### PURPOSE

The purpose of this policy is to describe the special contents required
in protocols of DAIDS-funded and/or sponsored human subjects clinical
research that include children. The requirement to submit these contents
in sufficient detail to the approving Institutional Review Board (IRB)/
Ethics Committee (EC) will assist the IRB/EC in ensuring that the study
is reviewed and conducted in accordance with applicable U.S. Federal
laws and regulations.

### SCOPE

> This policy applies to all DAIDS-funded and/or sponsored human subject
> clinical research that intends to enroll children (including
> adolescents) in clinical research.

### BACKGROUND

> DAIDS-funded and/or sponsored human subject clinical research may
> involve children in the U.S. and, increasingly, children who reside in
> international settings. A significant portion of DAIDS-funded and/or
> sponsored human subject clinical research includes multi-center and
> network studies requiring centralized development of study (protocol)
> documents that are subsequently reviewed by multiple IRBs/ECs at
> diverse institutions. In order to ensure that DAIDS-funded and/or
> sponsored human subject clinical research is in compliance with all
> applicable laws and regulations governing the enrollment of children,
> DAIDS has established requirements for protocol content and
> requirements for clinical research sites to maintain written site
> policies and procedures. This policy describes the protocol document
> requirements. A companion policy, *Policy for Enrolling Children
> (including Adolescents) in DAIDS-Funded and/or Sponsored Human Subject
> Clinical Research: Clinical Research Site Requirements,* describes
> required written site policies and procedures and responsibilities of
> the Protocol Team, IRB/EC, and the Principal Investigator (PI).

[U.S. Regulatory Requirements]{.underline}

> In addition to 45 CFR 46.111 *[Criteria for IRB Approval of
> Research]{.underline}* and 21 CFR 56.111 *[Criteria for IRB Approval
> of Research]{.underline}*, U.S. Federal regulations governing research
> in human subjects identify children as a vulnerable population and
> mandate additional scrutiny and protections prior to their involvement
> in research. These additional requirements found in 45 CFR 46 Subpart
> D and 21 CFR 50 Subpart D are described in this policy.

[Categories]{.underline}

> Three of the four categories of human research involving children may
> be approved by an IRB/EC. The four categories differ from one another
> according to the level of risk involved, the prospect of direct
> benefit to the research participants, and the anticipated research
> findings. For all four categories, the proposed research activity must
> satisfy the requirements for parental or guardian permission   and
> child assent. Depending on the category, additional conditions must be
> met in order for the IRB/EC to approve the research activities (see
> Appendix 1).

### DEFINITIONS

> [Advocate]{.underline}: An individual who has the background and
> experience to act in, and agrees to act in, the best interests of the
> child throughout the duration of the child's participation in the
> research and who is not associated in any way (except in the role as
> an advocate or member of the IRB/EC) with the research, the
> investigator(s), or the guardian organization. 45 CFR 46.409(b)
>
> [Assent]{.underline}: A child's affirmative agreement to participate
> in research. Mere failure to object should not, absent of affirmative
> agreement, be construed as assent. 45 CFR 46.402(b) and 21 CFR 50.3(n)
>
> [Children]{.underline}: Persons who have not attained the legal age
> for consent to treatments or procedures involved in research, under
> the applicable law of the jurisdiction in which the research will be
> conducted. 45 CFR 46.402(a) and 21 CFR 50.3(o)

[Clinical Investigation]{.underline}: Any experiment that involves a
test article and one or more human subjects and that either is subject
to the requirements for prior submission to the Food and Drug
Administration (FDA) under section 505(i) or 520(g) of the act, or is
not subject to the requirements for prior submission to the FDA under
these sections of the act, but the results of which are intended to be
submitted later to, or held for inspection by, the FDA as part of an
application for a research or marketing permit. 21 CFR 50.3(c)

