Intervention Research to Improve Native American Health (R34 Clinical Trial Optional)

Intervention Research to Improve Native American Health (R34 Clinical Trial Optional) is sponsored by NIH NIDA, NIA, NIAAA, NICHD, NIDCR, NIEHS, NIMH, NINR. Supports intervention research aimed at improving health outcomes among Native American populations.

PAR-25-378: Intervention Research to Improve Native American Health (R34 Clinical Trial Optional) This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute on Drug Abuse ( NIDA ) National Institute on Alcohol Abuse and Alcoholism ( NIAAA ) Eunice Kennedy Shriver National Institute of Child Health and Human Development ( NICHD ) National Institute of Dental and Craniofacial Research ( NIDCR ) National Institute of Environmental Health Sciences ( NIEHS ) National Institute of Mental Health ( NIMH ) National Institute of Nursing Research ( NINR ) National Center for Complementary and Integrative Health ( NCCIH ) All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers.

The following NIH Offices may co-fund applications assigned to those Institutes/Centers.

Division of Program Coordination, Planning and Strategic Initiatives, Office of Disease Prevention ( ODP ) Office of Behavioral and Social Sciences Research ( OBSSR ) Office of Research on Women's Health ( ORWH ) Tribal Health Research Office ( THRO ) Funding Opportunity Title Intervention Research to Improve Native American Health (R34 Clinical Trial Optional) Notices of Special Interest associated with this funding opportunity January 28, 2026 - NIH Removing AIDS Application Due Dates from NOFOs.

See Notice NOT-OD-26-029 . April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 .

August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy.

See Notice NOT-OD-22-189 . Funding Opportunity Number (FON) Companion Funding Opportunity See Section III. 3.

Additional Information on Eligibility . Assistance Listing Number(s) 93. 279, 93.

213, 93. 866, 93. 121, 93.

313, 93. 273, 93. 865, 93.

242, 93. 113, 93. 361, 93.

310 Funding Opportunity Purpose The purpose of this notice of funding opportunity (NOFO) is to support planning and development, including pilot or feasibility research, to improve health in Native populations. Proposed research may address health promotion, disease prevention, treatment, recovery, or services research to inform intervention implementation and dissemination.

Research with Native populations requires engagement with tribal partners and communities to develop and/or adapt interventions and clinical trial protocols, understand intervention feasibility and acceptability, and identify and/or develop scientifically rigorous and culturally appropriate study designs and methods.

Preparatory studies may fill information gaps, address unknowns, allow for strengthening of partnerships with Native community leaders and organizations, and pilot test the feasibility of the intervention and clinical trial design, thereby improving scientific rigor and cultural appropriateness of a future efficacy, effectiveness, or implementation trial.

This NOFO is part of the Intervention Research to Improve Native American Health (IRINAH) initiative, which also includes PAR-25-379 , which uses the R01 Research Project Grant mechanism. Research projects may address topics within the identified interests of any of the participating Institutes or Centers; projects are not limited to substance use and addiction research.

For the purposes of this NOFO, Native Americans are defined as people who are members of Indigenous Tribes and communities, irrespective of where they live or reside, that have been recognized as having a special political and trust relationship with the United States, including those Tribes, bands or groups terminated since 1940 and those recognized now or in the future by the State in which they reside.

This includes members or up to second generation descendants of federally recognized American Indian and Alaska Native Tribes (U.S. Constitution, Article I, Section 8, Clause 3; Cherokee Nation v. Georgia, 30 U.S. 1 (1831); Worcester v. Georgia, 31 U.S. 515 (1832); 25 U.S.C.

5301(a)), and state recognized tribes and Urban Indians as described in the Indian Health Care Improvement Act (Public Law 94-437, 25 U.S.C. 1601 et seq. , as amended by Public Law 117-58, November 21, 2021)).

Also included for purposes of this NOFO are Native Hawaiian communities as described in the Native Hawaiian Health Care Improvement Act (42 U.S.C. 11701 et seq.) Funding Opportunity Goal(s) NIH’s mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.

