The NIH has developed the following Questions and Answers to facilitate implementation of the Policy on the Inclusion of Children in Research Involving Human Subjects. These Q's and A's are prepared to provide guidance to NIH staff, advisory groups, and the extramural community as they consider the policy and associated issues.

The Questions and Answers are grouped in the following categories:

• Overview and Policy:  Q/A 1- 13
• Application Preparation:  Q/A 14-29
• Review of Applications/Proposals:  Q/A 30-35
• Funding:  Q/A 36-42
• Appendix 1: Scientific Review Group (SRG) Codes for Inclusion of Children as Participants in Research

1. Why is a policy being developed to promote the inclusion of children in research?

NIH and members of Congress are concerned about using treatments for children that are based on data from research conducted on adults, without adequate research data from children. To explore this issue and possible remedies, NIH held a workshop in June 1996, cosponsored by the American Academy of Pediatrics. Participants of the workshop recommended that NIH develop a policy for promoting the age-appropriate participation of children in research.

NIH has developed and moved to implement a policy stipulating that when there is sound scientific rationale for including children in research involving adult human subjects, investigators will be expected to include them, unless there is a strong justification for their exclusion. Although the scientific rationale for this policy is similar to that of the policy for inclusion of women and minorities in research, this policy does not mandate the inclusion of children in all research involving human subjects, because the issues and sensitivities surrounding the age-appropriate participation of children in research are different from those for women and minorities.

2. What is the purpose of the policy?

The aim of the policy is to collect meaningful data on children, relative to the purpose of the study.

3. What is the potential impact of this policy?

This policy promotes the participation of children in projects where their involvement is scientifically and ethically warranted. In 1996, the National Institute of Child Health and Human Development (NICHD) reviewed a sample of NIH-supported clinical research abstracts. The results suggested that 10-20% of the projects inappropriately excluded children.

4. What is the definition of a child?

For the purposes of this policy a child is an individual under the age of 21. This definition covers the age range from birth to age 21 and spans the period when many individuals are still within the education system and are dependent on their families.

5. Does the policy change in any way the scope of research that can be studied with children as research subjects?

There have been no changes in the regulations for involving children as participants in research. The new policy is designed to increase the opportunity for children to participate in research studies when their participation benefits children and is appropriate under existing Federal guidelines.

6. What changes will be required in order to implement the policy?

The development and implementation of the policy will require adjustments in administrative mechanisms and the education and preparation of parents, the scientific community, institutional review boards, scientific review groups, other advisory bodies, and NIH extramural and intramural program staff. Appropriate expertise will be needed on a broad range of scientific review panels as well as in intramural review to ensure that the inclusion or exclusion of children is well supported scientifically, does not deviate from ethical practices regarding children, and the research methods are appropriate.

7. When will the policy be implemented?

NIH published an announcement on this policy in the January 31, 1997 issue of the Guide to Grants and Contracts, Volume 26, Number 3, and also placed the announcement on its World Wide Web page to solicit input. The final policy was published on March 6, 1998, and will be applicable to all initial (type 1) applications/proposals and intramural projects submitted for receipt dates after October 1, 1998.

8. Once implemented, does this policy apply to research that has been previously reviewed and funded? Does this policy apply to competing research that was received prior to the implementation date, but not yet funded?

This policy applies to initial applications submitted after the implementation date. Studies currently in progress under non-competing funding that have already been peer-reviewed are not subject to this policy. Similarly, amended studies that were initially reviewed prior to implementation of the policy are not subject to the policy. In addition, competing continuation studies submitted after implementation are likewise not subject to the policy.

9. Who has responsibility for carrying out the policy?

Investigators have the responsibility of addressing the inclusion of children in their research applications and proposals, specifically under a section "Participation of Children." The Institutional Review Board (IRB) is responsible for making a determination on the appropriateness of the inclusion or exclusion of children in the study under review and for compliance with the policy. Extramural and intramural review groups and program staff ensure that the policy is carried out. Subsequent Questions and Answers address specific aspects of these responsibilities.

10. What definitions govern this policy?

The policy is covered by the NIH definition of research involving human subjects (i.e., research that involves the intervention or interaction with a living individual as well as research that obtains individually identifiable private information). The policy is in addition to the human subjects protection regulations found at Title 45, part 46, of the Code of Federal Regulations (45 CFR 46), including the regulatory definition of human subjects. The policy applies to all research involving human subjects, including research that is otherwise exempted under Sections 101(b) and 401(b) of 45 CFR 46, Subparts A and D, e.g., certain educational, observational, and survey research.

