It is critical that applicants follow the instructions in the Research Instructions for 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

Recent technological innovations in screening technologies (from high throughput target-focused approaches through moderate throughput phenotypic- and fragment-based approaches), a wide variety new chemical synthesis approaches, and cheminformatics tools now provide an unprecedented opportunity for investigators to translate knowledge about diseases into tangible tools for translational research. Despite the availability of these approaches, we are facing an increased failure rate of potential therapeutics for reasons of both safety and lack of human efficacy. A critical need exists to implement better assays using more efficient and informative screening approaches which can initially identify therapeutic or imaging agents that can safely alter or track disease progression and outcomes in humans.

Assays should have the potential for significant enhancement in throughput (the number of simultaneous measurements) and/or content (the types of measurements) compared to existing methods. In general, assays should have the potential to enable an unbiased screen of hundreds of thousands of perturbations (e.g., small molecules, siRNAs, peptides, etc.). However, for novel measures and approaches more modest increases in throughput may be reasonable. Assays may utilize any appropriate preparation, including cell-free systems, cultured cells, organotypic tissue slices, or model organisms (e.g., zebrafish, C. elegans), which adequately recapitulate important aspects of health-related outcomes relevant to the National Institute of Diabetes and Digestive and Kidney Diseases and are sufficiently scalable. Projects may carry considerable risk but should have the potential for generating high impact assays and datasets

Projects submitted to this FOA should be directly focused on assay development and screening for a therapeutic or imaging agent that will modulate or track a health-related outcome of interest to the NIDDK. This includes outcomes relevant to obesity, diabetes, nutrition, and related aspects of endocrinology and metabolism; benign digestive and liver diseases; benign kidney, urological and hematologic disease; and specific aspects of cystic fibrosis. Additional information concerning programmatic areas at NIDDK is available at: www.niddk.nih.gov/research-funding/research-programs/Pages/default.aspx. Prior to submitting an application, investigators are strongly encouraged to contact the Scientific/Research Contact for this FOA to discuss the appropriateness of the proposed research to this FOA. Projects in areas that are primarily within the missions of other Institutes or Centers (ICs) of the NIH are not appropriate for this FOA and will not be supported. For example, research on diabetic retinopathy should be submitted to the NEI, research on cardiovascular disease, hypertension, or dyslipidemia should be submitted to the NHLBI, and research on cancers should be submitted to the NCI.

Staging of Therapeutics Discovery and Validation

The process of identifying and validating therapeutic leads or imaging agents such as small molecules or peptides for the treatment, diagnosis, or study of human disease begins with a hypothesis and can be viewed as progressing along a continuum of increasing confidence, leading to widespread acceptance of its use in people (www.niddk.nih.gov/research-funding/process/translational-research-therapeutic-discovery-development/Pages/default.aspx). For the purposes of this FOA, these stages are defined as:

Identification of therapeutic or imaging leads: This may occur through a variety of approaches and stages such as developing an assay, screening compound libraries, or constructing prototype peptides with preliminary evidence that they may significantly impact or track a disease process.

Early-stage preclinical validation: Pre-clinical hypothesis testing to generate data that, over time, increases confidence that manipulation or monitoring of disease processes via a specific strategy may be clinically meaningful and safe. This process occurs prior to clinical testing of a new therapeutic or imaging agent, and ideally should include the use of human-derived data, tissues, cells, and systems.

Clinical validation: Studies conducted in human patient populations to fully understand the efficacy and safety profiles of a therapeutic or imaging agent. True validation of a therapeutic or imaging agent may take decades of post-regulatory approval data accumulation.

This FOA is intended to stimulate research that furthers the development of and/or screening with assays in order to identify therapeutic or imaging agents that may serve as 1) possible therapeutic or imaging agents or 2) the starting points for medicinal chemistry or protein engineering campaigns to develop such agents. It is NOT intended to support early-stage preclinical validation or clinical target validation. Later stage validation, discovery, and development efforts may be pursued via mechanisms outside of this FOA such as, but not limited to, spin-off companies, licensing to or partnering with pharmaceutical companies, other funding opportunity announcements, and non-profit organizations.

Examples of the type of assay development and screening projects that can be pursued under this funding opportunity include, but are not limited to:

• Generating data that demonstrates a biologically-relevant phenotypic assay can be conducted at a scale sufficient to screen a meaningful library of molecules, including an appropriate statistical analysis of the assay’s rigor and reproducibility as well as technical and logistical feasibility;
• Conducting a high- or medium-throughput screening campaign with a well validated assay against a well-characterized library (focused or large) of small molecules, macrocycles, or peptides, including appropriate follow-up validation and characterization of hits.

