It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) 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.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. 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

Purpose

The purpose of this funding opportunity announcement (FOA) is twofold: (1) to stimulate basic and mechanistic science that facilitates the development of effective probiotics or pre-/probiotic combinations of relevance to human health and disease; and (2) determine biological outcomes for the evaluation of efficacy of pre/probiotics in appropriate test systems and animal models. This FOA encourages basic and mechanistic studies using in vitro, in vivo, ex vivo, and in silico models that focus on prebiotic/probiotic strain selectivity, interaction, and function. It will also encourage inter and multidisciplinary collaborations among scientists in a wide range of disciplines including nutritional science, immunology, microbiomics, genomics, other '-omic' sciences, biotechnology, and bioinformatics.

Background

Probiotics are defined as "live microorganisms which, when administered in adequate amounts confer a health benefit on the host". This definition is sufficiently inclusive of a broad range of microbes and applications, and captures the essence of probiotics (microbial; viable; and beneficial to health). Prebiotics are considered as "non-viable food component that confers a health benefit on the host associated with modulation of the microbiota". Despite the exponential growth in the marketing of prebiotic/probiotic products, fundamental knowledge gaps regarding their health benefits remain, including the understanding of their molecular mechanisms of action, long-term effects and their potential interactions with the host physiology. For example, to design therapeutic/preventive manipulations of the gut microbiota, it is critical to understand the evolutionary and ecologic interplay among the GI microbiota and host physiology. This FOA will support the generation of valid and reliable evidence to show that prebiotic/probiotics as singular or combination formulations can stimulate specific measurable and beneficial functions of the host microbiota. The study of biochemical and genomic expression pathways and host-microbial interactions among prebiotic compounds, probiotic strains and the host microbiota will provide a sound basis for developing effective singular or combination pre/probiotic applications for enhancing or restoring functional health.

Many events can shape or alter microbial communities. For example, human/microbial co-evolution is uniquely selected for coupling structure-specific nutrient (prebiotic) substrates with (probiotic) strain-specific functions to promote growth of a 'healthy' microbiota in breast-fed infants. Diet may potentially serve as the primary modulator of mammalian microbiota for infant growth and development. However, competing selective pressures (e.g., from exposures to xenobiotics or broad-spectrum antibiotics) disturb the normal ecological balance of host-microbial interactions. Current knowledge of the molecular interface between pre/probiotic factors and host-specific interactions with resident microbes is limited. Therefore, omics-based and other novel approaches are needed for elucidating the functional effects of pre/probiotic singular or combination formulations and microbial metabolites on the host and for the study of the taxonomic composition of the microbiome. Well characterized probiotic strains (e.g., selected lactobacillus; bifidobacterium) secrete a variety of signaling molecules that can modify inter-bacterial signaling (quorum sensing) and potentially suppress the expression of virulence genes and pathogenic-strain growth patterns. Thus, there is a need for identifying the functional roles of bacterially derived low molecular weight (LMW) bioactive molecules including bacteriocins and others that affect human health.

The LMW microbial metabolites and signal molecules in human physiologic fluids may have diagnostic value or provide key information to design products with specific nutritional and medicinal effects. Because in vivo production of bioactive small molecules of human and microbial origin is often connected with prebiotic secondary metabolism, there is much interest in developing the rational basis for conducting mechanistic studies of specific pre/probiotic singular or combination formulations for nutritional and medical purposes for specific health functions in the host.

A wide variety of concepts and technologies can guide research in this area to include:

Structure/function relationships within endogenous microbial populations Metagenomic reconstruction of community metabolism has shown that similar metabolic networks are common among individual strains suggesting functional redundancy within microbial consortia. Systems-level approaches can be utilized to determine microbial community function particularly at the metagenomic, and chemical and biological levels in diverse communities.

