Applicants should check the type size using a standard device for measuring type size, rather than relying on the font selected for a particular word processing/printer combination. Figures, charts, tables, figure legends, and footnotes may be smaller in size but must be readily legible. The type size used must conform to all four requirements. Small type size makes it difficult for reviewers to read the application; consequently, the use of small type will be grounds for the PHS to return the application without peer review. Adherence to type size and line spacing requirements is also necessary so that no applicant will have an unfair advantage, by using small type, or providing more text in their applications.

Page Limitations and Content Requirements

All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in NIH solicitations, internet Web site addresses (URLs) may not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Moreover, reviewers are cautioned that they should not directly access an Internet site as it could compromise their anonymity.

Observe the page number limitations given in Table 1. Only in cases involving interdependent multiple subprojects (e.g., Program Projects and Multi-Center Clinical Trials) will the PHS accept applications that exceed the page number limitations. However, specific page number limits may apply to each subproject. For information pertaining to page number limits for such projects, contact the awarding component to which the application may be assigned. (See Section II-C, "Interactions Before Submission".) The page number limitations may also be different for other specialized grant applications. For information regarding page number limitations, request and follow the additional instructions for those applications.

Note:  Failure to comply with the formatting and page specifications will be grounds for the PHS to reject and return the entire application without peer review.

The Division of Receipt and Referral has the responsibility to make the final determination of legibility and authority to return applications. Questions should be directed to the Division of Receipt and Referral, Center for Scientific Review, (301) 435-0715.

Table 1. Page Limitations and Content Requirements

C. SPECIFIC INSTRUCTIONS

1. Face Page: Use the form page provided (fp1.doc)

Item 1. Title of Project

Do not exceed 56 characters, including the spaces between words and punctuation. Choose a title that is specifically descriptive, rather than general. A new application must have a different title from any other PHS project with the same principal investigator/program director. A competing continuation or revised application should ordinarily have the same title as the previous grant or application. If the specific aims of the project have significantly changed, choose a new title. A supplemental application must have the same title as the currently funded grant.

Item 3. Principal Investigator/Program Director

Item 3a. Name of Principal Investigator/Program Director

Name the one person responsible to the applicant organization for the scientific and technical direction of the  project. A supplemental application must have the same principal investigator/program director as the currently funded grant. PHS staff conduct official business only with principal investigators and institutional officials.

Item 4. Human Subjects

(See Section III-A, "DEFINITIONS")

No Human Subjects

Check "No" if activities involving human subjects are not planned at any time during the proposed project period. The remaining parts of Item 4 are then not applicable.

Human Subjects Involved

Check "'Yes" if activities involving human subjects are planned at any time during the proposed project period, either at the applicant organization or at any other performance site or collaborating institution. "Yes" should be  checked even if the research is exempt from regulations for the protection of human subjects (See Exemption Categories).

Item 5. Vertebrate Animals

Check "No" if activities involving vertebrate animals are not planned at any time during the proposed project period. The remaining parts of Item 5 are then not applicable. Check "Yes" if activities involving vertebrate animals are planned at any time during the proposed project period, either at the applicant organization or at any other performance site or collaborating institution,

Item 14. Principal Investigator/Program Director Assurance

An original signature, in ink, is required. "Per" signatures are not acceptable. Date of signature must be included.

2. Description, Performance Sites and Key Personnel

FORM PAGE 2 (MS Word or PDF)

Note:

Do not insert additional pages between Form Page 1 and Form Page 2.

Description

Instructions for this section are on Form Page 2.

8. Research Plan

There is no Form Page for the Research Plan. The Research Plan should include sufficient information needed  for evaluation of the project, independent of any other document. Be specific and informative, and avoid redundancies. Organize Items a-d of the Research Plan to answer these questions:

1. What do you intend to do?
2. Why is the work important?
3. What has already been done?
4. How are you going to do the work?