11. How will variations in state and local law affect policy implementation?

The Principal Investigator (PI) and the IRB need to be familiar with Federal, State, and local law. Again, the policy defines children as persons under 21 years of age for purposes of inclusion. However, the age at which a child may give legally effective informed consent is defined by State law. State laws vary, but many do not address when a child can consent to participation in research as distinguished from consent to treatment. For example, Federal Regulations (45 CFR 46, subpart D, sections 401-409) address DHHS protections for children who participate in research. IRBs have special review requirements to protect the well-being of children who participate in research. These requirements relate to risk, benefit, parental/guardian permission, and assent by children, and to research involving children who are wards of the State or of another institution. The local IRB may approve only research that satisfies the conditions set forth in the Regulations. A Summary Chart showing the requirements under the Federal Regulations is provided in the Guidelines.

12. Does this policy apply to NIH-supported research conducted in countries other than the United States?

Yes. 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 United States. The research proposals should be in conformance with national and local laws and regulations and should consider the local culture and conditions of the collaborating host countries.

13. Does the policy apply to research contract proposals and projects?

Yes, the policy applies to these projects also. The relevant information will be included as part of the Request for Proposals (RFP), which includes the statement of work and evaluation criteria. SRGs will evaluate proposals based on the published evaluation criteria, and use the same coding format.

14. Must all research include children?

No. The answer to this question depends on the scientific questions being addressed and the risks involved. The NIH policy describes certain exemptions where inclusion of children may not be necessary or appropriate. A "Decision Tree for Participation of Children in Research" is provided in the Guidelines to facilitate the determination of policy implementation by principal investigators and reviewers with regard to the inclusion of children in research involving human subjects. Seven areas of exclusion are identified in the policy section of the Guidelines that are allowed with full justification.

15. How does the evaluation of the application differ when children are added to research studies, given the differences between children and adults?

Reviewers will have to ensure that the research is appropriate for the inclusion or exclusion of children in light of the nature of the research and the age and developmental level of the children, both physically and psychologically.

16. Will parallel or collaborative studies be acceptable?

Yes, if they have appropriate controls and reliability/validity issues are addressed. Parallel and collaborative studies are separate studies on children that address essentially the same research question. NIH program staff should provide guidance to PI's on possible collaborations.

17. When is the inclusion of children appropriate? Under what circumstances, at what ages, and at what numbers of subjects is it appropriate, given the information available from adult data? How will the Principal Investigator determine the age range of the children to be included in a study?

The answers to these questions depend on the scientific questions being addressed. The appropriateness of the exclusion or inclusion of age-appropriate groups of children must be determined by the principal investigator (PI), the IRB, and by the peer reviewers for extramural research and the scientific reviewers and IRBs that review NIH intramural research. It is not necessary for a given study to have sufficient power to test for group differences between children and adults. However, studies not including children cannot be generalized to the entire population, which includes children.

Determination of the age range of a study population is dictated by the scientific question being asked. The PI will need to consider not only whether the disease, disorder, or condition is appropriate for study in children and adolescents, but what specific ages should be studied. However, age groupings provide only one way of identifying children and adolescents in an investigation. Developmental level (physical, cognitive, behavioral) may be the critical factor (rather than age) for selection and grouping in some studies. It is the PI's responsibility to review the scientific and ethical factors relevant to the research questions, and to state and justify the age and/or developmental parameters for participants in the study.

18. What if the disorder is the same in adults and children?

If a disorder is believed to have fundamentally similar genetics, biology, pathophysiology, and response to interventions in adults and children, investigators should include age-appropriate children in studies, unless the criteria of one of the other exclusions for involvement of children as research subjects are met. Both adults and children can contribute to the data in such studies allowing results to be generalized across ages.

19. What evidence is needed to determine whether a pooled or separate analysis of data from children is appropriate?

Investigators evaluating an experimental treatment approach for adults with a specific disease or condition should consider what factors need to be addressed when determining whether data from children with the same disease or condition should be included in a combined analysis with data from adult patients, or whether a separate analysis should be carried out for children (either as an individual stratum of the adult study or as an entirely separate study).

Because of the substantial physiological and psychological differences between adults and children at different developmental stages, the investigator should review the available literature to evaluate the likelihood of a similar treatment effect in children and adults for the intervention being studied. The likelihood of a similar treatment effect is dependent upon both disease factors (e.g., is the disease pathophysiology similar in adults and children) and on host factors (e.g., are the toxicity and tolerability of the treatment similar for adults and children). From this review, there are three principal possibilities:

• Available data support the likelihood of a similar treatment effect in adults and children.

In this first situation, it would be appropriate to enter children into the adult study and to conduct a pooled adult/children analysis of treatment effect (because available data indicate that the effect of the intervention is likely to be the same for adults and children).

• Available data indicate that children are likely to respond qualitatively or quantitatively differently to the potentially toxic therapeutic intervention.

In this second situation, a separate analysis of the effect of the intervention in children should generally be conducted (i.e., children evaluated in either a separate stratum of an adult study or in an entirely separate study).