Functional Omics-based Technologies and Biologic Signatures of Host-Microbial Interactions High dimensional methods including meta-omic approaches that provide qualitative and quantitative information on genes, transcripts, proteins and metabolites present in microbial communities at specific points in space and time. Such approaches will highlight the intricate cross-feeding and signaling pathways between the human and microbial ecosystems by deciphering differential gene expression profiles, microbial biotransformation pathways, host epigenetic patterns and protein functions for development and safety testing of pre/probiotics in the future.

Modeling Microbial-Host Metabolite Interactions To better understand the complexity of interactions of pre/probiotics and/or their combinations in different host anatomical sites, host-microbial modeling will require further development and refinement to include:

Basic Modeling Robust in vivo, in vitro and ex vivo models, used singly or in combination, which will allow high-throughput first-pass experiments aimed at proving cause-and-effect relationships prior to hypothesis testing in animal models.

Animal Modeling - Use of animal models (germ free, gnotobiotic or others such as CONV-R treated with antibiotics) to understand the causal relationship between microbiota and host interactions.

Systems Biology Modeling In silico models in combination with in vitro, ex vivo and in vivo experimental data are promising approaches to predict metabolic interactions between gut microbes and their host in both diseased and healthy states.

Specific Objectives and Scope of this FOA

Research areas of interest may include, but not limited to and not in any order of priority, the following:

Accelerating Mechanistic Studies to Feed the Translational Pipeline

(1) Study the effect of prebiotics/probiotics on: microbial composition and function, microbial-host interactions and co-metabolism, interactions with diet, dietary supplements or dietary components, changes in microenvironment (i.e. pH, toxin production), local and systemic inflammatory response, pathogenic control.

(2) Identification of bacterial strains and bacteriophage types and characterization of the underlying mechanisms of robustness of prebiotic/probiotic formulation and microbial resilience to prevent or treat human diseases (e.g., caries, gingivitis, periodontitis, necrotizing enterocolitis, inflammatory bowel disease, cancer, hematological disease, enteric bowel infections.

(3) Characterization of commensal microbes, including probiotic strain(s) or a prebiotic compound/consortia of strains, that secrete a variety of signaling molecules that can affect microbial community dynamics and human metabolic and signaling pathways by: (a) modifying inter-bacterial signaling (e.g., quorum sensing) mechanisms and optimizing the composition and function of indigenous microbiota; (b) regulating metabolic and/or behavior reactions; (c) suppressing the expression of virulence genes in pathogens; (d) stimulating the growth of beneficial endogenous microorganisms; and (e) elucidating possible functional redundancy and synergy among the human microbiota and probiotic strains.

(4) Identification of low molecular weight bioactives (both chemical and biological molecules) and characterization of their functional role in human health and disease risk.

(5) Development of potential microbial starter cultures of human origin as a platform for meta-biotic production. This culture could be used for synthesis of structural and excreted bioactive substances participating in or regulating pathways associated with metabolism of carbohydrates, fat, and cholesterol; effect on the immune, hormone, and nervous systems; metagenome and epigenome stability; and gene expression regulation.

(6) Development and validation of animal models and characterizing their ability to recapitulate the microbial ecology of a particular body site.

(7) Characterization of mechanisms of probiotic action on host phenotypes or diseases such as IBD, chronic pulmonary, cardiac, and renal diseases, or metabolic/endocrine diseases; study the impact of the microbiome and pre/probiotic interventions on immune function, inflammation, or chronic immune activation and potential effect on therapy. These studies may, for example, implicate mechanisms of adhesion to various body surfaces; competition with pathogens for receptor binding, nutrients and colonization; enhancement of mucosal barrier function; promotion of innate and adaptive immune responses; elaboration of bacteriocins and antimicrobial action; and modulation of cell kinetics.

(8) Analysis of probiotic modulation of cell kinetics through effects on cell proliferation and apoptosis by examining the importance to homeostasis of cell death and reproduction (i.e. the ability of certain probiotics to promote normal cell propagation and concurrently inhibit abnormal cell apoptosis).

