how assent must be documented.

	º46.409 Wards.
46.409(a) Children who are wards may be included only if the research is:	(a) Children who are wards of the State or any other agency, institution, or entity can be included in research approved under º46.406 or º46.407 only if such research is:
46.409(a)(1) Related to their status as wards, or	(1) related to their status as wards; or
46.409(a)(2) Conducted in settings in which most children participating are not wards	(2) conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards.
46.409(b) For permissible research with wards, an advocate will be appointed to act in the best interests of the child	(b) If the research is approved under paragraph (a) of this section, the IRB shall 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. One individual may serve as advocate for more than one child. The advocate shall 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.