This FOA advances basic research findings into therapeutic and imaging agent discovery by promoting the adaptation and implementation of state-of-the-art measures of basic cellular processes or molecular events that are key mediators of disease pathogenesis into novel assays with the intent to probe or modulate mechanisms or perturbations in an unbiased and efficient manner. Proposed projects may involve collaboration with an academic, nonprofit, or commercial screening facility that has the requisite expertise and experience to conduct a screening-ready assay for the discovery and validation of therapeutic or imaging agents. Assays are expected to target outcomes relevant to the NIDDK mission.

Suitable assays development projects include, but are not limited to:

• Novel adaptation of assays to increase throughput or include high content, multiplexed measures that maximize the amount and value of the captured data;
• Optimizing phenotypic assays for outcome measures relevant to disease pathophysiology such as monolayer assays, microfluidic assays such as engineered microphysiological systems, or self-organizing organotypic assays;
• Novel adaptation of assays for imaging and quantifying dynamic changes in the localization of signaling molecules, intracellular compartmentalization, regulatory networks, or folding/sorting machinery;
• Assays to identify highly specific molecular markers that might be useful for identifying or tracking a particular cell or phenotype;
• Phenotypic, model organism-based assays (e.g., Drosophila, C. elegans, zebrafish), in particular projects that aim to significantly improve on the automation of imaging analysis and whole organism handling;
• Development of screens for targeted phenotypes in cellular models derived from human patient populations (e.g., induced pluripotent stem cells, cadaveric donor cells, biopsy samples) to identify alterations in cellular processes associated with disease processes;
• Novel target-focused in vitro or cell-based assays to modulate the activity of a target strongly implicated in a disease-relevant network.

For projects conducting a screen with an assay, suitable library types may include, but are not limited to:

• Small focused collections (hundreds to tens of thousands) to large collections (hundreds of thousands to millions) of small molecules;
• DNA barcoded macrocyclic chemical libraries;
• Collections of fragment molecules that serve as starting points for medicinal chemistry;
• Cheminformatics approaches utilizing virtual libraries of compounds;
• Libraries based on peptides or metabolites (e.g., metabolic intermediates, microbiome-derived products, lipid derivatives).

The following are types of projects that are NOT appropriate for this FOA:

• Research focused on understanding normal biology or disease processes, rather than developing the tools to facilitate such;
• Projects that propose significant efforts in molecular optimization that do not directly follow a proposed screening campaign;
• Projects in which the primary focus is assay development or screening without an integrated plan to evaluate the validity of the assay for a health-related outcome within the mission of the NIDDK;
• Projects in areas that are primarily within the missions of other Institutes or Centers (ICs) of the NIH are not appropriate for this FOA and will not be supported. For example, research on diabetic retinopathy should be submitted to the NEI, research on cardiovascular disease, hypertension or dyslipidemia should be submitted to the NHLBI, and research on cancers should be submitted to the NCI.

1. Assay development applications. Experiments need not initially include the use of assays in screens or even the final stages of adaptation for screening. Rather, the emphasis can be on designing and validating creative approaches to assaying biological and disease processes that can potentially be used to identify therapeutic or imaging agents.

The submission of applications which include the co-development of necessary downstream assays and a pilot screen is encouraged to increase the overall likelihood of a successful project.

2. Assay screening projects. Experiments may begin with an assay ready for screening or propose to complete assay development (primary or secondary) and begin screening within a single project period. Iterative approaches in which initial screening data are used to refine assay optimization are acceptable.

Applicants should take note of additional Application Instructions in Section IV.2.

Additional information on guidance for assay development may be found in the online comprehensive Assay Guidance Manual (http://www.ncbi.nlm.nih.gov/books/NBK53196/), HTS assay protocols deposited in the PubChem BioAssay Database (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pcassay), or the BioAssay Research Database (https://bard.nih.gov/) as well as the published literature. Applicants are also encouraged to take advantage of the resources provided by and currently being utilized by the NIH Molecular Libraries and Imaging Program (https://commonfund.nih.gov/molecularlibraries/index). For applicants looking for screening facilities to partner with, the Academic Screening Facilities Directory (http://www.slas.org/screeningFacilities/facilityList.cfm) may serve as a useful starting point.

Applications may propose interaction with NIDDK-funded existing research consortia, such as the Human Islet Research Network (hirnetwork.org), the Rebuilding a Kidney Consortium (rebuildingakidney.org), Tissue Chip approaches (http://www.ncats.nih.gov/tissuechip/about), the Nuclear Receptor Signaling Atlas (www.nursa.org), the Diabetic Complications Consortium (www.diacomp.org), the Mouse Metabolic Phenotyping Centers (www.mmpc.org), the Intestinal Stem Cell Consortium (iscc.coh.org), or the GenitoUrinary Development Molecular Anatomy Project (www.gudmap.org).