(9) Study of the mechanisms by which bacterial products interact with or affect host pathways related to intestinal barrier function, differentiation and regulation of immune cell function, regulation of intestinal regeneration and repair, and modulation of electrolyte and nutrient transport.

(10) Use of novel probiotic approaches as mucosal adjuvants to enhance vaccine immunogenicity and derived antimicrobials that provide alternatives to conventional antibiotics that are refractory to resistance development.

(11) Study the effects of substances of abuse (narcotics/opiates, alcohol, tobacco) on the efficacy of pre/probiotics and intestinal microbiome/microflora in populations with co-occurring infections including HIV, HCV and others; study if manipulation of the microbiome/human virome would alter the pathogenesis of complications of drug use such as HIV, HCV-related disease, and interactions with pre/probiotics.

New Innovative Methods and Experimental Approaches

(1) Identification, development and validation of diagnostic test assays for microbial metabolites and signal molecules produced by microorganisms in human physiological fluids.

(2) Characterization of singular or combined meta-biotic prebiotic/probiotic food and drug applications targeted to host microbiota or to indigenous microflora associated host functions, metabolic and behavior reactions.

(3) Characterization of microbial O- and N-glycans to identify possible glycosylated proteins released from probiotics and their effects on glycan-mediated signaling pathways in response to disease or under normal health conditions.

(4) Development of nutritional and pharmacologic pre/probiotic strategies: Systems biology methods and tools to study pre/probiotic associated changes in microbial ecology.

(5) Study of optimal diet against specific pathogenic bacteria related to disease prevention and characterization of the underlying mechanisms.

(6) Developing novel intervention methods including narrow-spectrum antimicrobials and probiotics that selectively target pathogenic organisms while avoiding killing of beneficial microbiota.

New Technology and Database Platforms

(1) Development and validation of rapid in vitro simulated organ systems, organoid systems, and other tissue/organ-on-a-chip systems, in the context of probiotic/prebiotic (commensal) targets and host-microbial co-metabolism.

(2) Biovalidation of high throughput screening models for preclinical toxicity testing or to ensure virulence traits are not present in candidate probiotics: testing, cataloguing, multi-omic development of standards and approaches to reduce variability.

(3) Development of integrative biology approaches for nutrigenomics and/or pharmacogenomics of prebiotic/probiotics and host-microbial co-metabolism.

(4) Development of tools and technologies that enable identification, quantification and characterization of temporal dynamics establishing causative links between external stimuli (i.e. probiotic strains, microbial bioactives or prebiotics) and the imbalance or rebalance of the human microbiota.

(5) Development of computational models that enable the generation of hypothesis testing from multi-omic data to elucidate the molecular (including small molecules) underpinnings in microbe-microbe and microbe-host interactions.

(6) Development of novel computational approaches e.g., ecological principles with predictive and therapeutic algorithms.

(7) Development of tools and technologies to program bacteria to sense and manipulate the local environment for a controlled therapeutic response.

The National Cancer Institute (NCI) encourages research on the microbiome and cancer, including the influence of pre/probiotics on functional and molecular profiles in cancer prevention, development and treatment. The Division of Cancer Biology at the NCI is interested in basic/mechanistic studies that seek to understand probiotic's underlying molecular mechanisms of action related to tumor etiology, their interactions with host cells or other resident microbes as it relates to their effects on host cell signaling, physiology or metabolism. Within the scope of the Division of Cancer Prevention, the NCI encourages research to understand how pre/probiotics compete with pathogens associated with cancer, modulate the production of metabolites and/or reduce the production of pro-carcinogens relevant to key well known risk factors or pre-neoplastic lesions. Studies concerning the effect of probiotics on biofilm composition and luminal vs. mucosal-associated functional changes related to cancer prevention would also be encouraged. Since food plays a critical role in maintaining and/or changing the gut microbiota, diet and nutrition should be considered in conjunction with pre/probiotic studies, i.e. nutrient-microbial interaction, the dose and strain of probiotics, the effect from/on underlying medical conditions (i.e. obesity, inflammatory bowel disease) and the linkages to those outcomes and cancer risk. The Division of Cancer Treatment and Diagnosis at the NCI encourages research focused on xenobiotic metabolism and the effects of probiotics and microbial metabolism on the bioavailability of anticancer agents; on the role of probiotics on immunotherapeutic interventions or cancer vaccine efficacy; and the development of molecular signatures of the biome at all stages of cancer, how that signature changes with treatment, and whether those changes predict response or resistance.