Page Limitations

Do not exceed 15 pages for Items a-d. All tables, graphs, figures, diagrams, and charts must be included within the 15-page limit. Applicants are encouraged to be succinct and are reminded that there is no necessity to use all 15-pages allotted to Items a-d of the Research Plan.

All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet Web site addresses (URLs) may not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Moreover, reviewers are cautioned that they should not directly access an internet site as it could compromise  their anonymity.

Notice of Proprietary Information and Trade Secrets

Applicants are discouraged from submitting information considered proprietary unless it is deemed essential for proper evaluation of the application. However, if the application contains information that the applicant organization considers to be trade secrets or information that is commercial or financial; or information that is confidential or privileged, identify the pages in the application which contain this information by marking those  paragraphs or lines containing this information with an asterisk (*) in the left-hand margin and providing the page numbers before "a. Specific Aims."

When information in the application constitutes trade secrets or information that is commercial or financial, and confidential or privileged, it is furnished to the Government in confidence with the understanding that the information shall be used or disclosed only for evaluation of this application. If a grant is awarded as a result of or in connection with the submission of this application, the Government shall have the right to use or disclose the information to the extent authorized by law. This restriction does not limit the Government's right to use the  information if it is obtained without restriction from another source.

Research Plan Format and Page Distribution

The PHS recommends the following format and page distribution.

a. Specific Aims

List the broad, long-term objectives and what the specific research proposed in this application is intended to accomplish, e.g., to test a stated hypothesis, create a novel design, solve a specific problem, or develop new technology. One page is recommended.

b. Background and Significance

Briefly sketch the background leading to the present application, critically evaluate existing knowledge, and specifically identify the gaps that the project is intended to fill. State concisely the importance and health relevance of the research described in this application by relating the specific aims to the broad, long-term objectives. Two to six pages are recommended.

d. Research Design and Methods

Describe the research design and the procedures to be used to accomplish the specific aims of the project. Include how the data will be collected, analyzed, and interpreted as well as the data sharing plan as appropriate. Describe any new methodology and its advantage over existing methodologies. Discuss the potential difficulties and limitations of the proposed procedures and alternative approaches to achieve the aims.

Although no specific number of pages is recommended for the Research Design and Methods section, the total for Items a-d may not exceed 15 pages, including all tables  and figures. Applicants are encouraged to be as succinct as possible and reminded that there is no requirement that all 15 pages allotted for this section be used.

e. Human Subjects Research

Applicants are encouraged to use the decision charts on OHRP's website (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/decisioncharts.htm) for guidance in determining whether the proposed research involves human subjects research as defined in part A of the human subjects regulations  (45 CFR 46) (See Section III A., "Definitions").

If you have marked "Yes" for Item 4 on the Face Page of the application, create a section heading entitled Human Subjects Research immediately following the last entry in the Research Design and Methods section. When you have completed this section, you will need to address the instructions in the sections entitled "Women and Minority Inclusion in Clinical Research" and the "Inclusion of Children" and Data and Safety Monitoring if the research involves a clinical trial. Although no specific page limitation applies to this section of the application, be succinct.

Special Populations

Investigators who conduct research involving fetuses, pregnant women, human in vitro fertilization, prisoners, or children must follow the provisions of the regulations in Subparts B, C, and D of 45 CFR 46, respectively, which describe the additional protections required for these populations. Relevant information may be obtained at the OHRP website http://ohrp.osophs.dhhs.gov/polasur.htm). Exemptions 1-6 below do not apply to research involving prisoners, fetuses, pregnant women, or human in vitro fertilization (see Subparts B and C.) Also, Exemption 2 below, for research involving survey or interview procedures or observation of public behavior, does not apply to research with children (see Subpart D), except for research involving observations of public behavior when the investigator(s) do not participate in the activities being observed.

