Required Application Instructions

It is critical that applicants follow the 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

Probiotics 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.

Diet 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.

Quorom 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.

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 microbiota

Common 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 viruses .

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.

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 by pro/prebiotics.

The success of cancer preventive and treatment interventions involves many biochemical reactions and pathways and a number of variables may influence the final result. New or known specific biomarkers, gene expression and/or molecular targets influenced by pro/prebiotic interventions in the context of cancer risk and prevention should be used to predict and determine the variability in response. Studies may generate and characterize biochemical and genetic profiles of subjects likely to benefit of such interventions, and the ones placed at risk by the use of pro/prebiotics.

Several probiotics appear to have cancer protective characteristics. A few of these studies are briefly discussed below as examples, 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 microbial metabolites.

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. 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 will be supported.

Examples of appropriate projects include, but are not restricted to:

• Studies of probiotics addition in conjunction with antibiotics or after antibiotic treatment to evaluate a possible change in the rate of eradication Helicobacter pylori infection and/or prevent re-infection.
• Studies of immunomodulation through pro/prebiotics intervention in regard to vaccines efficacy and effectiveness (HPV, Hepatitis B vaccines, etc.).
• Analysis of the effect of probiotics, like bifidus, on the mucin production, degradation and configuration as it relates to colorectal cancer prevention and progression.
• 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.
• Studies of the effects of pro/prebiotics and the microbiome with host genetics in the context of cancer treatment as they contribute to the variability in response, development of molecular signatures that are predictive of treatment response due to these interactions.
• The effect of pro/prebiotics on bioavailability and efficacy of chemotherapeutic agents.
• The effect of pro/prebiotics on the alleviation of symptoms (such as diarrhea) resulting from cancer therapy including radiation.
• Evaluation of metabolites associated with inflammation in individuals undergoing probiotic intervention.
• Co-occurrence among microbes reflected in shared response to the environment as opposed to competitive interactions
• Evaluation of pro/prebiotics consumption in relation to cancer risk, prevention and progression outside of the gastro-intestinal tract.
• The effect of pro/prebiotics on cancer treatment outcomes including recurrence, survival and particularly adverse events

Microbiome and Complications of Drug abuse and Co-occurring Infections (HIV, HCV, & others)

It is increasingly appreciated that alterations in the gut microbiome underlie a whole range of systemic disease states, including obesity, systemic inflammatory conditions, inflammatory bowel disease, and liver disease. Active narcotic drug (opiates) use also has potential effects on the microbiome indirectly through alterations in gut motility, a known influence on the subpopulations of gut microflora. In addition, the blood borne viral infections occur at increased rates injection drug users. The primary intestinal CD4 depletion that accompanies HIV infection is also 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. However, there are also increased rates of viruses like GB virus C and SEN-V whose pathogenicity is unknown. Thus, 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.

NIDA will consider supporting research on areas for investigation that may include, but are not limited to:

• Study the direct impact of narcotic/opiate abuse on composition of the intestinal microbiome? and determine the impact of alterations on associated disease conditions?
• Study the effects of HIV disease on the intestinal microflora and determine what implications does this have for immune activation?
• Study the interaction of active injection drug use with HIV in regard to their collective impact on the microbiome;
• Study whether successful cART have on restitution of the microbiome; does this restitution have a beneficial effect on systemic immune activation,
• What effect does the composition of the microbiome have on liver disease related to complications of drug use, including HCV, HBV, and fatty liver disease?
• Does manipulation of the microbiome alter the pathogenesis of complications of drug use such as HIV and HCV related disease?

NICHD will support research to:

• Develop and validate diagnostic tests and biomarkers to measure the effects of pre/probiotics interventions in normal infants and children and in infants with necrotizing enterocolitis and children with inflammatory bowel disease or enteroviral infections.
• Validate "omics" approaches to understand the variability in response to prebiotics and probiotics in regard to prevention and treatment of necrotizing enterocolitis, inflammatory bowel disease, and enteric viral or bacterial disease.
• Develop systems biology methods and computational methods to study changes in microbial ecology due to prebiotic, probiotic, and pre/probiotic interventions, in health and in diseased conditions.
• Identify and characterize microbial metabolites and signal molecules in human physiologic fluids that could have diagnostic value in designing prebiotics and probiotics and combinations of pre and probiotics for the amelioration of specific enteric diseases.
• With regard to prevention of NEC, study the use of prebiotics, such as inulin, fructooligosaccharides (FOS), glactooligosaccharides (GOS), and lactulose in NICUs to coax the infant microflora toward a predominance of bifidobacter spp. and lactobacillus spp. and away from enterobacter/proteobacter spp.
• In infants at high risk of NEC, explore the use of probiotics, such as bifidobacter and lactobacilli, in preventing onset of NEC or ameliorating established NEC.
• In infants with viral gastroenteritis, explore the use of probiotics, such as bifidobacter and lactobacilli, in ameliorating the condition.
• In children with inflammatory bowel disease explore the effect of both prebiotics and probiotics in ameliorating or curing the condition.
• In children with irritable bowel syndrome, explore the use of both prebiotics and probiotics in ameliorating or curing the condition.
• In areas rife with enteric bacterial disease, evaluate the use of both prebiotics and probiotics in preventing and treating enteric bacterial disease.

The NCCIH interest is to support inter-disciplinary collaborations that seek to examine the effects of probiotics, with or without natural products, on gut microbiome-brain interactions. . Investigators are encouraged to review the NCCIH Clinical Research Toolbox (http://NCCIH.nih.gov/grants/toolbox) to learn more about NCCIH's requirements for clinical research and NCCIH's policy on natural product integrity (http://NCCIH.nih.gov/research/policies/naturalproduct.htm).

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 co-funding 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.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are 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).

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the "Apply for Grant Electronically" button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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:

Research Strategy: Please consider the following additional instructions, as applicable, when preparing the Research Strategy.

• Applications 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.
• 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).

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, with the following modification:

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

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 our Post Submission Application Materials policy.

Important Update: See NOT-OD-16-006 and NOT-OD-16-011 for updated review language for applications for due dates on or after January 25, 2016.

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? 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? 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?

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 five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. 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.

For Renewals, the committee will consider the progress made in the last funding period.

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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 Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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 the Center for Scientific Review (CSR), 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 submitted in response to this FOA. 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.

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.

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 progress report, 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.

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)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Finding Help Online: https://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 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

Gabriela Riscuta, MD, CNS
National Cancer Institute (NCI)
Telephone: 240-276-7118
Email: [email protected]

Tawnya C. McKee, Ph. D.
National Cancer Institute (NCI)
Telephone: 240-276-5719
Email: [email protected]

Anil Wali, Ph.D
National Cancer Institute (NCI)
Telephone: 240-276-6183
Email: [email protected]

Andrew N. Freedman, PhD
National Cancer Institute (NCI)
Telephone: 240-276-6697
Email: [email protected]

Jag H. Khalsa, MS, PhD
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-2159
Email: [email protected]

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

Gilman Grave, M.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-5593
Email: [email protected]

Cindy D. Davis, Ph.D.
Office of Dietary Supplements (ODS)
Telephone: 301-496-0168
Email: [email protected]

Linda Duffy, PhD, MPH
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-1285
Email: [email protected]

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

Bryann Benton
National Cancer Institute (NCI)
Telephone: 240-276-5863
Email: [email protected]

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

Bryan Clark
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
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.