NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

Release Date:  March 6, 1998

P.T.

National Institutes of Health

SUMMARY:  With this notice, the National Institutes of Health (NIH) establishes
guidelines on the inclusion of children in research involving human subjects,
including, but not limited to, clinical trials, supported or conducted by the
NIH.

EFFECTIVE DATE:  This policy applies to all initial (Type 1) applications/
proposals and intramural projects submitted for receipt dates after October 1,
1998.

I. Introduction

This document sets forth the policy and guidelines on the inclusion of children
in  research involving human subjects that is supported or conducted by the
National Institutes of Health (NIH).  The goal of this policy is to increase the
participation of children in research so that adequate data will be developed to
support the treatment modalities for disorders and conditions that affect adults
and may also affect children.  For the purposes of this NIH policy, studies
involving human subjects include categories of research that would otherwise be
exempted from the DHHS Policy for Protection of Human Research Subjects.  These
categories of research are exempted from the DHHS policy because they pose
minimal risk to the participants, and not because the studies should not include
children.  Examples of such research include surveys, evaluation of educational
interventions, and studies of existing data or specimens that should include
children as participants.  Nevertheless, the inclusion of children as
participants in research must be in compliance with all applicable subparts of
45 CFR 46 as well as with other pertinent federal laws and regulations whether
or not the research is otherwise exempted from 45 CFR 46.

II. Background

The policy was developed because medical treatments applied to children are often
based upon testing done only in adults, and scientifically evaluated treatments
are less available to children due to barriers to their inclusion in research
studies.  These concerns were specifically articulated in Congressional
directives to the NIH as reflected in language from the FY 1996 House and Senate
Appropriations Committee reports as follows:

HOUSE

The Committee is concerned that inadequate attention and resources are devoted
to pediatric research conducted and supported by the National Institutes of
Health.  Most research on the cause, treatment and cure of diseases which affect
children rely primarily on adults as subjects in clinical trials.  Consequently,
treatment options which may be effective for adults can have an adverse impact
on the outcome of children as well as on their future growth and development. 
The Committee strongly encourages the NIH to strengthen its portfolio of basic,
behavioral and clinical research conducted and supported by all of its relevant
Institutes, to establish priorities for pediatric research, and to ensure the
adequacy of translational research from the laboratory to the clinical setting. 
The Committee encourages the NIH to establish guidelines to include children in
clinical research trials conducted and supported by NIH.  The Committee expects
NIH to develop performance indicators to measure specific progress on the above,
demonstrated by the development of new programs or strengthening of existing
programs and to report to the Committee prior to the 1997 appropriations hearings
(H.R. Report No. 209, 104th Congress, 1st session, 80-81, 1995).  

SENATE

Pediatric research---The Committee recognizes the substantial benefits that
biomedical research offers to the health and well-being of our Nation's children. 
Savings from productive innovations in health care, derived from scientific
investigations of the highest quality, can be significant in terms of dollars and
quality of life for children.  The opportunities for advancements in the
prevention and treatment of diseases which affect children or begin in childhood
have never been greater.  The Committee intends to work with the Office of the
Director as it explores ways to take advantage of such opportunities and
strengthen the NIH's capacity to support and encourage extramural pediatric
research.  Of particular interest is the establishment of guidelines to include
children in clinical research trials conducted and supported by the NIH (S.
Report No. 145, 104th Congress, 1st session, 112, 1995).

In June 1996, the National Institute of Child Health and Human Development
(NICHD) and the American Academy of Pediatrics convened a workshop to address the
inclusion of children as participants in research.  After reviewing reports,
background papers, and a study of a sample of NIH-sponsored clinical research
abstracts that suggested that 10-20% inappropriately excluded children, the
conveners concluded that there is a need to enhance the inclusion of children in
clinical research.  This conclusion is based upon scientific information,
demonstrated human need, and considerations of justice for children in receiving
adequately evaluated treatments.  The need reaches across a broad spectrum of
clinical research, including studies on pharmaceutical and therapeutic agents,
behavioral, developmental and life cycle issues including childhood antecedents
of adult disease, and prevention and health services research.

The American Academy of Pediatrics has reported that only a small fraction of all
drugs and biological products marketed in the U.S. have had clinical trials
performed in pediatric patients and a majority of marketed drugs are not labeled
for use in pediatric patients.  Many drugs used in the treatment of both common
childhood illnesses and more serious conditions carry little information in the
labels about use in pediatric patients.  In order to address these inadequacies,
the Food and Drug Administration (FDA) has published (http://www.fda.gov/) a
proposed regulation calling for changes in the testing of prescription drugs to
ensure that manufacturers specifically examine the drugs effects on children if
the medications are to have clinically significant use in children.