Human Subjects Research Section

In the Human Subjects Research section, applicants must (1) address the involvement of human subjects and protections from research risk relating to their participation in the proposed research plan (see Non Exempt  Human Subjects Research for specific requirements), or (2) provide a justification for exemption with sufficient information about the involvement of the human subjects to allow a determination by peer reviewers and NIH staff that a claimed exemption is appropriate (see Exempt Human Subjects Research for specific requirements).

The following table is intended to provide guidance on what must be addressed in the Human Subjects Research section.

Guidance for Preparing the Human Subjects Research Section

Non Exempt Human Subjects Research

Protection of Human Subjects

If you marked "Yes" for Item 4 on the Face Page of the application and did not claim any exemptions from the  regulations, create a section entitled "Protection of Human Subjects." In this section, you must provide information to address all four evaluation criteria below as they apply to the research you are proposing.

Under each criterion, indicate whether the information relates to the primary research site, or to a collaborating performance site(s), or to all sites.

1. RISKS TO THE SUBJECTS

Human Subjects Involvement and Characteristics: Describe the proposed involvement of human subjects in the work outlined in the Research Design and Methods section. Describe the characteristics of the subject population, including their anticipated number, age range, and health status. Identify the criteria for inclusion or exclusion of any subpopulation. Explain the rationale for the involvement of special classes of subjects, such as fetuses, neonates, pregnant women, children, prisoners, institutionalized individuals, or others who may be considered vulnerable populations.

Sources of Materials: Identify the sources of research material obtained from individually identifiable living human subjects in the form of specimens, records, or data. Indicate whether the material or data will be obtained specifically for research purposes or whether use will be made of existing specimens, records, or data.

Potential Risks: Describe the potential risks to subjects (physical, psychological, social, legal, or other) and assess their likelihood and seriousness to the subjects. Where appropriate, describe alternative treatments and procedures, including the risks and benefits of the alternative treatments and procedures to participants in the proposed research.

2. ADEQUACY OF PROTECTION AGAINST RISKS

Recruitment and Informed Consent: Describe plans for the recruitment of subjects and the process for obtaining informed consent. Include a description of the circumstances under which consent will be sought and obtained, who will seek it, the nature of the information to be provided to prospective subjects, and the method of documenting consent. The informed consent document need not be submitted to the PHS unless requested.

Protection Against Risk: Describe the planned procedures for protecting against or minimizing potential risks, including risks to confidentiality, and assess their likely effectiveness. Where appropriate, discuss plans for ensuring necessary medical or professional intervention in the event of adverse effects to the subjects. In studies that involve clinical trials (biomedical and behavioral intervention studies), describe the plan for data and safety monitoring of the research to ensure the safety of subjects.

3. POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND OTHERS

Discuss the potential benefits of the research to the subjects and others. Discuss why the risks to subjects are reasonable in relation to the anticipated benefits to subjects and others.

4. IMPORTANCE OF THE KNOWLEDGE TO BE GAINED

Discuss the importance of the knowledge gained or to be gained as a result of the proposed research. Discuss why the risks to subjects are reasonable in relation to the importance of the knowledge that reasonably may be expected to result.

Note: If a test article (investigational new drug, device, or biologic) is involved, name the test article and state whether the 30-day interval between submission of applicant certification to the Food and Drug Administration and its response has elapsed or has been waived and/or whether use of the test article has been withheld or restricted by the Food and Drug Administration.

Exempt Human Subjects Research

If you marked "Yes" for Item 4 on the Face Page and claimed an exemption from the human subjects regulations, then identify which one or more of the exemptions identified below is claimed. Provide a justification with sufficient information about the involvement of human subjects in the proposed research to allow a determination by peer reviewers and NIH staff that the designated exemption is appropriate. 

Population Sample: Describe the characteristics of the subject population, including their anticipated number, age range, and health status. Identify the criteria for inclusion or exclusion of any subpopulation. Explain the rationale for the involvement of special classes of subjects, such as children, prisoners, institutionalized individuals, or others who may be considered vulnerable populations.