• There are insufficient data to conclude that children are likely to respond in a similar manner as adults.

In this third situation, the most useful approach might be to begin by cautiously including older children and periodically assessing the impact of the research on them (using a data and safety monitoring committee if the study is blinded), and move to progressively younger children and the numbers of children needed for either a combined or separate analysis as indicated by the accumulating pilot data.

20. What if children do not have the disorder under study?

If children do not have the disorder under study, this might constitute appropriate grounds for exclusion. For any study, it is the investigator's responsibility to make the case for inclusion or exclusion of children on the scientific merits.

21. When can healthy children be studied? When can children be exposed to greater than minimal risk?

Guidelines for the inclusion of children in research, including healthy children, are set forth in the Federal Regulations at 45 CFR 46, Subpart D, Sections 46.401-409, which describe DHHS protections for children who participate in research. Generally, healthy children can be studied when the research is considered as "not greater than minimal risk" (Section 46.404). Children can be involved in research with greater than minimal risk only when it presents the prospect of direct benefit to the individual child (Section 46.405) or is likely to yield generalizable knowledge about the child's disorder or condition (Section 46.406). DHHS can support other research involving children only with the approval of the Office for Prevention from Research Risks after consultation with an appropriate panel of experts (Section 46.407).

22. What if there are no reliable assessments of children for the research issues under study?

This policy allows, as a justification for excluding children, situations in which there are insufficient data available in adults to judge potential risk in children. Alternatively, one of the research objectives could be to obtain sufficient adult data to make this judgment. Children would not usually be included in the initial group to be studied; however, in some instances the nature and seriousness of the illness may warrant their participation earlier, based on careful risk-benefit analysis.

23. Are adult-onset diseases that have their roots in childhood considered part of this policy?

Yes, if the focus of the study is on the pathogenesis, prevention, or amelioration of future onset.

24. What if the proposed study only includes human tissue (e.g., cells, DNA). Must such a study also include children?

If the study involves pooled tissue samples without clear demographic identifiers, the specific inclusion of children is not required. However, when the tissue samples have clear demographic identifiers with age, the policy for inclusion of children is applicable.

25. What should a Principal Investigator do if there are not a sufficient number of children available for a study because of the PIs geographic location or the rarity of the disease in children?

Applicants must select study participants in terms of the purpose of the research and other factors, such as prior research findings, the size of the study, relevant characteristics of and gaps in knowledge about the disease, disorder, or condition, and the feasibility of developing a collaboration or consortium or other arrangements to include sufficient number of children in the proposed research. If geography is the only basis for lack of representation, it cannot be used to justify limited representation of children. Each investigator is given the opportunity to provide a clear and compelling description and rationale for the proposed study population and its appropriateness for the purpose of the research, or to provide an appropriate justification for an exemption.

If the appropriate participants are not available in the locale of the applicant institution, investigators are encouraged to seek collaborators in other geographic areas. Plans should be presented to recruit outside the area either by the investigator or through collaborative arrangements with investigators who do have access to children. Particularly when multi-center clinical trials are proposed, the inclusion requirements may be met by combining recruitment from the multiple sites; in these trials, each clinical site must still describe its planned recruitment, and will be evaluated on that basis.

26. What if adding children to a study makes the cost significantly greater than without them?

Budgetary considerations and constraints do not preclude the necessity of investigators' careful consideration of the scientific merit of inclusion or exclusion of children.

27. What should the investigator do if he/she does not have research or clinical experience with children? It is problematic to require such investigators to include children in research, and couldn't this expose children to additional risks?

If children should be included in the research, investigators should obtain, when necessary, appropriate consultation and expertise regarding research with children.

28. Where should the PI include information about inclusion of children?

In the application research plan (PHS form 398), the PI must describe, under a section "Participation of Children," 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. Additional information is required in the Human Subjects section.

29. Does the policy on gender and minorities apply as well as the policy on inclusion of children in all proposed studies?

As it states, the NIH policy on gender and minorities applies to research subjects of all ages. Thus, the scientific rationale for selection of the study population with regard to each policy must be included, as well as any justifications for exclusion that are relevant. Both policies will be evaluated during review by the SRG, the IRB, the Councils/Boards, and the NIH staff.

30. Who reviews the appropriateness of inclusion or non-inclusion in the applications submitted?

The appropriateness is reviewed at several steps in the process before awards are made.

The PI must describe in the application, under a section "Participation of Children," 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. Additional information is provided in the Human Subjects section.