> [DAIDS sponsored:]{.underline} DAIDS is responsible for the management
> (including submission of the Investigational New Drug Application
> (IND) to the Food and Drug Administration (FDA) and the initiation of
> the study) and oversight for the clinical trial or study.
>
> [DAIDS funded:]{.underline} DAIDS is providing financial support for
> the clinical trial or study.
>
> [Family Member]{.underline}: Any one of the following legally
> competent persons: Spouse; parents; children (including adopted
> children); brothers, sisters, and spouses of brothers and sisters; and
> any individual related by blood or affinity whose association with the
> subject is the equivalent of a family relationship. 21 CFR 50.3(m)
>
> [Federalwide Assurance (FWA)]{.underline}: The Federalwide Assurance
> (FWA) is the only type of assurance of compliance accepted and
> approved by the Office for Human Research Protections (OHRP) for
> institutions engaged in non-exempt human subjects research conducted
> or supported by the U.S. Department of Health and Human Services
> (DHHS). Under an FWA, an institution commits to DHHS that it will
> comply with the requirements set forth in 45 CFR 46, as well as the
> Terms of Assurance
>
> (see http://www.hhs.gov.ohrp/humansubjects/assurance/filasurt.htm).
> (OHRP)
>
> [Guardian]{.underline}: An individual who is authorized under
> applicable State or local law to consent on behalf of a child to
> general medical care. 45 CFR 46.402(e). An individual who is
> authorized under applicable State or local law to consent on behalf of
> a child to general medical care when general medical care includes
> participation in research. 21 CFR 50.3(s)
>
> [Minimal Risk]{.underline}: The probability and magnitude of harm or
> discomfort anticipated in the research are not greater in and of
> themselves than those ordinarily encountered in daily life or during
> the performance of routine physical or psychological examinations or
> tests.\
> 45 CFR 46.102(i) and 21 CFR 50.3(k)

[Parent]{.underline}: The child's biological or adoptive parent. 45 CFR
46.402(d) and 21 CFR 50.3(p)

> [Permission]{.underline}: The agreement of parent(s) or guardian to
> the participation of their child or ward in research. 45 CFR 46.402(c)
> and 21 CFR 50.3(r)
>
> [Principal Investigator (PI)]{.underline}: The qualified person
> designated by the applicant institution to direct the research. PIs
> oversee the scientific and technical aspects of a grant and the
> day-to-day management of the research. (NIAID)
>
> [Protocol]{.underline}: A document that describes the objective(s),
> design, methodology, statistical considerations, and organization of a
> trial. The protocol usually also gives the background and rationale
> for the trial, but these could be provided in other protocol
> referenced documents. ICH E6 1.44
>
> [Protocol Team]{.underline}: A team of individuals comprised of
> grantees, investigators, statisticians, and other protocol support
> personnel who work to develop concepts into DAIDS-funded and/or
> sponsored research studies. DAIDS medical officers maybe involved as
> members of this team. (DAIDS)
>
> [Ward]{.underline}: A child who is placed in the legal custody of the
> State or other agency, institution, or entity, consistent with
> applicable Federal, State, or local law. 21 CFR 50.3(q)
>
> *For additional definitions see DAIDS Glossary*

### RESPONSIBILITES

1.  The Protocol Team is responsible for providing sufficient detail in
    the protocol document to allow for the performance of a risk/benefit
    analysis and an assessment of the need for child assent.

2.  The IRB/REC identified on the Federalwide Assurance of the
    institution where the research will be conducted is responsible for
    the review of all clinical research enrolling children, determining
    if risks to subjects (in this case, children) are reasonable in
    relationship to anticipated benefits (in accordance with U.S. 45 CFR
    46.111 and Subpart D; 21 CFR 50, Subpart D, 21 CFR 56.109; 21 CFR
    56.111(2), and making the determination that adequate provisions for
    soliciting the assent of the child and permission of participants'
    parents or guardians are in place (as set forth in 45 CFR 46.408 and
    21 CFR 50.55). The IRB/REC is responsible for determining when each
    child or the children are capable of assent, when assent is not
    necessary or can be waived, and communicating its findings to the
    investigator. 45 CFR 6.408(a)

3.  The Principal Investigator (PI) is responsible for ensuring that
    written policies and procedures are developed and maintained at the
    clinical research site that ensure that the enrollment of children
    into clinical research is consistent with applicable laws and
    regulations regarding initial and ongoing parental or guardian
    permission and child assent, that such procedures are in compliance
    with local institutional and IRB/EC policies and procedures, and
    that they are consistently applied. The PI is also responsible for
    ensuring that DAIDS is informed of the IRB/EC determinations
    including risk/benefit analysis, IRB/EC approval of studies and
    amendments, and decisions regarding the need for child assent.