Open Date (Earliest Submission Date) The following table includes NIH standard due dates marked with an asterisk. Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Workspace to prepare and submit your application and eRA Commons to track your application. Part 1.

Overview Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Section II.

Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V.

Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII.

Other Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description The purpose of this notice of funding opportunity (NOFO) is to support planning and development, including pilot or feasibility research, in advance of a clinical trial testing interventions to improve health in Native populations.

Proposed research may address health promotion, disease prevention, treatment, recovery, or services research to inform intervention implementation and dissemination.

Although the scientific literature or preliminary data may provide the rationale for conducting a clinical trial, investigators often lack critical information about the study population, recruitment challenges, intervention feasibility and acceptability, outcome measures, data and statistical challenges or operational risks necessary to finalize the trial protocol completely.

Native populations experience unique sociopolitical, historical, and environmental stressors and risks that may exacerbate health conditions and/or impact the effectiveness of existing solutions to address the conditions. They also possess unique strengths and resiliencies that can mitigate stressors and inform intervention strategies.

Research with Native populations requires engagement with tribal partners and communities to develop or adapt interventions and evaluate them with clinical trial protocols that are rigorous and culturally appropriate.

Preparatory studies may fill information gaps, address unknowns, allow for strengthening of tribal partnerships, and pilot test the feasibility of the intervention and clinical trial design, thereby improving scientific rigor and cultural appropriateness of the future clinical trial.

Research projects may address topics within the identified interests of any of the participating Institutes or Centers (see Overview Information, Components of Participating Organizations in Part 1 for a list of participating ICs).

For the purposes of this NOFO, Native Americans are defined as people who are members of Indigenous Tribes and communities, irrespective of where they live or reside, that have been recognized as having a special political and trust relationship with the United States, including those Tribes, bands or groups terminated since 1940 and those recognized now or in the future by the State in which they reside.

This includes members or up to second generation descendants of federally recognized American Indian and Alaska Native Tribes (U.S. Constitution, Article I, Section 8, Clause 3; Cherokee Nation v. Georgia, 30 U.S. 1 (1831); Worcester v. Georgia, 31 U.S. 515 (1832); 25 U.S.C.

5301(a)), and state recognized tribes and Urban Indians as described in the Indian Health Care Improvement Act (Public Law 94-437, 25 U.S.C. 1601 et seq. , as amended by Public Law 117-58, November 21, 2021)).

Also included for purposes of this NOFO are Native Hawaiian communities as described in the Native Hawaiian Health Care Improvement Act (42 U.S.C. 11701 et seq.) Despite tremendous strengths, Native populations have significantly varying rates of disease across many health outcomes such as chronic disease, substance use and addiction, cancer, mental illness, and sexually transmitted diseases.

These disease outcomes in many cases can be traced to social and environmental challenges such as poverty, unemployment, pollution, and poor access to health care in combination with unique factors impacting Native people, such as historical trauma. In the face of these challenges, resiliencies and strengths within Native communities and individuals have been drawn upon to improve health outcomes.

A critical step towards ensuring scalable and sustainable interventions to reduce significantly varying rates of diseases and health conditions impacting Native communities is the development of scientifically rigorous and culturally appropriate clinical trials to test intervention efficacy, effectiveness, and implementation.

Active and meaningful engagement of tribal communities and tribal leadership is essential to successful intervention development, adaptation, testing, implementation, and dissemination and to accelerate the translation of findings generated by the proposed research into practice.

To this end, this R34 NOFO supports planning studies to strengthen community and tribal partnerships, develop and adapt interventions, collect intervention feasibility and acceptability data, test recruitment and retention strategies, and/or address clinical trial study design questions.

Studies under this R34 planning grant are intended to address issues that will prepare the future clinical trial protocol for successful implementation and completion and facilitate rigorous full-scale testing of promising interventions to improve health of Native people and communities.

