Enhancing Mechanistic Research on Precision Probiotic Therapies (R61/R33 Clinical Trial Optional) (PAR-24-238)

Enhancing Mechanistic Research on Precision Probiotic Therapies (R61/R33 Clinical Trial Optional) (PAR-24-238) is sponsored by National Institutes of Health (NIH), National Center for Complementary and Integrative Health (NCCIH), National Institute on Aging (NIA), National Institute of Dental and Craniofacial Research (NIDCR), National Cancer Institute (NCI). Enhancing Mechanistic Research on Precision Probiotic Therapies (R61/R33 Clinical Trial Optional) (PAR-24-238) is sponsored by National Institutes of Health (NIH), National Center for Complementary and Integrative Health (NCCIH), National Institute on Aging (NIA), National Insti…

Expired PAR-24-238: Enhancing Mechanistic Research on Precision Probiotic Therapies (R61/R33 Clinical Trial Optional) This notice has expired. Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Center for Complementary and Integrative Health ( NCCIH ) National Institute of Dental and Craniofacial Research ( NIDCR ) National Cancer Institute ( NCI ) 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.

Office of Dietary Supplements ( ODS ) Office of Research on Women's Health ( ORWH ) Office of Nutrition Research ( ONR ) Funding Opportunity Title Enhancing Mechanistic Research on Precision Probiotic Therapies (R61/R33 Clinical Trial Optional) R61 / R33 Exploratory/Developmental Phased Award October 31, 2024 - This PAR has been reissued as PAR-25-211 .

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 Exploratory/Developmental Grants Phase II See Part 2, Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s) 93. 213, 93. 866, 93.

313, 93. 121, 93. 393 Funding Opportunity Purpose The purpose of this notice of funding opportunity (NOFO) is to support highly innovative mechanistic research to accelerate the development of effective precision probiotic interventions using a milestone-driven, biphasic award mechanism.

It aims to identify, understand, and develop strategies to address barriers in precision probiotic interventions to account for the heterogenicity in humans that often causes inconsistent probiotic therapeutic responses.

Specifically, this NOFO solicits applications that will characterize person-specific features affecting probiotic responses to identify subgroups of probiotic responders, which may then help enhance probiotic clinical outcomes.

The first phase, funded by the R61 mechanism, will provide 1 or 2 years of support to identify host biological patterns (e.g., native microbiome, immune system, sex and/or gender, diet, age, genetic background, lifestyle, or health history) that are correlated with differences in probiotic clinical effects using observational or secondary data analysis studies.

The second phase, funded under the R33 mechanism, will support studies to assess the causality of the factors identified in the R61 phase that impact probiotic responsiveness through rigorous mechanistic study designs in animal models or human subjects. This NOFO will not support efficacy or effectiveness clinical trials. The combined R61/R33 should not exceed 5 years.

Transition to the R33 phase requires administrative review by NIH staff and is not guaranteed. Approval of the transition to the R33 phase will be based on the original R61/R33 peer review recommendations, successful completion of transition milestones, any proposed changes to the R33 research based on R61 findings, program priorities, and availability of funds. It is not expected that all applications will continue to the R33 phase.

Support for a single phased award that does not need the R61 Exploratory phase is available in the companion (R33) NOFO, PAR-24-239 . This Notice of Funding Opportunity (NOFO) requires a Plan for Enhancing Diverse Perspectives (PEDP).

Open Date (Earliest Submission Date) Letter of Intent Due Date(s) 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.

New Date October 31, 2024 per issuance of PAR-25-211 . (Original Expiration Date: June 03, 2027) 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 How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide , follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review. 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 highly innovative mechanistic research to accelerate the development of effective precision probiotic interventions using a milestone-driven, biphasic award mechanism.

It aims to identify, understand, and develop strategies to address barriers in precision probiotic interventions to account for the heterogenicity in humans that often causes inconsistent probiotic therapeutic responses.