The National Institute on Drug Abuse (NIDA) supports basic, pre-clinical, clinical, and epidemiologic research on drugs of abuse and co-occurring infections (e.g., HIV, HCV) and associated consequences including the impact on human microbiome. Active drug use (opiates, alcohol, tobacco) and natural opiate and cannabinoid receptors have potential effects on the microbiome indirectly through alterations in gut motility, a known influence on the subpopulations of gut microflora. The bloodborne viral infections also occur at increased rates in injection drug users. The primary intestinal CD4 depletion that accompanies HIV infection is associated with alterations in intestinal microflora. Although, transmission of HIV, hepatitis B virus, and hepatitis C virus are the best studied, the effects of successful CD4 recovery with cART on the microbiome are incompletely understood. It is likely that the human virome is different in injection drug users. Since the composition of the human virome has been reported to affect HIV pathogenesis, it is plausible that injection drug use affects HIV pathogenesis by alteration in the virome. Thus, NIDA is interested in research on areas that may include, but not limited to: (i) the direct impact of narcotic/opiate abuse on composition of the intestinal microbiome; the impact of alterations on associated disease conditions; (ii) the effects of HIV disease on the intestinal microflora and determine what implications does this have for immune activation; (iii) the interaction of active injection drug use with HIV in regard to their collective impact on the microbiome; (iv) whether successful cART have on restitution of the microbiome; does this restitution have a beneficial effect on systemic immune activation, (v) what effect does the composition of the microbiome have on liver disease related to complications of substance abuse, including co-occurring infections such as HCV, HBV, and fatty liver disease; and (vi) does manipulation of the microbiome alter the pathogenesis of complications of drug use such as HIV and HCV related disease.

The National Institute of Dental and Craniofacial Research (NIDCR) encourages projects that pertain to the microbiota of the human oral cavity (specifically those communities composed of dentally-relevant archaea, bacteria, and fungi). Likewise, dental pre/probiotics are defined here as those agents/formulations/combinations targeting the human oral cavity and under study to treat dental diseases or to improve dental, oral, and craniofacial health.

The National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS) encourages applications that address immune or non-immune mechanisms by which a) the skin microbiome interacts with the skin at homeostasis, and b) the microbiome modulates pathogenesis of the skin, rheumatic and musculoskeletal diseases and conditions at preclinical, clinical onset and chronic phases. Examples of mechanistic studies include: 1) Characterization of microbiome-host molecular and cellular interactions. 2) Characterization of the signaling pathways that affect the dynamics of the relevant microbial communities. 3) Characterization of microbiome changes during therapy for skin, rheumatic and musculoskeletal diseases and conditions. 4) Studies of the impact of the prebiotic/probiotic interventions. Examples of skin, rheumatic and musculoskeletal diseases and conditions of interest to the NIAMS in the context of this FOA include but are not limited to: chronic skin wounds, atopic dermatitis, psoriasis, alopecia areata, vitiligo, acne, pemphigus vulgaris, rosacea, systemic sclerosis, rheumatoid arthritis, systemic lupus erythematous, inflammatory myopathies, autoinflammatory diseases, osteoarthritis, and osteoporosis.