Applicants must include specific milestones and/or study targets that, if met, will indicate readiness to conduct the planned future intervention efficacy, effectiveness, or implementation trial. This NOFO is part of the Intervention Research to Improve Native American Health (IRINAH) initiative (see: https://cancercontrol. cancer.

gov/native-american-intervention ). The initiative also includes PAR-25-379 , which uses the R01 Research Project Grant mechanism. Not all NIH Institutes and Centers (ICs) participate in all three NOFOs .

Please speak with the Scientific Contact for the IC listed in Section VII below for the IC you wish to target to discuss which NOFO might be the best fit for your proposed project. The activities proposed will depend on the stage of intervention development, the delivery setting, and the type of future trial proposed (e.g., efficacy, effectiveness, or implementation).

Pilot tests of feasibility and acceptability of the intervention and/or future trial protocol are within scope of this NOFO. Research should be designed in such a way that there is a high probability that interventions delivered can be scaled and sustained if the future trial finds the intervention to be effective.

To ensure sustainability of intervention designs and service delivery strategies tested, applicants should, whenever possible, partner with tribes/communities and localities that use existing programming funds (e.g., funding from CDC, SAMHSA, Indian Health Services, Medicaid, Medicare and other insurance providers, and other program funding as appropriate) to support evidence-based programs and leverage those resources as the foundation for building infrastructure.

Examples of appropriate research activities include the following, but this list is not intended to be exhaustive: Activities to further develop and establish meaningful and trusted partnerships with Native communities.

Develop culturally grounded study designs in collaboration with Native community partners to ensure acceptability and feasibility in Native communities, including developing and/or selecting an intervention, defining the appropriate study population, outcome, study endpoint, and control or comparison group to use in the subsequent efficacy, effectiveness, or implementation trial.

Determine the acceptability and feasibility of the intervention for study participants, Native communities, and tribal partners, including standardization across sites and measures of intervention fidelity when appropriate. Adapt, standardize, and/or validate an intervention or assessment originally designed for non-Native populations for Native populations.

Develop a novel intervention grounded in Indigenous Knowledge, empirical and/or theoretical evidence, and/or adapt or standardize an intervention currently used in Native communities to plan for a future efficacy or effectiveness trial. Develop culturally appropriate recruitment and retention strategies that engage Native communities.

Develop culturally informed study protocols, data and safety monitoring plans, analytical plans, and data management and sharing plans. Standardize and test the effectiveness of training tools for implementation of the intervention or clinical trial protocol.

Employ qualitative methods, including talking circles, interviews, or focus groups as needed to address study aims and the development, testing and validation of quantitative survey tools. Qualitative or mixed methods research may also be helpful to assess community or tribal approval and commitment and to contextualize quantitative research findings as appropriate.

Planning activities to assess the potential feasibility and acceptability of implementation strategies to be utilized in a future implementation research trial in Native communities, including planning for hybrid effectiveness implementation studies. This R34 NOFO will not support research testing intervention efficacy or effectiveness.

Efficacy or effectiveness research could be submitted to the companion IRINAH R01 NOFO ( PAR-25-379 ). Preliminary data are not required for this NOFO.

Applications Not Responsive to this NOFO The following types of studies are not responsive to this NOFO and will not be reviewed: Applications that do not include an intervention or proposal to develop an intervention within the award period Applications that propose efficacy or effectiveness testing of an intervention Applications that only propose to write a protocol or manual Applications that propose research objectives that are not aligned with the mission of any of the participating ICs Applications that do not propose community-engaged projects Additional Considerations for Proposed Research Applicants are encouraged to consult American Indian and Alaska Native Research in the Health Sciences: Critical Considerations for the Review of Research Applications, which can be found at https://dpcpsi.

nih. gov/sites/default/files/Critical_Considerations_for_Reviewing_AIAN_Research_508. pdf Coordination across projects .

Although the studies supported by the IRINAH initiative will not use a common study protocol, investigators are expected to meet regularly to participate in activities in support of advancing research on Native health. Such activities could include participating in cross-cutting interest groups, sharing and discussion of measures, and developing collaborative publications and products.