### POLICY

> In order to ensure that the requirements of 45 CFR 46 *[Subpart D
> Additional Protections for Children Involved as Subjects in
> Research]{.underline}* and 21 CFR 50 *[Subpart D Additional Safeguards
> for Children in Clinical Investigations]{.underline}* are satisfied,
> the Protocol Team will provide, in a section of the protocol, the
> following information required for the IRB/EC to review and approve
> the protocol.

1.  A description of the research activities in sufficient detail for
    the IRB/EC to determine into which of the four categories the
    research activity falls (see\
    Appendix 1);

    1.  The team will include a brief description of findings from
        previous related studies and justification in sufficient detail
        for the enrollment of children into the study.

2.  A discussion that would support an IRB/EC assessment that the risks
    to participants are reasonable in relation to the anticipated
    benefits (if any) to participants, and the importance of the
    knowledge that may reasonably be expected to result;

    1.  Considerations for risk/benefit in sufficient details for the
        IRB/EC to determine into which of the four categories the
        research activity falls (see Appendix 1)

    2.  Classifying a particular activity into one of these categories
        involves, among other things, determining whether the proposed
        research involves "minimal risk" to the participants. The
        Subpart D regulations rely on the definition of "minimal risk"
        provided in Subpart A of the regulations.

    3.  Determining that a research activity presents no more than
        minimal risk involves comparing the possible harms or
        discomforts experienced in normal daily life or during routine
        physical or psychological examinations or tests with the
        possible harms or discomforts that will be faced by participants
        as a consequence of research participation. The nature of the
        harms or discomforts (e.g., physical, psychological, legal)
        should be considered, as well as the chances that they will
        occur and the seriousness of their impact if they were to
        happen. Including measures to prevent or decrease the likelihood
        of harm or discomfort from the research may affect whether the
        proposed research activity involves no more than minimal risk.
        (See OHRP *FAQs on Research with Children.)*

3.  When the child reaches legal age of consent

    A description of the plan, where appropriate, for continuation of
    research participation when the child reaches legal age of consent;

    If a study involves children who may r/each the legal age of consent
    during their participation in the research, the Protocol Team will
    identify whether there is a need to obtain the legally effective
    informed consent for the now-adult subject. This may be appropriate,
    for example, when the research involves ongoing interactions or
    interventions with the participants after they have reached the
    legal age of consent. Also, when a child who was enrolled in
    research with parental or guardian permission subsequently reaches
    the legal age of consent to the procedures involved in ongoing
    research, the participant's participation in the research is no
    longer regulated by the requirements of Subpart D regarding parental
    or guardian permission and subject assent. (See OHRP *FAQs on
    Research with Children* and DAIDS *Policy for Enrolling Children
    (including Adolescents) in DAIDS-Funded and/or Sponsored Human
    Subject Clinical Research: Clinical Research Site Requirements*.)

4.  A description of the plan for obtaining informed consent from other
    individuals in addition to enrolled children, such as parents or
    family members who are human subjects in the research;

    When family members of children enrolled in the research are asked
    to provide identifiable private information about themselves for
    research purposes, these individuals are considered human subjects
    in the research and they must also give their informed consent
    unless the IRB/EC finds and documents the criteria for waiver of
    informed consent to be met.