Sources: Applicants should identify the sources of research material obtained from living human subjects in the  form of specimens, records, or data. Indicate whether the material or data will be obtained specifically for research purposes or whether use will be made of existing specimens, records, or data.

Exemption Categories

The six categories of research that qualify for exemption from coverage by the regulations include activities in which the only involvement of human subjects will be in one or more of the following categories:

Exemption 1. Research conducted in established or commonly accepted educational settings, involving normal  educational practices, such as (a) research on regular and special education instructional strategies, or (b) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.

Exemption 2. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior, unless: (a) information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and (b) any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, or reputation.

Exemption 3. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt under paragraph (2)(b) of this section, if: (a) the human subjects are elected or appointed public officials or candidates for public office; or (b) Federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.

Exemption 4. Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.

Exemption 5. Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine: (a) public benefit or service programs; (b) procedures for obtaining benefits or services under those programs; (c) possible changes in or alternatives to those programs or procedures; or (d) possible changes in methods or levels of payment for benefits or services under those programs. 

Exemption 6. Taste and food quality evaluation and consumer acceptance studies, (a) if wholesome foods without additives are consumed or (b) if a food is consumed that contains a food ingredient at or below the level and use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture. 

Note: Some exemptions do not apply when research involves vulnerable populations as indicated in 45 CFR.

Women and Minority Inclusion in Clinical Research

If you are conducting clinical research (See definition in Section III. A., DEFINITIONS), create a section heading entitled "Inclusion of Women" and a separate section heading entitled, "Inclusion of Minorities." Place these sections immediately after the Human Subjects Research section in your application. Address each of the items identified below with respect to your plans for the "Inclusion of Women" and the "Inclusion of Minorities" as they relate to the proposed research. Although no specific page limitation applies to these sections of the application, be succinct.

NIH policy requires that women and members of minority groups and their subpopulations be included in all  NIH-supported biomedical and behavioral clinical research projects involving human subjects (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html and also definition in Section III A., "DEFINITIONS").

The inclusion must be addressed in developing a research design appropriate to the scientific objectives of the study. Inclusion is required unless a clear and compelling rationale shows that inclusion is inappropriate with respect to the health of the subjects or that inclusion is inappropriate for the purpose of the study. Exclusion under other circumstances may be made based on a compelling rationale and justification. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources. Women of childbearing potential should not be excluded routinely from participation in clinical research. This policy applies to research subjects of all ages.

Information to be Provided for All Clinical Research Studies

See definition of clinical research in Section III., A., DEFINITIONS.

Provide information on the composition of the proposed study population in terms of sex/gender and racial/ethnic group and provide a rationale for selection of such subjects in terms of the scientific objectives and proposed study design. The description may include (but is not limited to) information on the population characteristics of the disease or condition under study, national and local demography, knowledge of the racial/ethnic/cultural characteristics of the population, prior experience and collaborations in recruitment and retention of the populations and subpopulations to be studied, and the plans, arrangements and letters of commitment from relevant community groups and organizations for the planned study.

This section of the research plan must include the following information:

• A description of the subject selection criteria and rationale for selection in terms of the scientific objectives and  proposed study design.
• A compelling rationale for proposed exclusion of any sex/gender or racial/ethnic group.
• The proposed dates of enrollment (beginning and end).
• A description of proposed outreach programs for recruiting women and minorities in clinical research as subjects.
• The proposed sample composition using the "5/01 Targeted/Planned Enrollment Format Page" and/or the "5/01 Inclusion Enrollment Report Format Page."

FOR ALL STUDIES INVOLVING HUMAN SUBJECTS, USE THE FOLLOWING ETHNIC AND RACIAL CATEGORIES.