Additional opportunities for those who have already identified hits and starting points, require additional assistance in pre-clinical development, or are considering commercialization of products should explore the NIDDK website on Translational Research for Therapeutic Discovery and Development (www.niddk.nih.gov/research-funding/process/translational-research-therapeutic-discovery-development/Pages/default.aspx).

Applicants are also encouraged to take advantage of the resources provided by the National Center for Advancing Translational Sciences' Clinical Translational Science Awards (CTSAs) program, (www.ncats.nih.gov/ctsa) to leverage resources for therapeutic discovery in areas described in this FOA. CTSA resources include, for example, core facilities, super computer centers, biostatistics, bioinformatics, community engagement network, tissue repositories, and animal models. For more information about resources available at individual CTSAs, please see the list of CTSA Hubs (www.ncats.nih.gov/ctsa/about/hubs).

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 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:

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 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).

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 instructions in the Research Instructions for 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.

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 plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent, preferably electronically, should be sent to:

Dr. Aaron Pawlyk
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
6707 Democracy Boulevard, Room 7207
Bethesda, MD 20892
Telephone: 301-451-7299
Email: [email protected]

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:

Fit for the NIDDK

Applications must include a strong justification for the relevance of the research project to health-related outcomes within the mission of the NIDDK. This includes outcomes relevant to obesity, diabetes, nutrition, and related aspects of endocrinology and metabolism; benign digestive and liver diseases; benign kidney, urological and hematologic disease; and specific aspects of cystic fibrosis. Additional information concerning programmatic areas at NIDDK is available at: www.niddk.nih.gov/research-funding/research-programs/Pages/default.aspx.

Technical Prerequisites

Applications must include detailed descriptions of their actual and proposed assays, including data or plans to obtain data indicating the robustness, reliability, and throughput of their assays. Assays must be presented within the context of a screening and follow-up assay flow diagram, demonstrating sufficient throughput to support testing based on their position in the flow diagram. Applications conducting a screen must include a rationale for the selection of the proposed library as well as provide sufficient characteristics of the library to justify its use against the proposed assay, such as composition, pilot screening data, storage conditions, availability of follow-up compounds, etc. Applications pursuing imaging agents must include plans detailing how agents will be made detectable and plans to assess how such modifications may alter the binding and/or functional properties of the agent.

To increase the overall likelihood of a successful assay development project, applicants are encouraged to consider incorporating discussion of the following suitable topics into their applications:

• Demonstration of a robust and reproducible response suitable to identify active molecules in an eventual screen (e.g., Z-factor);
• Downstream assays to verify specific activity of identified actives (e.g., counterscreens, orthogonal assays, selectivity assays, mode of action assays);
• Appropriate positive and negative controls to assess assay behavior during a screen;
• Availability and cost of reagents necessary to conduct a viable screen;
• Pilot screening activities to verify suitability of the assay for future screening efforts.

To increase the overall likelihood of a successful assay screening project, applicants are encouraged to consider incorporating discussion the following suitable topics into their applications:

• Rationale for the size and selection of the proposed library and its effectiveness against the proposed assay;
• Positive and negative controls, internal library controls, appropriate storage conditions of the library, and availability of molecules for follow-up testing;
• Appropriate reagents, equipment, and screening throughput of the laboratory or screening facility;
• Schema to follow up on hits to confirm activity, selectivity, and specificity as well as appropriate criteria for defining a useful active hit;
• For imaging agent screens, a detailed plan for modification for detection (e.g., radiolabeling, attachment of fluorophore, magnetic resonance agent) that addresses re-assessment of the properties compared to the parent molecule.

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 modifications:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• For the purpose of this FOA, the following data generated or developed under this FOA are expected to be released to PubChem: (1) primary assay data from high throughput screening (HTS), (2) data generated in all post-HTS follow-up assays, (3) protocols for assays utilized, and (4) the chemical structure of compounds tested.
• Applications should include a statement of willingness to deposit the aforementioned data to PubChem within the Data Sharing section of the application, consistent with achieving the goals of this program.

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.

Form only available in FORMS-D application packages for use with due dates on or before January 24, 2018.

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

Form only available in FORMS-E application packages for use with due dates on or after January 25, 2018.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a 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.

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.

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 our Post Submission Application Materials 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.

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

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.

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 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 the 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.

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.

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.

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.

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: https://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

Aaron C. Pawlyk, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-451-7299
Email: [email protected]

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

Christina Coriz
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8848
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.