Part 1. Overview Information

Key Dates

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.

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.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. 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.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
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

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 heterogeneity 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-25-210

Background

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.

Consultation With NIH

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)

ORWH is part of the Office of the Director of NIH and works in partnership with the 27 NIH Institutes and Centers to ensure that women's health research is part of the scientific framework at NIH and throughout the scientific community. Given the knowledge gaps in probiotic research in differential responses to the same probiotic intervention among individuals, there is a crucial need to understand the variability in clinical effects in terms of biological sex and gender. ORWH is interested in supporting projects focused on accelerating precision probiotic interventions for specific women’s health conditions across the lifespan, including but not limited to reproductive health, pregnancy, postpartum health, lactation, vaginal microbiome (bacterial vaginosis), menopause-related symptoms, and autoimmune disorders that are more prevalent in women. In addition, there is a crucial need to address sex influences in probiotic research relevant to women's health and, where appropriate, include both sexes to better understand the influence of sex as a biological variable on health and disease. Integrating the purposeful accounting for sex as a biological variable (SABV) into biomedical research on probiotic interventions will fill gaps in our knowledge and inform more effective, personalized approaches to control specific health conditions for women and men. For additional guidance, please see the NIH-Wide Strategic Plan for Research on the Health of Women, available on the ORWH website (https://www.nih.gov/women/strategicplan).

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 materials.

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

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

1. Eligible Applicants

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

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized).

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• 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
• Regional 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

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 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.

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 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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.

2. Cost Sharing

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

Number of Applications

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.

Letter of Intent

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:

Hye-Sook Kim, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Email: [email protected]

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

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.

SF424(R&R) Cover

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.

 Other Attachments:

All attachments listed below must be provided, or the application will not be peer reviewed.

Milestones and R61-to-R33 Transition Criteria Plan
A Milestones and R61-to-R33 Transition Criteria Plan must be provided as an attachment called "Milestones and R61-to-R33 Transition Criteria.pdf" and must not exceed three pages.

The milestone plan should describe the key milestones that need to be met for each phase of the application (R61 and R33) to ensure its success, the processes that will be used to reach the milestones, and a timetable identifying when each of these key milestones will be met.

All applicants must use the following definition of a milestone in their application: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, achievable, and measurable. The research plan should include anticipated challenges to meeting milestones and propose potential mitigation or corrective actions strategies. Milestones should address overall recruitment and retention goals. The Terms and Conditions under this NOFO will include a milestone plan that is mutually agreed upon by the investigators and NCCIH.

In addition, R61-to-R33 transition criteria must be included. Applications must provide this information in a section indicated by the heading “R61-to-R33 Transition Criteria”. This section should also provide quantitative details of the R61-to-R33 transition criteria as well as a timeline for completing the R61 and R33 phases. It is anticipated that the R61 study should be completed no later than 4 months prior to the end of the R61 phase to allow for a timely submission of the transition request to the R33 phase.

The R61-to-R33 transition criteria must contain:

Brief descriptions of the threshold(s) defined to determine target host biological patterns in a chosen clinical population in response to the specified probiotic effects. Examples of comparison groups include but are not limited to:

• Probiotic intervention versus placebo
• Probiotic responder versus nonresponder 

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)
• Other metrics of classification accuracy (e.g., sensitivity and specificity metrics of 70%).

Plan for Enhancing Diverse Perspectives (PEDP)

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of actionable strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity. 
• Applicants should align their proposed strategies for PEDP with the research strategy section, providing a holistic and integrated view of how enhancing diverse perspectives and inclusivity are buoyed throughout the application.
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured.
• The PEDP may be no more than 2 pages in length and should include:
  • Actionable strategies using defined approaches for the inclusion of diverse perspectives in the project;
  • Description of how the PEDP will advance the scientific and technical merit of the proposed project;
  • Anticipated timeline of proposed PEDP activities;
  • Evaluation methods for assessing the progress and success of PEDP activities.

Examples of items that advance inclusivity in research and may be appropriate for a PEDP can include, but are not limited to:

• Partnerships with different types of institutions and organizations (e.g., research-intensive; undergraduate-focused; HBCUs; emerging research institutions; community-based organizations).
• Project frameworks that enable communities and researchers to work collaboratively as equal partners in all phases of the research process.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as human subjects in clinical trials, including those from underrepresented backgrounds.
• Description of planned partnerships that may enhance geographic and regional diversity.
• Outreach and recruiting activities intended to diversify the pool of applicants for research training programs, such as outreach to prospective applicants from groups underrepresented in the biomedical sciences, for example, individuals from underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
• Plans to utilize the project infrastructure (i.e., research and structure) to enhance the research environment and support career-advancing opportunities for junior, early- and mid-career researchers.
• Transdisciplinary research projects and collaborations among researchers from fields beyond the biological sciences, such as physics, engineering, mathematics, computational biology, computer and data sciences, as well as bioethics.

