Advancing Translational and Clinical Probiotic/Prebiotic and Human Microbiome Research (R01 Clinical Trial Optional) is sponsored by National Institutes of Health (NIH). This grant aims to accelerate translational and clinical Phase I and II a/b safety and efficacy studies for probiotic/prebiotic components and combinations, and to understand their underlying mechanisms of action and variability in responses.

Expired PA-18-902: Advancing Translational and Clinical Probiotic/Prebiotic and Human Microbiome Research (R01 Clinical Trial Optional) This notice has expired. Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) of Participating Organizations National Cancer Institute ( NCI ) National Center for Complementary and Integrative Health ( NCCIH ) Office of Dietary Supplements ( ODS ) Funding Opportunity Title Advancing Translational and Clinical Probiotic/Prebiotic and Human Microbiome Research (R01 Clinical Trial Optional) R01 Research Project Grant March 10, 2020 - Reminder: FORMS-F Grant Application Forms & Instructions Must be Used for Due Dates On or After May 25, 2020- New Grant Application Instructions Now Available.

See Notice NOT-OD-20-077 . Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research. See Notice Changes to NIH Requirements Regarding Proposed Human Fetal Tissue Research.

See Notice NOT-OD-19-128 . November 26, 2018 - NIH & AHRQ Announce Upcoming Updates to Application Instructions and Review Criteria for Research Grant Applications. See Notice NOT-OD-18-228 .

Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity Additional Information on Eligibility . Catalog of Federal Domestic Assistance (CFDA) Number(s) Funding Opportunity Purpose The purpose of this funding opportunity announcement (FOA) is twofold: 1).

to accelerate translational and clinical Phase I and II a/b safety and efficacy studies for substantiating measurable functional benefits of probiotic/prebiotic components and/or their combinations; and; 2). to understand the underlying mechanisms of their action(s), and variability in responses to these interventions.

This FOA calls for interdisciplinary collaborations across scientific disciplines engaged in microbiome and pro/prebiotic research including, but not limited to: nutritional science, microbiology, virology, microecology and microbiome, genomics, immunology, computational biology, chemistry, bioengineering, as well as integration of omics and computational approaches in DNA technologies.

Open Date (Earliest Submission Date) Letter of Intent Due Date(s) dates apply , by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates. 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.

AIDS Application Due Date(s) dates apply , by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates. 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 Research (R) Instructions (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 I.

Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV.

Application and Submission Section V. Application Review Information Section VI. Award Administration Information Section VII.

Agency Contacts Section VIII. Other Information Full Text of Announcement Section I.

Funding Opportunity Description and Prebiotics - marketing, consumption, and knowledge: Marketing and consumption of pro/prebiotic products is growing exponentially, despite the gap in knowledge regarding their efficacy, the best probiotic/prebiotic (pro/prebiotic) formulations, dosage and the fact that many products using the term pro/prebiotic do not meet the requisite criteria.

Rigorous and reproducible studies are needed to demonstrate the mechanistic basis for pro/prebiotic consumption/administration, strain-specific health benefits and host characteristics (genetic, metabolic and biochemical, health status, gender, age) of subjects who could benefit from such interventions.

The specific conditions in which these interventions could be recommended, their underlying molecular mechanisms of action, their interactions with the host, and doses needed for measurable effective responses are not clearly understood.

The Probiotics definition as originally framed by World Health Organization (WHO) and Food and Agriculture Organization of the United Nations (FAO) and is broadly accepted and as " live microorganisms which, when administered in adequate amounts confer a health benefit on the host. Prebiotics are "non-viable food components that confer a health benefit on the host associated with modulation of the microbiota".

By definition, prebiotics are neither hydrolyzed nor absorbed in the upper part of the gastro-intestinal tract, constitute a selective substrate for one or a limited number of beneficial bacteria and are able to alter the colonic microbiota in favor of a healthier composition.

While widespread beneficial effects across taxonomic groups have been reported, rare adverse events, negative results, failure to meet specifications for well-defined pro/prebiotic preparations and available data for long-term safety have impeded definitively concluding clear health claims for strain-specific pro/prebiotic effects.

The lines of research require cautionary guidance and well-controlled settings to include studies of any short term or long term risks, in vulnerable populations e.g., preterm neonates and other immunocompromised individuals. and Gut Microbiota: Many environmental exposures, including the diet and the use of antibiotics, alter microbial communities and human microbial coevolution.