In January 1997 the NIH announced (NIH Guide for Grants and Contracts, volume 26,
Number 3, January 31, 1997) plans to develop a policy for the inclusion of
children in NIH-supported human subject research.  This publication fulfills the
goal of the announced plan.

III.  Policy

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. This
policy applies to all NIH conducted or supported research involving human
subjects, including research that is otherwise "exempt" in accord with Sections
101(b) and 401(b) of 45 CFR 46 - Federal Policy for the Protection of Human
Subjects.  The inclusion of children as subjects in research must be in
compliance with all applicable subparts of 45 CFR 46 as well as with other
pertinent federal laws and regulations.  Therefore, proposals for research
involving human subjects must include a description of plans for including
children.  If children will be excluded from the research, the application or
proposal must present an acceptable justification for the exclusion.  

In the research plan, the investigator should create a section titled
"Participation of Children".  This section should provide either a description
of the plans to include children and a rationale for selecting or excluding a
specific age range of child, or an explanation of the reason(s) for excluding
children as participants in the research.  When children are included, the plan
must also include a description of the expertise of the investigative team for
dealing with children at the ages included, of the appropriateness of the
available facilities to accommodate the children, and the inclusion of a
sufficient number of children to contribute to a meaningful analysis relative to
the purpose of the study.  Scientific review groups at the NIH will assess each
application as being "acceptable" or "unacceptable" in regard to the age-
appropriate inclusion or exclusion of children in the research project, in
addition to evaluating the plans for conducting the research in accord with these
provisions.  

Justifications for Exclusions

It is expected that children will be included in all research involving human
subjects unless one or more of the following exclusionary circumstances can be
fully justified: 

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.  For example, the regulations for protection of human subjects allow
consenting adults to accept a higher level of risk than are permitted for
children. 

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.  NIH program staff can be contacted for guidance on this issue if the
information is not readily available.

4.  A separate, age-specific study in children is warranted and preferable. 
Examples include:

a.  The relative rarity of the condition in children, as compared to adults (in
that   extraordinary effort would be needed to include children, although in rare 
diseases or disorders where the applicant has made a particular effort to
assemble an adult population, the same effort would be expected to assemble a
similar child population with the rare condition);

b.  The number of children is limited because the majority are already accessed 
by a nationwide pediatric disease research network, so that requiring inclusion
of children in the proposed adult study would be both difficult and unnecessary
(in that the topic was already being addressed in children by the network) as
well as potentially counterproductive (in that fewer children could be available
for the network study if other studies were required to recruit and include
them);

c.  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
(in which case one of the research objectives could be to obtain sufficient adult
data to make this judgment).  While children usually should not be the initial
group to be involved in research studies, in some instances, the nature and
seriousness of  the illness may warrant their participation earlier based on
careful risk and benefit analysis.

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
review group and the Institute Director.

IV.  Implementation

A.  Date of Implementation

This policy applies to all initial applications (Type 1)/proposals and intramural
projects submitted for receipt dates after October 1, 1998.

B.  Roles and Responsibilities

This policy applies to all NIH-conducted or -supported research involving human
subjects.  Certain individuals and groups have special roles and responsibilities
with regard to the adoption and implementation of these guidelines.

1.  Principal Investigators

Principal investigators should assess the scientific rationale for inclusion of
children in the context of the topic of the study.  Questions that should be
considered in developing a study involving human subjects may include, but are
not limited to, the following:  When is the exclusion of children appropriate? 
Under what circumstances is it appropriate?  At what ages is it appropriate?  The
principal investigator should address the policy in the application, providing
the required information on participation of children in research projects, and
required justifications for any exceptions allowed under the policy in the
research plan under a section titled "Participation of Children".

2.  Institutional Review Boards (IRBs)

The IRB addresses the appropriateness of the population studied in terms of the
aims of the research and ethical standards.  IRBs have the responsibility to
examine ethical issues, including equitable selection of research participants
in accordance with Federal Regulations (45 CFR 46)  The participation of children
in research, including children of both genders and children from minority
groups, is important to assure that they receive a share of the benefits of
research.  IRBs have special review requirements (45 CFR 46, Subpart D, Sec.
401-409) to protect the well-being of children who participate in research.  IRBs
may approve research involving children only if the special provisions are met.

3.  Scientific Review Groups

In conducting peer review of applications/proposals for scientific and technical
merit, appropriately constituted scientific review groups, technical evaluation
groups, and intramural review panels will evaluate the proposed plan for
inclusion or exclusion of children as acceptable or unacceptable.  Therefore,
these groups must include appropriate expertise in research involving children
to make the evaluation.