Specifically, this NOFO solicits applications that will characterize person-specific features affecting probiotic responses to identify subgroups of probiotic responders, which may then help enhance probiotic clinical outcomes.

The first phase, funded by the R61, will provide for 1 or 2 years of support to identify host biological patterns (e.g., native microbiome, immune system, sex and/or gender, diet, age, genetic background, lifestyle, or health history) that are correlated with differences in probiotic clinical effects using observational or secondary data analysis studies.

The second phase, funded under the R33, will support studies to assess the causality of the factors identified in the R61 phase to impact probiotic responsiveness through rigorous mechanistic study designs in animal models or human subjects. This NOFO will not support efficacy or effectiveness clinical trials. The combined R61/R33 should not exceed 5 years.

Transition to the R33 phase requires administrative review by NIH staff and is not guaranteed. Approval of the transition to the R33 phase will be based on the original R61/R33 peer review recommendations, successful completion of transition milestones, any proposed changes to the R33 research based on R61 findings, program priorities, and availability of funds. It is not expected that all applications will continue to the R33 phase.

Support for a single phased award that does not need the R61 Exploratory phase is available in the companion (R33) NOFO, PAR-24-239 . Naturally occurring microbial-based therapeutics include probiotics—living microorganisms such as bacteria and yeast that are reported to have beneficial health effects.

The broad range of reported effects may include alleviation of gastrointestinal symptoms, “strengthening” of the immune system, protection against infectious diseases, improvements in metabolic and mental health, and promotion of early development and general well-being.

A major challenge in probiotic research is variation in responses reported for the same intervention, both between trials and among individuals, resulting in significant variability in clinical effects and reported trial outcomes.

Such variability may stem from heterogeneity in humans related to diet, age, genetic background, sex and/or gender, health history, lifestyle, and native gut microbial composition including bacteria, fungi, viruses, archaea, and protozoa. These factors may hamper effective evaluation of clinical efficacy of probiotics and their integration as well as implementation into treatment regimens.

One potential solution to tackle this major challenge is to develop a precision probiotics intervention paradigm that has the capability to predict interindividual variations and tailor probiotic strains to individual-specific features.

However, this approach requires fundamental understanding of real-life variability of probiotic responses at the individual level as well as development of innovative research tools and strategies to address the complexity of person-specific characteristics.

In April 2022, the National Center for Complementary and Integrative Health (NCCIH) and the Office of Dietary Supplements (ODS) within the National Institutes of Health (NIH), in collaboration with other NIH Institutes, Centers, and Offices as well as the U.S. Department of Agriculture, convened a 2-day workshop, “Precision Probiotic Therapies—Challenges and Opportunities,” to better understand the status and potential future directions of precision probiotic research and to discuss the associated research questions and methodological challenges.

The video recordings (Day 1 and Day 2) and executive summary can be found here: https://www. nccih. nih.

gov/news/events/precision-probiotic-therapies-challenges-and-opportunities . During the workshop, several major areas of interest emerged.

First, it was recognized that the study designs of most probiotic clinical trials did not fully capture the complex patterns of the gut microbiome, host genetic variability, dietary differences, and environmental exposures of both the microbes and hosts, although all of these are critical considerations for probiotic responsiveness within individuals.

Second, although many cross-sectional observational epidemiologic studies have examined these complex patterns, few of their insights have been effectively translated to robust mechanistic studies to test for causality or to rigorous mechanistic clinical trials.

Third, understanding the intricate relationships among multiple complex systems, including the microbiome, host, and environment, requires advanced computational and artificial intelligence (AI) approaches.

Research Objectives and Requirements This NOFO is intended to support mechanistic research for characterization of person-specific features affecting probiotic responses to identify subgroups of probiotic responders and enhance probiotic health outcomes. The NOFO aims to achieve two major objectives using the R61/R33 phased approach.