For example, since the diet serves as a modulator of the gut microbiota, initial gut microflora would partially depend on whether the infant is breast-fed or bottle-fed. Despite the progress made, current knowledge of the molecular interface between pro/prebiotic factors and host interactions with resident microbes is limited.

Research is needed to better understand the effect of administering pro/prebiotic, singly or in combination, and the actions of their microbial metabolites on the host in the context of complex interactions with food, dietary patterns, antibiotics and other prescribed medications, health status, gender, age, etc. Research is also needed to understand whether supplementation with pro/prebiotics would have implications in restoring ecologic balance/resilience of perturbed microbiota, gut barrier reinforcement, production of specific metabolites, enzyme activity, and immunologic and competitive function against bacterial, fungal and viral infections, including a possible adjuvant role against emerging infections.

In addition, integrating omics technologies to validly and reproducibly measure the functional interplay of pre/probiotic interventions on composition and functional effects in gut microbiota and host physiology is also critical for designing effective therapeutic and preventive manipulations of the gastro-intestinal microbiota.

Sensing and Modulation by Probiotics: Well-characterized probiotic strains (e.g., lactobacillus; bifidobacterium) secrete a variety of signaling molecules that can modify inter-bacterial signaling (quorum sensing) and suppress the expression of virulence genes in some pathogens.

Probiotic strains can produce several classes of low molecular weight (LMW) bioactive molecules including: bacteriocins and other antimicrobial agents, short chain fatty acids, biosurfactants, vitamins, antioxidants, nucleic acids, etc. The presence of LMW microbial metabolites and signal molecules in human physiologic fluids could have particular physiological and/or diagnostic value that could be used to design products with specific beneficial 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 the rational basis for mechanistic studies of specific pre/probiotic combinations for nutritional and medical purposes targeted to specific functions in the human host. A growing body of recent evidence suggests that regular intake of probiotics suppresses H.

Pylori infection in humans, maintaining lower levels of this pathogen in the stomach but the mechanism is poorly understood.

Specific Objectives and Scope of this FOA This FOA encourages translational and clinical studies using a variety of pro/prebiotic carriers (foods, dietary supplements, etc.) to generate measurable functional evidence for the safety and effectiveness use of pro/prebiotics in maintaining health and/or prevent and treat diseases.

If food is used, information should be readily available regarding the food matrix or relevant dietary and microbial composition of it. Selection of probiotic strains will follow the FAO/WHO recommendations that probiotic microorganisms should not harbor transmissible drug resistance genes encoding resistance to clinically used drugs.

Screening and selection criteria for probiotics(s) prebiotics should be focused on probiotic strains with demonstrated quality for a number of parameters in animals and fit for human consumption.

Phase I and II a/b studies will require further proof of concept and testing assessments for a number of parameters, including antibiotic resistance assays, screening for virulence factors, resistance to host defense mechanisms and induction of hemolysis.

To ensure valid and reproducible results, appropriate animal models or human subjects enrolled in these studies must be characterized in terms of metabolic, biochemical, microbial, and health or disease status. The FOA will also support studies to develop new or to refine known biomarkers of health and disease with respect to the pro/prebiotics interventions.

The impact of pro/prebiotic interventions must be measured and objectively documented for health and/or disease. Where needed, it is mandatory that the applicant (s) proposing clinical studies should provide sufficient details of plans and appropriately documented evidence of pre-IND (Investigational New Drug) status or other relevant regulatory correspondence at the time of application.

Prior to any funded award being implemented in humans, investigators would be responsible for obtaining the approval for an IND from the United States Food and Drug Administration (FDA). Probiotics, as defined, should be able to survive the passage through the digestive system and proliferate in the gut.

Importantly, rigorous genomic and molecular identification and taxonomic profiling using omics based technologies of the species and the strain is crucial.

The ability to remain viable at the target site and to be effective should be demonstrated for the strain used (including colony formation units, strain identification and characterization, transient adhesion or interaction with the intestinal epithelium and colonization of the colon, if pertinent).