4.  Institute/Center Obligations

Following scientific review and Council review, Institute/Center Directors and
their staff shall determine whether:  (a) the research involves human subjects,
and (b) the inclusion or exclusion of children meets the requirements of the
policy.  Program staff should assess exceptions to this policy in view of the IC
research portfolio.

5.  Educational Outreach by NIH to Inform the Professional Community

NIH staff will present these guidelines to investigators, IRB members, peer
review groups, and Advisory Councils in a variety of public forums.

6.  Applicability to Foreign Research Involving Human Subjects

The policy of inclusion of children in NIH-conducted or supported research
activities in foreign countries (including collaborative activities) is the same
as that for research conducted in the U.S. 

V.  Definitions

For the purpose of implementing these guidelines, the following definitions
apply.

A.  Child

For purposes of this policy, a child is an individual under the age of 21 years. 
This policy and definition do not affect the human subject protection regulations
for research on children (45 CFR 46) and their provisions for assent, permission,
and consent, which remain unchanged. 

It should be noted that the definition of child described above will pertain
notwithstanding the FDA definition of a child as an individual from infancy to
16 years of age, and varying definitions employed by some states.  Generally,
State laws define what constitutes a "child," and such definitions dictate
whether or not a person can legally consent to participate in a research study. 
However, State laws vary, and many do not address when a child can consent to
participate in research.  Federal Regulations (45 CFR 46, subpart D, Sec.401-409)
address DHHS protections for children who participate in research, and rely on
State definitions of "child" for consent purposes.  Consequently, the children
included in this policy (persons under the age of 21) may differ in the age at
which their own consent is required and sufficient to participate in research
under State law.  For example, some states consider a person age 18 to be an
adult and therefore one who can provide consent without parental permission.  

Additionally, IRBs have special review requirements to protect the well-being of
children who participate in research. These requirements relate to risk, benefit,
parental/guardian consent, and assent by children, and to research involving
children who are wards of the State or of another institution. The local IRB 
approves research that satisfies the conditions set forth in the regulations.  


B.  Human Subjects

The definition of a human subject appears in Title 45 part 46 of the Department
of Health and Human Services Regulations for the Protection of Human Subjects and
is as follows: "Human subject means a living individual about whom an
investigator (whether professional or student) conducting research obtains:  (1)
Data through intervention or interaction with the individual, or (2) identifiable
private information."

VI.  Decision Tree for Participation of Children in Research
The inclusion of children in research is a complex and challenging issue.  
Nonetheless,  it also presents the opportunity for researchers to address the
concern that treatment modalities used to treat children for many diseases and
disorders are based on research conducted with adults.   The linked "decision tree"
is intended to facilitate the determination of policy implementation
by principal investigators and reviewers with regard to the inclusion of children
in research involving human subjects.


VII.  Additional Requirements for Research that Includes Children

The following chart summarizes the additional requirements under the DHHS
Regulations 45 CFR 46, Subpart D based on the risks and benefits to children who
participate in research: 
Types of Research                               Requirements

No greater than minimal risk                    Assent of child and permission
                                                of at least one parent

Greater than minimal risk AND                   Assent of child and permission 
prospect of direct benefit                      of at least one parent

                                                Anticipated benefit justifies the
                                                risk, AND

                                                Anticipated benefit is at least
                                                as favorable as that of
                                                alternative approaches.

Greater than minimal risk and                   Assent of child and permission 
no prospect of direct benefit                   of both parents

                                                Only a minor increase over
                                                minimal risk

                                                Likely to yield generalizable
                                                knowledge about the child's
                                                disorder or condition that is of
                                                vital importance for the
                                                understanding or amelioration of
                                                the disorder or condition, AND

                                                The intervention or procedure  
                                                presents experiences to the child
                                                that are reasonably commensurate
                                                with those in the child's actual
                                                or expected medical, dental,   
                                                psychological, social, or
                                                educational situations

Any other research                              Assent of child and permission 
                                                of both parents

                                                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

                                                The Secretary approves, after
                                                consultation with a panel of
                                                experts in pertinent disciplines
                                                (e.g., science, medicine,
                                                education, ethics, law) and
                                                following publication and public
                                                comment
 
VIII.  NIH Contacts for More Information

The following senior extramural staff from the NIH Institutes and Centers may be
contacted for further information about the policy and relevant Institute/Center
programs:

The following senior extramural staff from the NIH Institutes and Centers may be
contacted for further information about the policy and relevant Institute/Center
programs:

Dr. Marvin Kalt
National Cancer Institute Executive Plaza North, Room 600C, 6130 Executive
Boulevard,  Bethesda, Maryland  20892. Tel: (301) 496-5147. e-mail: mk74s@nih.gov