National Center for Complementary and Integrative Health (NCCIH) actively supports research to examine mechanisms of action for probiotics/prebiotics and microbiome as high research priorities. Particularly interested outcomes include prevention and symptom management of inflammatory and pain conditions, mild to moderate anxiety, depression, and sleep conditions, and behavioral research to promote healthier lifestyles [e.g., healthy eating, physical exercise]. NCCIH will accept applications focusing on probiotic (with or without prebiotic) studies, their interactions with other natural products, or the effects of mind-body modalities on microbes. NCCIH will not fund applications that include specific aims examining clinical efficacy/effectiveness.

Research approaches supported include mechanistic in vitro models and pre-clinical animal studies, as well as mechanistic clinical trials where applicable addressing the following problems:

• Probiotic [with or without prebiotic] studies that can produce a meaningful change in measurable biological signatures (e.g., mechanism of action) in the genotype/phenotype of interest.
• Probiotic [with or without prebiotic] studies that demonstrate mechanistic effects on essential functions [immunoregulatory; anti-inflammatory; signaling pathways; energy metabolism] that enhance health and justify selection of the modality proposed to be used in the study.
• Probiotic [with or without prebiotic] studies utilizing multi-omic and cell-based technologies and ensure rigor and reproducibility, validation or optimization strategies on essential functions [e.g., dose-dependent or cumulative effects] that impact biological signatures and minimize the risk of toxicity and adverse events.
• Probiotic [with or without prebiotic] studies that distinguish microbiome-genomic from host genomic expression, and their individual yield of metabolites, interactions, and impacts on human health [e.g., gut-brain; gut-hepatic; gut-bone axis].
• Probiotic [with or without prebiotic] studies focused on distinguishing impacts of microbially produced and dietary-metabolites, including their impacts on essential functions across the life span [e.g., developmental biology; senescence].
• Probiotic [with or without prebiotic] studies of lifestyle and behavior role on energy metabolism and health impacts.

The mission of the Office of Dietary Supplements (ODS) is to strengthen knowledge and understanding of dietary supplements, including prebiotics and probiotics, by evaluating scientific information, stimulating and supporting research, disseminating research results, and educating the public to foster an enhanced quality of life and health for the U.S. population. ODS is interested in research investigating the role of prebiotics and probiotics on health maintenance and disease prevention. Research interests of ODS are not limited to specific health conditions, organ systems or population groups.

See Section VIII. Other Information for award authorities and regulations.

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

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)

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)
• 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 Institutions) 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 SF 424 (R&R) 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. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) 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.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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 DUNS number and 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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

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. 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 NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide,

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) 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 SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

See Part 1. 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

Part I. Overview Information 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 Policy on Late Application Submission.

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 SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

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.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) 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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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 Component of the SF424(R&R) Application Package. 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 FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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 review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

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

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable

Not Applicable

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.

Not Applicable

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by Center for Scientific Review , in accordance with NIH peer review policy and procedures, 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:

• 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.
• Will receive a written critique.

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. 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:

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

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.

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.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. 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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that 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 FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Dr. Roberto Flores
National Cancer Institute (NCI)/DCP
Telephone: 240-276-7119
Email: [email protected]

Dr. Phil Daschner
National Cancer Institute (NCI)/DCB
Telephone: 240-276-6227
Email: [email protected]

Dr. Sudhir Kondapaka
National Cancer Institute (NCI)/DCTD
Telephone: 240-276-5365
Email: [email protected]

Dr. R. Dwayne Lunsford
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-827-4635
Email: [email protected]

Dr. Roger Little
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1316
Email: [email protected]

Dr. Ricardo R. Cibotti
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-451-5888
Email: [email protected]

Dr. Cindy D. Davis
Office of Dietary Supplements-NIH
Telephone: 301-496-0168
Email: [email protected]

Yisong Wang, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-480-9483
Email: [email protected]

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Dr. Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
Email: [email protected]

Diana Rutberg
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: [email protected]

Amy Bucheimer
National Institute on Drug Abuse (NIDA)
Telephone: 240-420-5302
Email: [email protected]

Erik Edgerton
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-7760
Email: [email protected]

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

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 45 CFR Part 75.