An annual meeting will be held of all investigators with optional attendance by community partners funded by the IRINAH initiative; monthly or bi-monthly phone calls will also be held. Locations of the annual meeting will vary depending on sites funded through the initiative. Project budgets should include costs for one or more study team members to attend the annual meeting.

Conceptions of Health. While the absence of a particular disease is a critical outcome, the concept of health within many Native communities embodies wellness and is broader than the absence of disease. All four elements of life — physical, emotional, mental, and spiritual — are intricately woven together and interact to support a strong and healthy person.

In this holistic perspective, illness results from imbalance and wellness from balance in these elements. For Native people who identify strongly with tribal or indigenous culture, working with traditional healers or engaging in traditional cultural practices may be a core strategy to address disease or improve wellness.

For this NOFO, investigators are encouraged to consider Native concepts of health and Native traditional practices as appropriate and approved by the community. Community Engagement. The appropriate conduct of research with Native populations has been widely documented; research must be conducted in a community-engaged manner, where the community has an equal voice as a research partner.

The research should be consistent with community desires and informed by these at every step of the process. Community based participatory research (CBPR) approaches are one way to ensure appropriate engagement with communities in research and the cultural appropriateness of the intervention, study design and overall approach. Where communities desire to do so, researchers should incorporate a CBPR approach.

Communities may choose to pursue approaches other than CBPR, and other forms of community-engaged research are acceptable for this NOFO. The community/tribe(s) must be appropriately involved in the study design and overall approach. Culturally Appropriate Research and Preparatory Activities.

Native communities and experts on Native research have made clear the importance of culture in addressing health outcomes.

Investigators are encouraged to consider culturally unique etiological factors or targets for intervention, relying on culturally relevant theories to frame research, considering culturally specific world views and Indigenous Knowledge as they relate to the research approach and design, culturally sensitive research processes, and culturally appropriate measurement strategies and processes. Strength-Based Focus.

Since many communities place a high value on the strengths and resilience of Native peoples, investigators are encouraged to incorporate community/cultural strengths and resilience. It is appropriate to consider community resilience in addition to the resilience of individuals. Interventions.

Interventions must be consistent with community cultural values, and be supported by theory or empirical knowledge, which can originate from Indigenous Knowledge or from culturally appropriate non-Native paradigms. Interventions may include traditional health, medical, and/or cultural practices independent of or in concert with practices that have been tested in research with non-Native populations.

Intervention delivery should, whenever possible and scientifically or otherwise appropriate, employ individuals from the community. Such interventionists could include behavioral professionals, community health workers, counselors, nutritionists, nurse practitioners, physician assistants, or traditional healers.

Beyond the Individual Reflecting the importance of community and relations, researchers should consider proposing studies that address community, institutional, familial, peer network, or other factors that directly influence health outcomes or that impact individual's abilities to enact health preserving practices.

This could include multi-level intervention approaches or addressing and reporting on changes in known contextual influences while intervening to create individual level change. However, the interventions should not be so intensive or time-consuming that they would exceed the resources of the participants/community to participate or affect sustainability.

Future Clinical Trial Design Considerations: Investigators are encouraged to work with Tribal partners and communities to identify potential research designs that will provide robust evidence of intervention efficacy or effectiveness in the future clinical trial. Rigorous research designs are expected, but investigators are not required to conduct randomized controlled trials in the future trial.

and to ensure that they have appropriate statistical expertise on the study team to address any non-independence or other potential sources of bias in the study design.

If participants are assigned to study arms for the future trial, other potentially appropriate study designs with randomization include parallel group or cluster-randomized trials, individually randomized group-treatment trials, and stepped wedge group or cluster-randomized trials.

When it is not possible to assign participants to study arms for the future trial, alternative rigorous research designs that provide robust evidence of intervention effectiveness include, but are not limited to, multiple baseline or repeated measures designs, interrupted time series studies, or stepped-wedge cluster randomized trials in which all subjects receive the intervention.