5.  A description of the legal status of children without parents or who
    are not in the custody of their parents in the jurisdiction of the
    research, and plans for determining who can serve as a legal
    guardian in that jurisdiction for the purpose of providing
    permission for research participation;

6.  Any additional conditions for certain research activities involving
    children who are wards of the State or any other agency,
    institution, or entity (see Appendix 3)

> For research in categories 45 CFR 46.406, 21 CFR 50.53, 45 CFR 46.407,
> and 21 CFR 50.54, additional requirements must be met when research
> involves wards. For research approved under categories 45 CFR 46.404,
> 21 CFR 50.51, 45 CFR 46.405, and 21 CFR 50.52, there are no additional
> requirements when the research involves wards as participants (see
> Appendix 3).

7.  Recommendations for obtaining parental or guardian permission

    The Protocol Team will make recommendations for obtaining parental
    or guardian permission based upon the regulations at 45 CFR 46.408
    and 21 CFR 50.55 and in accordance with written IRB/EC approved
    policies. (See Appendix 1 and DAIDS *Policy for Enrolling Children
    (including Adolescents) in DAIDS-Funded and/or Sponsored Human
    Subject Clinical Research: Clinical Research Site Requirements.)*

```{=html}
<!-- -->
```
8.  Waiver of parental/guardian permission

    If a waiver of parental/guardian permission is to be requested in
    accordance with the provisions at 45 CFR 46.116(c) or 46.116(d), the
    Protocol Team should make every effort to provide sufficient detail
    in the protocol to justify the waiver. In accordance with the
    regulations, the IRB/EC must find and document that the criteria for
    the waiver are met.

> NOTE: The provisions for waiver of parental/guardian permission in
> U.S. Food and Drug Administration (FDA) regulated clinical
> investigations are limited to 21 CFR 50.23, *Exception from General
> Requirements* and 21 CFR 50.24, *Exception from Informed Consent
> Requirements for Emergency Research*.
>
> When the research is not FDA-regulated and does not meet the
> requirement for the waiver under 45 CFR 46.116(c) or 46.116(d), the
> IRB/EC may waive the requirements for obtaining parental/guardian
> permission if it determines that the research protocol is designed for
> a condition or for a subject population for which parental/guardian
> permission is not a reasonable requirement, to protect participants
> provided an appropriate mechanism for protecting the children who will
> participate in the research is substituted. In addition, the waiver
> must be consistent with Federal, State or local law (see 45 CFR
> 46.408(c)).
>
> The conditions under which parental permission may be waived and
> examples of substitute protection mechanisms can be found in Appendix
> 2. An example of when waiver of parental/guardian permission may be
> appropriate would be the conduct of a non-FDA regulated study of
> abused children.

9.  Waiver of documentation of parental/guardian permission

> If the Protocol Team seeks to waive documentation of parental/guardian
> permission, they must include sufficient details in the protocol
> documents for the IRB/EC to make the findings for approval of the
> waiver.
>
> In accordance with 45 CFR 46.117(c)(2) and 21 CFR 56.109(c) the IRB/EC
> may waive the requirements for documentation of parental/guardian
> permission for research that presents no more than minimal risk of
> harm to participants and involves no procedure for which written
> consent is normally required outside of the research context. However,
> the IRB/EC may require the PI to provide parents/guardians with a
> written statement regarding the research.
>
> In addition, for non-FDA regulated clinical investigations, if the
> only record linking the child and the research would be the assent
> document and the principal risk would be potential harm resulting from
> a breach in confidentiality, then the documentation of
> parental/guardian permission can be waived. Each parent/guardian will
> be asked whether they want documentation linking the child with the
> research and the parent/guardian's wishes will govern. However, the
> IRB/EC may require the PI to provide parents/guardians with a written
> statement regarding the research. See 45 CFR 46.117(c)(1)
>
> NOTE: Studies that are subject to FDA regulation are not eligible for
> a waiver of documentation of parental/guardian permission unless they
> meet the criteria at 21 CFR 50.27 or 21 CFR 56.109(c).

10. Child Assent

    6.8.1 The protocol document will include a statement as to whether
    eligible children could be capable of providing assent and if so,
    indicate that the IRB/EC-approved process for obtaining and
    documenting the child's assent will be followed. Local laws
    regarding the age to give consent, circumstances under which
    children may act as adults and identification of responsible persons
    for orphan children vary from place to place. The IRB/EC-approved
    process will take into account the age, maturity, and psychological
    state of the children involved in the research (see DAIDS *Policy
    for Enrolling Children (including Adolescents) in DAIDS-Funded
    and/or Sponsored Human Subject Clinical Research: Clinical Research
    Site Requirements*).