The Office of Management and Budget (OMB) Directive No. 15 (http://www.whitehouse.gov/omb/fedreg/ombdir15.html) defines minimum standards for maintaining, collecting and presenting data on race and ethnicity for all Federal reporting (including NIH). The categories in this classification are social-political constructs and should not be interpreted as being anthropological in nature. The standards were revised in 1997 and now include two ethnic categories, "Hispanic or Latino" and "Not Hispanic or Latino." There are five racial categories: American Indian or Alaska Native; Asian; Black or African American; Native Hawaiian or Other Pacific Islander; and White. Reports of data on race and ethnicity shall use these categories. NIH is required to use these definitions to allow comparisons to other federal databases, especially the census and national health databases. The following definitions apply for the ethnic and racial categories (OMB Directive 15).

Ethnic Categories:

Hispanic or Latino: A person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin, regardless of race. The term, “Spanish origin,” can be used in addition to “Hispanic or Latino”. 

Not Hispanic or Latino  

Racial Categories:

American Indian or Alaska Native: A person having origins in any of the original peoples of North, Central, or South America, and who maintains tribal affiliation or community attachment.

Asian: A person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam.  (Note: Individuals from the Philippine Islands have been recorded as Pacific Islanders in previous data collection strategies.)

Black or African American: A person having origins in any of the black racial groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to “Black or African American.”

Native Hawaiian or Other Pacific Islander: A person having origins in any of the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands.

White: A person having origins in any of the original peoples of Europe, the Middle East, or North Africa.

Standards for Collecting Data.  When an investigator is planning data collection items on ethnicity and race, categories identified above should be used. The collection of greater detail is encouraged. However, more detailed items should be designed in a way that they can be aggregated into these required categories. Self-reporting or self-identification using two separate questions is the preferred method for collecting data on ethnicity and race. When ethnicity and race are collected separately, ethnicity shall be collected first.  Respondents shall be offered the option of selecting one or more racial designations.  When data on ethnicity and race are collected separately, provision shall be made to report the number of respondents in each racial category who are Hispanic or Latino.  When aggregate data are presented, the investigator shall provide the number of respondents who selected only one category, for each of the five racial categories.  If data on multiple responses are collapsed, at a minimum the total number of respondents reporting “more than one race” shall be made available. Federal agencies shall not present data on detailed categories if doing so would compromise data quality or confidentiality standards.

Additional Information to be Provided for NIH-Defined Phase III Clinical Trials

If an NIH-defined Phase III clinical trial (see "Definitions" in Section III-A) is proposed, the application must address whether the investigator expects to find clinically important sex/gender and/or race/ethnicity differences in the intervention effect. The discussion may include supporting evidence and/or data derived from prior animal studies, clinical observations, metabolic studies, genetic studies, pharmacology studies, and observational, natural history, epidemiology and other relevant studies. The research plan also must include one of the following plans: 

• plans to conduct valid analyses to detect significant differences in intervention effect among sex/gender and/or racial/ethnic subgroups when prior studies strongly support these significant differences among subgroups, OR

• plans to include and analyze sex/gender and/or racial/ethnic subgroups when prior studies strongly support no significant differences in intervention effect between subgroups. (Representation of sex/gender and racial/ethnic groups in not required as subject selection criteria, but inclusion is encouraged.), OR

• plans to conduct valid analyses of the intervention effect in sex/gender and/or racial/ethnic subgroups (without requiring high statistical power for each subgroup) when the prior studies neither support nor negate significant differences in intervention effect between subgroups.

Completing the Tables for Reporting Race and Ethnicity Data for Subjects in Clinical Research

New Applications

Use the "5/01 Targeted/Planned Enrollment Table Format Page (MS Word or PDF)." Provide the study title and plans for the total number of subjects proposed for the study. Also provide the distribution by ethnic categories and by sex/gender according to the format in the 5/01 Targeted/Planned Enrollment Table. If there is more than one study, provide a separate table for each study. List any proposed racial/ethnic subpopulations below the table. If the proposed research uses existing data, then applicants must use the formats for Competing Continuations, Competing Supplements and Annual Grant Progress Reports.