Dr. Jack McLaughlin, National Eye Institute, Executive Plaza South, Room 350,
6120 Executive Boulevard, Bethesda, Maryland 20892. Tel: (301) 496-9110. e-mail: 
jm82p@nih.gov

Dr. Ron Geller, National Health, Lung and Blood Institute, Rockledge Center 2,
Room 7100, 6701 Rockledge Drive, Bethesda, Maryland 20892. Tel: (301) 435-0260.
e-mail: rg33k@nih.gov

Dr. Mark Guyer, National Human Genome Research Institute, Building 38A, Room 604,
38 Library Drive, Bethesda, Maryland 20892. Tel: (301) 402-5407. e-mail:
mg25m@nih.gov

Dr. Miriam Kelty, National Institute on Aging, Gateway Building, Room 2C218F,
7201 Wisconsin Avenue, Bethesda, Maryland 20892. Tel: (301) 496-9322. e-mail: 
mk46u@nih.gov

Dr. Kenneth Warren, National Institute on Alcohol Abuse and Alcoholism, Room 409,
MSC 7003, 6000 Executive Boulevard, Bethesda, Maryland 20892-7003. Tel: (301)
443-4375.  e-mail:  kw46m@nih.gov

Dr. John McGowan, National Institute of Allergy and Infectious Diseases, Solar
Building, Room 3C20, 6003 Executive Boulevard, Bethesda, Maryland 20892. Tel:
(301) 496-7291. e-mail: jm80c@nih.gov

Dr. Steven Hausman, National Institute of Arthritis and Musculoskeletal and Skin
Diseases, Building 31, Room 4C32, 31 Center Drive, Bethesda, Maryland 20892. Tel:
(301) 402-1691. 
e-mail: sh41g@nih.gov

Dr. Yvonne Maddox, National Institute of Child Health and Human Development,
Building 31, Room 2A03, 31 Center Drive, Bethesda, Maryland 20892. Tel: (301)
496-1848. e-mail: ym16x@nih.gov

Dr. Craig Jordan, National Institute of Deafness and Other Communication
Disorders, Executive Plaza South, Room 400C, 6120 Executive Boulevard, Bethesda,
Maryland 20892. Tel: (301) 496-8693. e-mail: cj34b@nih.gov

Dr. Lois Cohen, National Institute on Dental Research, Building 45, Room 4AN18E,
45 Center Drive, Bethesda, Maryland 20892. Tel: (301) 594-7710. e-mail:
lc85n@nih.gov

Dr. Walter Stolz, National Institute of Diabetes and Digestive and Kidney
Diseases, Building 45, Room 6AS25C, 45 Center Drive, MSC 6600, Bethesda, Maryland
20892-6600. Tel: (301) 594-8834. e-mail: ws23e@nih.gov

Dr. Teresa Levitin, National Institute on Drug Abuse, Parklawn Building, Room 10-
42, 5600 Fishers Lane, Rockville, Maryland 20857. Tel (301) 443-2755. e-mail:
tl25u@nih.gov

Dr. Anne Sassaman, National Institute of Environmental Health Sciences, Building
3, Room 301, P.O. Box 12233, Research Triangle Park, North Carolina, 27709. Tel:
(919) 541-7723. e-mail: as56j@nih.gov

Dr. Sue Shafer, National Institute of General Medical Sciences, Building 45, Room
2AN32D, 45 Center Drive, MSC 6200, Bethesda, Maryland, 20892-6200. Tel: (301)
594-4499. e-mail: ss78v@nih.gov

Dr. Richard Nakamura, National Institute of Mental Health, Parklawn Building,
Room 17C-26, 5600 Fishers Lane, Rockville, Maryland 20857. Tel: (301) 443-4335.
e-mail: rn3p@nih.gov

Dr. Constance Atwell, National Institute of Neurological Disorders and Stroke,
Federal Building, Room 1016, 7550 Wisconsin Avenue, Bethesda, Maryland 20892.
Tel: (301) 496-9248. e-mail: ca23c@nih.gov

Dr. Mary Leveck, National Institute of Nursing Research, Building 45, Room 3AN12,
45 Center Drive,  MSC 6300,  Bethesda, Maryland, 20892-6300. Tel: (301) 594-5963.
e-mail: ml118t@nih.gov

Dr. Louise Ramm, National Center for Research Resources, Building 31, Room 3B11,
31 Center Drive, Bethesda, Maryland 20892. Tel: (301) 496-6023. e-mail:
lr34m@nih.gov

Dr. Kenneth Bridbord, Fogarty International Center, Building 31, Room B2C39, 31
Center Drive, Bethesda, Maryland 20892. Tel: (301) 496-2516. e-mail:
kb16r@nih.gov


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