This shows the importance of the food matrix, including the amount of food that must be ingested in order to obtain the health benefit and proof for stability and viability of the strain in the food, until the consumption time. Food and supplements may be transporters of their own microbiomes as ingested and this aspect has to receive appropriate attention, due to microbe-microbe interactions.

Understanding the functional niche, evolutionary and ecologic interplay among gut microflora and host physiology including its genetics is critical for designing therapeutic/preventive manipulations of the gastrointestinal NIH research areas of interest may include, but are not limited to and are not in any priority order, the following: 1.

Identification of the underlying mechanisms of action of pro/prebiotic formulation(s) to prevent and/or treat human diseases including conditions caused by emerging pathogens, such as bacteria, fungi and 2. Studies of pro/prebiotics interventions on: microbial composition, co-metabolism, microbial-host interactions, and microbiome resilience, as it affects local and systemic metabolism, gene expression and signaling pathways. 3.

Interactions of pro/prebiotic formulations with diet, dietary supplements and/or dietary components, which produce microbial metabolites with measurable effects in risk reduction and disease prevention. 4. Development of predictive models to understand variability in response to pro/prebiotic interventions, as influenced by variables such as: nutritional status, dietary patterns, health status, age, gender, race, or other factors.

5. Characterization of probiotic strain activities on glycans and identification of glycan-mediated signaling pathways in health and disease, including further clarification of the effect of probiotics on mucin degradation and its consequences. 6.

Examination of the effects of drug abuse (narcotics/opiates) on the efficacy of pre/probiotics and intestinal microbiome/microflora in populations with co-occurring infections including HIV, HCV and others; study how manipulation of the microbiome would alter the human virome and pathogenesis of complications of drug use such as HIV, HCV-related disease, and interactions with pro/prebiotics. 7.

Studies of probiotics pharmacokinetics/pharmacodynamics in healthy and immunocompromised subjects. 8. Development and validation of diagnostic tests and biomarkers to evaluate early response to pro/prebiotics interventions.

9. Analysis of pro/prebiotic effect on resident biofilm-growing pathogens. 10.

Analysis of interaction between pro/prebiotics with medications including antibiotics and other chemotherapeutic agents as it relates to bioavailability, treatment outcome, efficacy and adverse events. 11. Metabolomic profiling in samples from individuals/populations undergoing pro/prebiotic intervention to identify individuals/populations susceptible to the intervention.

12. Microbial comparison of oral cavity and gut of individuals undergoing pro/prebiotic intervention.

Areas of Interest to the National Cancer Institute (NCI) NCI plans to support rigorous translational and clinical studies to promote cancer prevention and treatment and to understand the molecular processes (including how pro/prebiotics compete with pathogens, increase the production of protective metabolites and reduce the production of pro-carcinogens, etc.) with the aim to determine how a person's risk of developing cancer or cancer treatment outcomes can be modified Several probiotics appear to have cancer protective characteristics but there are still many unanswered questions regarding the dose and timing of probiotics and the pro/prebiotics formulations which should be used for optimal result and a consideration of the types and stages of cancer or carcinogenesis for obtaining the optimal result.

The pro/prebiotic consumption has local effect in the gastrointestinal tract lumen, and/or distant effect, involving immunological messengers, hormonal intermediates, and Because food plays a critical role in maintaining and/or changing the gut microbiota, diet and nutrition should be considered in conjunction with pro/prebiotic interventions along with the subject's stage of life and health condition, the dose and strain of probiotics, concurrent diseases and the medications taken for them, etc. The Division of Cancer Prevention (DCP) at the NCI encourages research to understand, but The role of diet, bioactive food components and vaccines in modulating the metabolic output or diversity of the microbiota and how these interactions specifically alter cancer risk and progression.

Evaluating new or known specific biomarkers, gene expression and/or molecular targets influenced by pro/prebiotic interventions in the context of cancer risk and prevention. Studies to generate and characterize biochemical and genetic profiles of subjects likely to benefit from prebiotic and/or probiotic interventions, and the ones placed at risk by these of interventions.

Analysis of the effect of probiotics, like bifidus, on the mucin production, degradation and configuration as it relates to colorectal cancer prevention and progression.