Competing Continuations, Competing Supplements and Annual Grant Progress Reports

For Competing Continuations involving the collection of new/additional clinical data, use the  "5/01 Targeted/Planned Enrollment Table (MS Word or PDF)"(see Note below) to estimate the distribution of subjects proposed for the study. Provide the study title and plans for the total (cumulative) number of subjects proposed for the study (total planned enrollment). Provide the distribution of subjects by ethnic and racial categories and by sex/gender according to the format in the 5/01 Targeted/Planned Enrollment Table.  If there is more than one study, provide a separate table for each study.

For Competing Continuations that do not involve the collection of new/additional clinical data, the data on ethnicity/race and sex/gender may be presented in EITHER the 4/98 Version of the Inclusion Table (MS Word or PDF) or the 5/01 Inclusion Enrollment Report (MS Word or PDF). If data were originally collected using two questions (one about ethnicity and one about race) and subjects were given the option of selecting more than one race, then the 5/01 Inclusion Enrollment Report should be used.  Otherwise, the 4/98 Version of the Inclusion Table should be used.

For Competing Supplement Applications and Annual Grant Progress Reports investigators may choose to report ethnicity/race and sex/gender composition using EITHER the format in the 4/98 Version of the Inclusion Table (MS Word or PDF) or the 5/01 Inclusion Enrollment Report (MS Word or PDF). If data are being collected using two questions (one about ethnicity and one about race) and subjects were given the option of selecting more than one race, then the 5/01 Inclusion Enrollment Report should be used. Note: If you choose to report information with the new 5/01 Inclusion Enrollment Report, you must continue to use this format for the remaining years of the project.

For Annual Grant Progress Reports, if there are changes from the targeted/planned enrollment originally approved, a revised targeted/planned enrollment page and an inclusion enrollment report reflecting data collected to-date should be submitted.

Note on use of the "5/01 Inclusion Enrollment Table": Principal Investigators of successful competing continuation awards involving collection of new/additional clinical data will be required to use the new " 5/01 Inclusion Enrollment Report (MS Word or PDF)" in subsequent annual PHS 2590 Progress Reports (5/01). The 5/01 Inclusion Enrollment Report contains two parts: part A is for all subjects and part B is for Hispanics or Latinos. For Part A provide the distribution of subjects by ethnic and racial categories and by sex/gender according to the format in the 5/01 Enrollment Report Table. Part B should include information on the race of all Hispanics (or Latinos) enrolled in Part A.  If there is more than one study, provide a separate table for each study. List any proposed ethnic/racial subpopulations as an attachment to the table. In filling out the 5/01 Inclusion Enrollment table, the investigator should not assume or guess a subject's ethnic or racial affiliation. The investigator should collect the data using instruments that, at a minimum, allow all respondents to select their ethnic and racial affiliation separately. Under racial affiliation, subjects must be provided the option of selecting more than one race. When reporting these data to NIH, subjects who selected only one of the five racial categories should be designated in that category. Subjects who selected more than one racial category should be reported in the "More than one race" category. For previously funded studies that used an earlier NIH reporting format, the earlier reporting format is NOT directly transferable to the new format. Investigators should review the instructions and frequently asked questions about using the new format at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html.

Inclusion of Children

If you have marked "Yes" for Item 4 on the Face Page of the application, create a section heading entitled "Inclusion of Children." Place it immediately following the "Women and Minority Inclusion in Clinical Research" section of the application.

NIH policy requires that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH see http://grants.nih.gov/grants/funding/children/children.htm for additional information),, unless there are clear and compelling reasons not to include them. 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. NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

In the section entitled "Inclusion of Children", the applicant should provide either a description of the plans to include children or if children will be excluded from the research, the application or proposal must present an acceptable justification (see below) for the exclusion.

If children are included, the description of the plan should include a rationale for selecting or excluding a specific age  range of children. When children are included, the plan also must 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 will assess each application as being "acceptable" or "unacceptable" with regard to the age-appropriate inclusion or exclusion of children in the research project.