Objective 1 (R61 Phase): Observational or Secondary Data Analysis Studies (1 or 2 years) The R61 phase will support observational clinical studies or secondary data analysis to identify patterns of host biology (e.g., native microbiome, immune system, sex and/or gender, diet, age, genetic background, lifestyle, or health history) that are correlated with probiotic usage or interventions.

Examples of activities for R61 phase include but are not limited to: Scanning host characteristics to uncover person-specific factors showing highly significant associations with probiotic responses. Developing computational analysis or machine learning approach to identify host biological factors.

Discovering new microbial strains from human samples that are correlated with probiotic activity and improving consistency of probiotic clinical outcomes. Objective 2 (R33 Phase): Mechanistic Studies (Clinical Trial Optional, remainder of the 5 years) The R33 phase will use the patterns identified in the R61 phase to test for causality in rigorously designed mechanistic studies in animal models or human subjects.

Examples of activities for the R33 phase include but are not limited to: Determining causal effects of the host biological patterns observed in the R61 phase on modifying probiotic responses in clinically relevant preclinical models or human populations. Elucidating the mechanisms through which the patterns identified in the R61 phase modify probiotic responses.

Optimizing and verifying the ability of the computational and machine learning tools developed in the R61 phase to identify host biological patterns in clinically relevant preclinical models or human populations. Determining the effects and underlying mechanisms of probiotic activity by the microbial strains identified from the R61 phase.

For applications proposing a clinical trial, note the following definitions and restrictions for this NOFO: Clinical trials are research studies in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.

The following types of clinical trials are considered to be in scope of this NOFO: Mechanistic trials , defined as studies designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention (i.e., how an intervention works, but not if it works or is safe).

Clinical trials designed primarily to determine the clinical feasibility, efficacy, and effectiveness of a probiotic intervention will not be supported under this NOFO . Preliminary/Supporting Data Requirements No preliminary data are required for the R61 phase. However, feasibility may be demonstrated through literature citations or preliminary data in animal or human subject studies.

Applications should be based on a clear scientific premise, and compelling rationales should be presented for the proposed study and selection of probiotic usage or intervention. Regulatory Requirements to Consider The U.S. Food and Drug Administration (FDA) establishes and enforces the regulatory requirements for clinical research on probiotics when used as drugs.

Because NCCIH is a Federal agency, any research supported with NCCIH funding must adhere to relevant FDA regulations. Prior to submitting an application, investigators must contact the FDA to determine whether an Investigational New Drug (IND) application is necessary for the proposed clinical research.

For trials using an FDA regulated product and requiring an IND application, the applicant must either hold or be able to reference an open IND for the trial, or the applicant must obtain an IND with no clinical hold prior to any award. If the FDA has granted a waiver for the trial proposed in the application, the applicant can provide this letter as part of the Regulatory Communication Plan.

Guidance on the IND evaluation process can be found on the NCCIH Natural Products Clinical Trials Resource webpage: https://www. nccih. nih.

gov/grants/natural-products-clinical-trials-resource . Applications Not Responsive to This NOFO The following types of applications will be considered nonresponsive and will be withdrawn prior to review: Applications that do not provide clear milestones and a clear path to transition from the R61 to the R33 phase of the award.

Clinical trials designed primarily to determine the clinical feasibility, efficacy, or effectiveness of a probiotic intervention. R61 to R33 Transition Criteria and Process Investigators are expected to describe a set of transition criteria in the form of quantitative milestones (please see Section IV.

2 Other Project Information and Research Plan for detailed instructions) that will allow for a definitive assessment of whether the R61 phase provides sufficient evidence to support the R33 phase of this bi-phasic award. Key evidence in the transition criteria should include thresholds for quantitative measures of host biological patterns proposed to study in the R61 phase.

If multiple thresholds are proposed, prioritization should be provided to determine which measure(s) would be moved forward into the R33 phase for further development. Alternatively, the threshold of a composite measure may be described and proposed for R33 phase development if multidimensional measures of host biological patterns are assessed in the R61 phase. Quantitative milestones must include specific thresholds.