Examples of items that are not appropriate in a PEDP include, but are not limited to:

• Selection or hiring of personnel for a research team based on their race, ethnicity, or sex.
• A training or mentorship program limited to certain researchers based on their race, ethnicity, or sex.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see PEDP Guidance materials.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed.

R&R Budget

All instructions in the How to Apply- Application Guide must be followed.

PEDP implementation costs:

Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7): https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm.

R&R Subaward Budget

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.

PHS 398 Research Plan

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

Specific Aims should include brief descriptions of both the R61 and R33 phase as well as transition criteria.

The Research Strategy section should provide a rationale that is based on clear and rigorous data from preclinical or clinical studies conducted by the applicant or from the literature to support a meaningful and detectable health effect of the probiotic usage or intervention that led to the proposed studies.

This section should also provide diagrams and describe the study designs as well as the analytic plan for the R61 phase and the R33 phase separately.

R61 phase (1 or 2 years): The R61 phase should include a clear, definitive, and quantitative set of roles for the measures of target host biological patterns to determine whether the patterns are correlated with probiotic responses.

R33 phase (remainder of the 5 years): The R33 phase must describe a rigorous mechanistic animal or clinical study using a probiotic intervention to test the host biological patterns identified in the R61 phase. The R33 phase should also propose to test the sensitivity and specificity of the R61 patterns to monitor the probiotic treatment response and predict the clinical outcomes.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

Other Plan(s): 

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any year, must address a Data Management and Sharing Plan.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply- Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the How to Apply- Application Guide must be followed.

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply - Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - Application Guide.

See more tips for avoiding common errors.

Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

Upon receipt, applications will be evaluated for completeness and compliance with the application instructions by the Center for Scientific Review and responsiveness by NCCIH or Components of Participating Organizations. Applications that are incomplete, non-compliant, and /or nonresponsive will not be reviewed. 

Applications must include milestones and R61-to-R33 transition criteria. Applications that fail to include milestones and R61-to-R33 transition criteria will be considered incomplete and will be withdrawn.  

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular NOFO, note the following: This NOFO is primarily focused on exploring host biological patterns that may cause inconsistent probiotic health outcomes as proposed in the R61 phase. Secondarily, the R33 phase must determine the reproducibility and causation of these patterns to identify subgroup populations that are more likely to respond to the probiotic intervention and to enhance probiotic clinical outcomes. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed).  An application does not need to be strong in all categories to be judged likely to have a major scientific impact. As part of the overall impact score, reviewers should consider and indicate how the Plan for Enhancing Diverse Perspectives affects the scientific merit of the project.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by CSR, in accordance with NIH peer review policies and practices, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions, consistent with applicable law.

• Scientific and technical merit of the proposed project, including the PEDP, as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

Please note that reviewers will not consider race, ethnicity, age, or gender of a researcher, award participant, or trainee, even in part, in providing critiques, scores, or funding recommendations. NIH will not consider such factors in making its funding decisions.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and 
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

Not Applicable

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

• Awardees will provide updates at least annually on implementation of the PEDP.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Hye-Sook Kim, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-827-6910
Email: [email protected]

Gabriela Riscuta MD, MS, CNS
National Cancer Institute (NCI)
 Telephone: 240-276-7118

E-mail: [email protected]

Elena K Gorodetsky, M.D., Ph.D.
ORWH - Office of Research on Women's Health
Phone: (301) 594-9004
E-mail: [email protected]

Annina Catherine Burns, Ph.D., R.D.N.
ORWH - Office of Research on Women's Health
Phone: (301) 402-1770
E-mail: [email protected]

Roberto Flores-Munguia, PhD, MPH
Division of Aging Biology
National Institute on Aging (NIA)
Telephone: 301-827-4766
Email: [email protected]

Tamara L Mcnealy, PhD
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: (202) 430-1474
E-mail: [email protected]

Center for Scientific Review (CSR)
Email: [email protected]

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: [email protected]

Crystal Wolfrey
National Cancer Institute
Telephone: 240-276-6277
Email: [email protected]

Jeni Smits
National Institute on Aging (NIA)
E-mail: [email protected]

Gabriel Hidalgo. MBA
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: 301-827-4630
E-mail: [email protected]

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.