Justifications for Exclusion of Children

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 not relevant 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. 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:
   1. 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); or
   2. The number of children is limited because the majority are already accessed by a nationwide pediatric disease research network; or
   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; or 
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; or
6. Study designs aimed at collecting additional data on pre-enrolled adult study subjects (e.g., longitudinal follow-up studies that did not include data on children); or
7. Other special cases justified by the investigator and found acceptable to the review group and the Institute Director.

Definition of a Child

For the purpose of implementing these guidelines, a child is defined as an individual under the age of 21 years.

The definition of child described above will pertain to these guidelines (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.

Data and Safety Monitoring Plan

If you have marked "Yes" for Item 4 on the Face Page of the application, and your proposed research includes a clinical trial create a section heading entitled "Data and Safety Monitoring Plan." Place it immediately following the "Inclusion of Children" section.

NIH policy requires that investigators submit a general description of the Data and Safety Monitoring Plan for clinical trials (biomedical and behavioral intervention studies) as part of the research application. In developing your Data and Safety Monitoring Plan, you should refer to the NIH Policy For Data and Safety Monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. See also (http://grants.nih.gov/grants/guide/notice-files/not98-084.html ).

A general description of a monitoring plan establishes the overall framework for data and safety monitoring. It should describe the entity that will be responsible for monitoring, and how Adverse Events (AEs) will be reported to the Institutional Review Board (IRB), the NIH Office of Biotechnology Activities (OBA), and the Food and Drug Administration (FDA) in accordance with IND or IDE regulations. Although no specific page limitation applies to this section of the application, be succinct.

The frequency of monitoring will depend on potential risks, complexity, and the nature of the trial; therefore, a number of options for monitoring trials are available. These can include, but are not limited to, monitoring by a: 

• Principal Investigator (required)
• Independent individual/Safety Officer
• Designated medical monitor
• Internal Committee or Board with explicit guidelines
• Data and Safety Monitoring Board (DSMB - required for multi-site trials)
• Institutional Review Board (IRB - required)

NIH specifically requires the establishment of Data and Safety Monitoring Boards (DSMBs) for multisite clinical trials involving interventions that entail potential risk to the participants, and generally for Phase III clinical trials. Although Phase I and Phase II clinical trials may also use DSMBs, smaller clinical trials may not require this oversight format, and alternative monitoring plans may be appropriate.

A detailed Data and Safety Monitoring Plan must be submitted to the applicant's IRB and subsequently to the funding IC for approval prior to the accrual of human subjects (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html).

f. Vertebrate Animals.

If you have marked Item 5 on the Face Page of the application "Yes," create a section heading entitled "Vertebrate Animals." Place it immediately following the "Research Design and Methods" section of the application (or after Item e, if applicable.)

Under the Vertebrate Animals heading address the following five points. In addition, when research involving vertebrate animals will take place at collaborating site(s) or other performance site(s), provide this information before discussing the five points. Although no specific page limitation applies to this section of the application, be succinct.

1. Provide a detailed description of the proposed use of the animals in the work outlined in the Research Design and Methods section. Identify the species, and numbers of animals to be used in the proposed work; discuss the strains, ages, and sex of the animals if important.
2. Justify the use of animals, the choice of species, and the numbers to be used. If animals are in short supply, costly, or to be used in large numbers, provide an additional rationale for their selection and numbers.
3. Describe the procedures for ensuring that discomfort, distress, pain, and injury will be limited to that which is unavoidable in the conduct of scientifically sound research. Describe the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices, where appropriate, to minimize discomfort, distress, pain, and injury.
4. Describe what will become of each animal

g. Literature Cited

List all references. The list may include, but may not replace, the list of publications required in the Progress Report for competing continuation applications.

Each reference must include the title, names of all authors, book or journal, volume number, page numbers, and year of publication. The reference should be limited to relevant and current literature. While there is not a page limitation, it is important to be concise and to select only those literature references pertinent to the proposed research.

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