Examples of metrics include but are not limited to effect sizes (e.g., Cohen’s d >0. 3), average area under the curve (e.g., AUC of 0. 7), or other metrics of classification accuracy (e.g., sensitivity and specificity metrics of 70%).

It is anticipated that the R61 study should be completed within 20 months post award to allow for a timely submission of the transition request to the R33 phase. Awardees will submit the R33 transition package, which includes a detailed progress report describing advancement toward the initial R61 milestones and a description of how the completed work justifies continuation with the originally proposed R33 studies.

These materials will be evaluated by NIH program staff. It is understood that the proposed milestones for the R33 phase may be revised based on activities during the R61 planning phase. In the event of an award, the PD(s)/PI(s) and NIH staff will negotiate a list of milestones for each year of support.

Transition to the R33 phase is neither automatic nor guaranteed. R33 funding decisions will be based on the original R61/R33 peer review recommendations, successful completion of R61 milestones, program priorities, and availability of funds. Applications that only propose R61 or R33 activities will be considered incomplete and will not be accepted for this NOFO.

Studies that have already identified unique patterns of interplay and/or putative probiotic strains should be supported by the R33 phase directly. Support for a single phased award that does not need the R61 Exploratory phase is available in the companion R33, PAR-24-239 .

Applicants are encouraged to consult with the NIH scientific contacts listed in the NOFO before they begin developing their applications (see Section VII, Agency Contacts). This early contact will provide an opportunity to clarify whether the research topic is a fit with the NOFO’s purpose and priorities.

NIH Institute and Center Interests and Guidance The National Center for Complementary and Integrative Health (NCCIH) NCCIH is interested in projects focused on accelerating precision probiotic interventions for specific health conditions within the mission of NCCIH.

Topics of special interest include but are not limited to pain, stress, anxiety, sleep and other symptoms, health promotion and restoration, resilience, metabolic and mental disorders, and gastrointestinal dysfunction. Investigators are strongly encouraged to discuss their research plans with the NCCIH scientific/research contact prior to submitting their applications.

The National Institute of Dental and Cranial Facial Research (NIDCR) NIDCR is interested in projects focused on accelerating precision probiotic interventions for specific health conditions within the mission of NIDCR. Topics of special interest include but are not limited to prevention and treatment of caries, periodontal disease, and oral fungal disease and promotion or restoration of oral health.

Investigators are strongly encouraged to discuss their research plans with the NIDCR scientific/research contact prior to submitting their applications. NIDCR will accept Basic Experimental Studies involving Humans (BESH) clinical trial but not mechanistic clinical trial applications through this mechanism.

The NIH Office of Dietary Supplements (ODS) The NIH Office of Dietary Supplements (ODS) is interested in co-funding projects focused on probiotics for health conditions within the mission of ODS. Topics of special interest include, but are not limited to promoting mucosal immunity, preventing, and ameliorating symptoms associated with digestive diseases, and optimizing health and resilience in diverse populations across the lifespan.

The ODS will not support projects focused on diagnosis and/or treatment of disease. The ODS does not award grants; therefore, applications must be relevant to the objectives of at least one of the participating NIH Institutes and Centers (IC) listed in this announcement. Please contact the relevant IC Scientific/Research Contact(s) listed for questions regarding IC research priorities and funding.

The Office of Research on Women’s Health (ORWH) The National Institute on Aging (NIA) The Division of Aging Biology (DAB) in NIA is interested in pre-clinical and clinical research projects focused on understanding the host factors and mechanisms affecting age-related changes in probiotic responses (e.g. immune-senescence and other innate/adaptive immune responses in next-gen probiotic research).

Identification of bacterial strains and their metabolites that can be used as probiotics/postbiotics to improve health outcomes in older adults. Mechanistic research on the effects of probiotics applied to understudied anatomical niches (e.g. oral mucosa and periodontal disease; cervicovaginal and bacterial vaginosis; and skin probiotics that improve dermatosis associated with aging).