The Division of Cancer Treatment and Diagnosis (DCTD) at the NCI encourages mechanistic and translational researches focusing on: The modulating effect of pro/prebiotics on outcomes of conventional cancer care, immunotherapy, and investigational drug/treatment immunotherapy, such as overall survivor, quality of life, metastasis and The adverse effect and interaction of pro/prebiotics on standard The development of pre/probiotic-based microbiota cancer Modulation effect of natural products interventions (e.g. medicinal natural product, diet, nutrient, bioactive food component) on pre/prebiotics for cancer treatment outcome.

Computation modeling and experimental approaches including biomarker discovery associated this field of study.

Interrelationship of circadian rhythm/clock and pre/probiotics on of Cancer Control and Population Studies (DCCPS) at NCI encourages studies to understand: Assessment of multiple interactions among pro/prebiotics and commensal microbiome with host genetics in the context of nutritional status, demographics and other factors that may contribute to the variability in response as it relates to cancer prevention and progression.

Co-occurrence among microbes reflected in shared response to the environment as opposed to competitive interactions to Reduce Cancer Health Disparities (CRCHD) at NCI encourages research focused on the interplay of race/ethnicity with pro/prebiotics combinations, and the underlying biological factors that may contribute to cancer health disparities in response to these interventions.

Areas of Interest to the National Center for Complementary and Integrative Health (NCCIH) 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 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. VIII.

Other Information for award authorities and regulations. Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity. Application Types Allowed Glossary and the SF424 (R&R) Application Guide provide details on Optional: Accepting applications that either propose or do not propose clinical trial(s) help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Application budgets are not limited but need to reflect the actual needs of the proposed project. The scope of the proposed project should determine the project period.

The maximum period is 5 years. 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: o Hispanic-serving Institutions o Historically Black Colleges and Universities (HBCUs) o Tribally Controlled Colleges and Universities (TCCUs) o Alaska Native and Native Hawaiian Serving Institutions o Asian American Native American Pacific Islander Serving Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Nonprofits without 501(c)(3) IRS Status (Other than Institutions For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Institutions) Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible Foreign components, as defined in the NIH Grants Policy Statement , are allowed. Applicant organizations must complete and maintain the following registrations as described in the 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 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 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. 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.

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 must have an active DUNS number and SAM registration in order to complete the Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account.

PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal 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 This FOA does not require cost sharing as defined in the NIH Grants Policy Statement . 3.

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

This means that the NIH will A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission 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 ). Section IV. Application and Submission Information 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. 2. Content and Form of Application Submission It is critical that applicants follow the Research (R) Instructions (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 For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant 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 IC staff to estimate the potential review workload and By the date listed in Part 1.

Overview Information , prospective applicants are asked to submit a letter of intent that includes the following information: Descriptive title of proposed activity Name(s), address(es), and telephone number(s) of the PD(s)/PI(s) Names of other key personnel Participating institution(s) Number and title of this funding opportunity The letter of intent should be sent to: National Cancer Institute (NCI) All page limitations described in the SF424 Application Page Limits must be followed.

Instructions for Application Submission The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an All instructions in the SF424 (R&R) Application Guide SF424(R&R) Project/Performance Site Locations All instructions in the SF424 (R&R) Application Guide SF424(R&R) Other Project Information All instructions in the SF424 (R&R) Application Guide SF424(R&R) Senior/Key Person Profile All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide PHS 398 Cover Page Supplement All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: Sharing Plan : Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification: All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Only limited Appendix materials are allowed.

Follow all instructions for the Appendix as described in the SF424 (R&R) Application PHS Human Subjects and Clinical Trials Information 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 Record: PHS Human Subjects and Clinical Trials Information All instructions in the SF424 (R&R) Application Guide must be followed with the following additional instructions: All instructions in the SF424 (R&R) Application Guide PHS Assignment Request Form All instructions in the SF424 (R&R) Application Guide Foreign (non-U.S.) institutions must follow policies Grants Policy Statement , and procedures for foreign institutions.

3. Unique Entity Identifier and System for Award Management (SAM) 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 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 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 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. 5.

Intergovernmental Review This initiative is not subject to intergovernmental 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 .

Requirements and Information 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 Electronically .

If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must for Applicants Experiencing System Issues . For assistance with application submission, contact the Application Submission Contacts in Section VII . 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 Requests of $500,000 or more for direct costs in any year 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 Post Submission Materials 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 Section V. Application Review Information 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 A proposed Clinical Trial application may include study design, methods, and intervention that are