> These provisions may be made for all children involved in the research
> or for each child as deemed appropriate by the IRB/EC. A study that
> may enroll children over a wide age range is an example of a study
> that may have different assent requirements.

1.  For eligible children who are adolescents, the assent requirements
    would more closely resemble that of an adult consent process.

2.  Where children are less mature or of an age that limits their
    ability to understand, the process would involve more description of
    what the actual experience of participation in research is likely to
    be, how long it will take, or whether it might involve any pain or
    discomfort.

```{=html}
<!-- -->
```
11. Waiver of Child Assent

> The Protocol Team may request a waiver of assent from the IRB/EC if
> one of the three following circumstances is met (see Appendix 2):

1.  the capability of some or all of the children is so limited that
    they cannot reasonably be consulted;

2.  the intervention or procedure involved holds out the prospect of
    direct benefit to the health or well-being of the child and is only
    available in the research (they may document this determination and
    submit it to the IRB/EC for approval);

3.  the research meets the same conditions as those for waiver or
    alteration of informed consent in research involving adults, as
    specified in the regulations at either 45 CFR 46.116(c) or 45 CFR
    46.116(d).

```{=html}
<!-- -->
```
12. Research that is otherwise exempt from IRB/EC review:

The Protocol Team must take into account that some research activities
that would be exempt if the research participants were adults requires
IRB/EC review if the research activities involve children (45 CFR
46.101(b) and 21 CFR 56.104).

Examples of research **not** exempt from IRB/EC review when conducted in
children include:

-   surveys;

-   interviews; and

-   research involving public observation when the PI participates in
    the activities being observed.

### REFERENCES

> Code of Federal Regulations, Title 45, Part 46 Protection of Human
> Subjects
>
> <http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm>
>
> Code of Federal Regulations, Title 45, 46 Subpart D, Additional
> Protections for Children Involved as Subjects in Research
>
> <http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm>
>
> Code of Federal Regulations, Title 21, Part 50 Protection of Human
> Subjects
>
> <http://www.access.gpo.gov/nara/cfr/waisidx_06/21cfr50_06.html>
>
> Code of Federal Regulations, Title 21, Part 50 Subpart D, Additional
> Safeguards for Children in Clinical Investigations
>
> <http://www.access.gpo.gov/nara/cfr/waisidx_06/21cfr50_06.html>
>
> 21 CFR 56, Institutional Review Boards
>
> <http://www.access.gpo.gov/nara/cfr/waisidx_06/21cfr56_06.html>
>
> Office for Human Research Protections (OHRP) *FAQs on Research with
> Children*
>
> <http://www.hhs.gov/ohrp/policy/index.html#children>
>
> Federal Register: April 24, 2001 (Volume 66, Number 79) Additional
> Safeguards for Children in Clinical Investigations of FDA-regulated
> Products\
> <http://www.fda.gov/OHRMS/DOCKETS/98fr/042401a.pdf>
>
> DAIDS *Policy for Enrolling Children (including Adolescents) in
> DAIDS-Funded and/or Sponsored Human Subject Clinical Research:
> Clinical Research Site Requirements*

### INQUIRIES

> Questions and comments regarding this policy may be directed to the
> OPCRO Policy Group at: <NIAIDOPCROPOLICYGROUP@mail.nih.gov>

### AVAILABILITY

> This policy is available electronically at the following URL:
> <http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/Default.htm>

### CHANGE SUMMARY

This policy is the first version. It does not supersede any other
version.

### APPENDICIES

-   Appendix 1 Risk/Benefit Categories

-   Appendix 2 Waivers of Parental/Guardian Permission or Child Assent

-   Appendix 3 Wards

-   Appendix 4 Examples of Templated Language

### APPROVAL

/Dr. Richard Hafner, MD/

Richard Hafner