Interrogating mechanistic insights of the probiotic effects on health outcomes across the lifespan. Characterization of factors affecting the efficacy of probiotic intervention (e.g. microbial composition, quorum sensing, role of keystone species, and long-term effects of probiotic treatment).

Developing computational analysis and AI/ML algorithms to build predictive models to identify patient subpopulations and critical factors in response to probiotic treatment (e.g. in frailty and older individuals).

The National Cancer Institute (NCI) The National Cancer Institute (NCI) supports research on the microbiome's role in cancer, particularly the effects of pre/probiotics on cancer prevention, interception, progression, and treatment. This includes studies on how probiotics interact with host cells and other microbes, influencing cellular functions and tumor development.

The Division of Cancer Prevention ( DCP) is interested in investigating the potential benefits of probiotics in cancer prevention. Specifically, DCP is interested in understanding the interaction of probiotics with cancer-associated pathogens, alterations in metabolite production, and reduction of pro-carcinogens. Applications of biomarkers in measuring aforesaid counteractive interactions of probiotics are highly encouraged.

Additionally, DCP fosters research on how probiotics impact biofilm composition, functional changes, and their effectiveness in preventing cancer.

The Division of Cancer Biology is interested in basic and mechanistic studies on how probiotics affect tumor formation at the molecular level and the interactions between probiotics, host cells, and the resident microbiome, focusing on how these interactions influence cellular signaling, physiology, and metabolism.

The Division of Cancer Control and Population Sciences seeks to advance research to demonstrate whether genomic background in different racial and ethnic populations makes them responsive to pre/probiotic exposure and their effects on improving cancer outcomes.

Plan for Enhancing Diverse Perspectives (PEDP): The NIH recognizes that teams comprised of investigators with diverse perspectives working together and capitalizing on innovative ideas and distinct viewpoints outperform homogeneous teams.

There are many benefits that flow from a scientific workforce rich with diverse perspectives, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH encourages inclusivity in research guided by the consideration of diverse perspectives. Broadly, diverse perspectives can include but are not limited to the educational background and scientific expertise of the people who perform the research; the populations who participate as human subjects in research studies; and the places where research is done.

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), which will be assessed as part of the scientific and technical peer review evaluation. Assessment of applications containing a PEDP are based on the scientific and technical merit of the proposed project.

Consistent with federal law, the race, ethnicity, or sex of a researcher, award participant, or trainee will not be considered during the application review process or when making funding decisions. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review. The PEDP will be submitted as Other Project Information as an attachment (see Section IV).

Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance See Section VIII. Other Information for award authorities and regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

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. Both the R61 and R33 budgets should not exceed $350,000 in direct costs per year. The scope of the project should determine the project period for each phase.

The maximum period of the combined R61 and R33 phases is 5 years, with 1 or 2 years for the R61 phase. 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 The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education: Hispanic-serving Institutions Historically Black Colleges and Universities (HBCUs) Tribally Controlled Colleges and Universities (TCCUs) Alaska Native and Native Hawaiian Serving Institutions Asian American Native American Pacific Islander Serving Institutions (AANAPISIs) 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. Foreign components, as defined in the NIH Grants Policy Statement , are allowed. 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 NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information 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 registrations; 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.

Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities , NOT-OD-22-019 .

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 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 How to Apply - Application Guide is required and strictly enforced.

Applications that are out of compliance with these instructions may be delayed or not accepted for review. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows Institute and Center (IC) staff to estimate the potential review workload and plan the review. By the date listed in Part 1.

Overview Information , prospective applicants are asked to submit a letter of intent that includes the following information: Descriptive title of proposed activity Name(s), address(es), and telephone number(s) of the PD(s)/PI(s) Names of other key personnel Participating institution(s) Number and title of this funding opportunity The letter of intent should be sent to: National Center for Complementary and Integrative Health (NCCIH) 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. All attachments listed below must be provided, or the application will not be peer reviewed. 1.

Milestones and R61-to-R33 Transition Criteria