In these studies, special methods may be warranted for analysis and sample size estimation, particularly for small samples where traditional experimental randomization is not possible without impacts on bias or contamination. Planning activities proposed under this NOFO may include working to incorporate such methods into the clinical trial protocol and research design.

Participating NIH ICs have identified priority research areas (see Overview Information, Components of Participating Organizations in Part 1 for a list of participating ICs). Applicants are encouraged to speak with IC representatives for technical assistance (see Agency Contacts in Section VII).

Applicant organizations with limited research experience are strongly encouraged to develop applications in collaboration with research organizations. Applicants should ensure that the IC they wish to target participates in the IRINAH NOFO to which they wish to submit. Applications that do not align with the missions of any of the participating ICs will be considered non-repsonsive.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs. See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity. Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types.

Only those application types listed here are allowed for this NOFO. Optional: Accepting applications that either propose or do not propose clinical trial(s). Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Applicants may request direct costs of up to $450,000 for three years.

Although variations from year to year are permissible, in no case may any year be more than $225,000 in direct costs, and total direct costs for the entire project period may not exceed $450,000. The scope of the proposed project should determine the project period. The maximum project period is 3 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO. Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply. Applicant organizations must complete and maintain the following registrations as described in the How to Apply-Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted.

Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2. 3.

9. 2 Electronically Submitted Applications . System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually .

The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code. NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.

Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM. gov registration process. The same UEI must be used for all registrations, as well as on the grant application.

eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.

Grants. gov – Applicants must have an active SAM registration in order to complete the Grants. gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role.

Obtaining an eRA Commons account can take up to 2 weeks. Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply- Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

This means that the NIH will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application. A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced.

Applications that are out of compliance with these instructions may be delayed or not accepted for review. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply-Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the How to Apply-Application Guide must be followed.

Milestone and Study Target Plan - Required - 2 page maximum Applicants must include an Other Attachment entitled Milestone and Study Target Plan. This R34 NOFO is intended to provide planning time for a future trial; the Milestone and Study Target Plan should describe the decision points that would justify moving to a full trial based on the planned activities in the R34 and the nature of the future trial.

Such targets might include agreements reached with community and tribal partners, success metrics for recruitment strategies, measure validation metrics, thresholds for measures of intervention and/or protocol acceptability and feasibility, or any other appropriate milestone or target. These decision points should be specific, well justified and, when appropriate, should be quantified.

Milestones and study targets should not be a restatement of the study aims. The justification for the milestones and study targets should be discussed in the context of the goal of the future trial (e.g., testing intervention efficacy, effectiveness, or implementation) and include the specific ways that reaching these targets will indicate readiness for a future trial of the intervention.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions: The combined budget for direct costs for the project period may not exceed $450,000. No more than $225,000 in direct costs may be requested in a single year.

Budgets should include domestic travel funds for one or more study team members to attend the annual IRINAH investigators meeting. All instructions in the How to Apply-Application Guide must be followed. PHS 398 Cover Page Supplement All instructions in the How to Apply- Application Guide must be followed.

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions: The Research Strategy should describe the significance of the proposed research in the context of the future efficacy, effectiveness, or implementation trial it is meant to inform.

Applicants must provide evidence that the research question addressed is relevant to and prioritized by the Native community partners for the study and that the project, if completed successfully, can improve the health of one or more Native communities. Applicants should clearly articulate how their research builds fundamental knowledge relevant to Native health.

NIH’s mission is to seek fundamental knowledge about the nature and behavior of living systems and to use that knowledge to enhance health, lengthen life, and reduce illness and disability. Through this initiative, fundamental knowledge includes findings that may be specific to a Native American community or group of communities, even if the outcomes may not generalize broadly.

Fundamental knowledge may also be defined as principles for community engaged research, or methodological innovations. Applicants must demonstrate innovation in their proposed research. Some examples of the types of innovations that may be included are the use