The IRB addresses the appropriateness of the population studied in terms of the aims of the research and ethical principles and practices. The IRB should include appropriate research and ethical expertise relative to children. IRBs have the responsibility to examine ethical issues, including equitable selection of research subjects in accordance with Federal Regulations (45 CFR 46). IRBs have special review requirements to protect the well-being of children who participate in research. These requirements relate to risk, benefit, parental/guardian permission, and assent by children, and to research involving children who are wards of the State or of another institution. The local IRB may only approve research that satisfies the conditions set forth in the Regulations. Federal Regulations (45 CFR 46, subpart D, sections 401-409) address DHHS protections for children who participate in research. IRBs may approve research involving children only if these special provisions are met or a waiver of them is approved.

The NIH Scientific Review Group (SRG), using principles of peer review, assesses the proposed research plan for inclusion or exclusion of children as acceptable or unacceptable. The SRG evaluates the appropriateness of the population studied in terms of the aims of the research and ethical standards, the expertise of the investigative team in dealing with children at the ages included, and the appropriateness of the facilities.

NIH staff and Advisory Councils/Boards roles in reviewing appropriateness are noted below.

31. If children are inappropriately not included in the current design as determined by the SRG, what action will be taken by NIH?

NIH may concur with the SRG and not fund the study, or may seek additional information and advice to determine if the study can be made acceptable.

32. Can failure to include children affect the priority score of an application?

Yes, the exclusion may affect the priority score when reviewers evaluate the scientific merit of the project and the justification provided for exclusion.

33. What if an IRB says children cannot be included in the study as presently designed?

The NIH policy does not pre-empt the authority of the local IRB in determining the balance of risks and benefits and appropriateness of the proposed research with children. This information should be provided as part of a justification for exclusion of children that is provided.

34. Will both parents be required to provide consent?

Generally, the consent of one parent is sufficient when the research is not greater than minimal risk or presents the prospect of direct benefit to the individual child. When the research is considered greater than minimal risk with no prospect of direct benefit to the child, consent of both parents is necessary unless one parent is not reasonably available or only one parent has legal responsibility for the care and custody of the child. [45 CFR 46.408(b)]

35. What is the role of the NIH Advisory Council/Board?

The Council reviews policy compliance as part of its general secondary level of review of grant applications.

36. How will conformance to this policy affect funding of projects?

Regardless of the priority score, percentile ranking or program relevance of the proposed research, the NIH funding components will not fund/award grants or contracts or intramural research projects that do not comply with this policy.

37. What is the role of the Institute/Center program staff?

Program staff has the responsibility of ensuring that the study is in compliance with the policy, and reviews applications before award. Staff may allow some research that does not include children to proceed if the research question is being addressed in children elsewhere in the Institute's or Center's research portfolio. Staff may also obtain additional information and advice about "unacceptable" applications in the process of determining whether to remove this "bar" to funding.

38. How will coding be handled?

Coding will be handled in a manner parallel to the coding of gender and minority inclusion. There are two aspects to the codes: type of representation and acceptability/unacceptability of the representation of children. (See Appendix 1).

39. Will a "bar" be placed to preclude funding if children are excluded and review determines that the justification is inadequate?

Yes. There are two aspects to the codes: type of inclusion and appropriateness of inclusion. Applications coded as unacceptable by scientific review groups will be barred from funding until NIH staff receive assurances of compliance from the investigators and determine that the applications are in compliance.

40. What if the FDA or some other governmental authority will not allow the research protocol to include children?

This may be presented as a justification for exclusion, and will be evaluated like any other justification. If found acceptable to the review group and Institute staff, the protocol may be allowed to proceed.

41. How will the policy be implemented for projects supported in the intramural program?

Intramural investigators will comply with the policy in the same way as Extramural investigators. Intramural protocols will address the inclusion of children under a section titled,"Participation of Children." NIH Institute scientific review of research protocols will evaluate the acceptability of the proposed inclusion or exclusion of children before protocols are sent to the intramural IRB. The IRB of each Institute's intramural program will consider the appropriateness of the inclusion of children as subjects in research. The Director of the Clinical Center makes the final determination of approval, but may only approve research that has been approved by the Institute's Clinical Director and the IRB.

42. What are the reporting requirements for this policy?

In their annual progress reports, investigators will indicate, where appropriate, whether children are involved in the study or how the study has relevance for conditions affecting children. NIH staff will review progress reports and take appropriate action as necessary.

SCIENTIFIC REVIEW GROUP (SRG) CODES FOR INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH

This Information will be on the Header on Summary Statements

C1A - Both children and adults are included; scientifically acceptable
C2A - Only children represented; scientifically acceptable
C3A - No children included; scientifically acceptable
C4A - Representation of children is unknown; scientifically acceptable

C1U - Both children and adults are included; scientifically unacceptable
C2U - Only children represented; scientifically unacceptable
C3U - No children included; scientifically unacceptable
C4U - Representation of children is unknown. Scientifically unacceptable

NOTES:

1. Children are defined as individuals under the age of 21.
2. Only applications that receive a priority score will have codes assigned.

For comments, please contact: cabanc@od.nih.gov

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