Part 1. Overview Information

Key Dates

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from 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 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose & Background

Through this FOA, NCI wishes to stimulate research in 1) discovery and development of novel, small molecules for their potential use in studying disease treatment relevant to the missions of the participating NIH Institutes (NDCD, NIMH), and 2) generation of new insight into the biology of relevant diseases and processes that have yet to be validated as important drug targets.

Assessment of the reasons for failures of small molecule therapeutic agents in the clinic points to several areas for improvement of the drug discovery and development process that are pertinent to this FOA:

• First, increased rigor in target identification is necessary. For instance, whether prior studies of the selected target were adequately controlled and powered are important considerations. Were cell lines verified, plasmids sequenced, and protein reagents tested for contaminants?
• Second, reproducibility of the proposed primary assay should be carefully considered because this assay is often the basis for assessing not only initial hits but also for iteratively assessing optimized hits during structure-activity relationship (SAR) studies. Development of primary screening assays that test a key biological function of the target of interest are likely to yield hits of increased relevance. In this respect, phenotypic screens have had a resurgence.
• Third, a hit validation scheme or critical path that includes orthogonal assay(s) to eliminate false positives, as well as a series of assays in diverse biological systems with diverse read-outs, particularly including assays that model human disease, is likely to yield hits of increased relevance.
• Fourth, the inclusion of skilled synthetic and/or medicinal chemists to assess the validity of the hit chemotypes to eliminate PAINS (pan-assay interference compounds) or other undesirable chemotypes is likely to be beneficial.
• A final area for improvement is the optimization of hits to yield high-quality probes. Technological innovations in high throughput screening, chemical synthesis, and cheminformatics have allowed the rapid discovery of novel, small-molecule probes for the study of disease-related biological processes and mechanisms in academic environments (see Academic Screening Facilities Directory; Academic Drug Discovery Consortium). The Chemical Probes Portal, established in July 2015, provides a list of credentialed probes. It is noted that probes may be the predecessors of drugs, but drugs with known off-target effects are seldom useful as probes of specific biological activities. Importantly, identification of chemical probe(s) for a given target provides an unprecedented opportunity for investigators to translate knowledge about diseases into tangible tools for translational research and opens the door to validation of the target prior to clinical testing. To that end, therapeutic lead validation should be tested in appropriate cellular, tissue, or animal models that are likely to be indicative of future use in human clinical trials.

Research Scope

Projects for this FOA may focus on one stage, or span several stages of discovery research:

1) assay development;

2) primary screen implementation;

3) hit validation; and

4) hit-to-lead optimization.

For applications requesting support for more than one stage, demonstration of feasibility is needed, including strong justification and supporting preliminary data for the stages proposed. Areas to be considered for each stage are described below and given in greater detail in Section IV (Application and Submission Information, PHS 398 Research Plan).

1. Assay Development

This FOA seeks to apply new knowledge and screening technologies to develop assays for novel targets and pathways. Projects for assay development should emphasize the design and validation of creative approaches to assay biological and disease processes that have the potential to be used for chemical probe or drug discovery. Assays focusing on areas and approaches that have been extensively studied should be avoided unless a strong rationale is provided for additional studies in the projected area. Targets associated with rare and neglected diseases are encouraged.

Proposed primary screening assays should be relevant to the scope of the research within at least one of the participating NIH ICs focusing on specific diseases or on relevant basic physiology, cell biology, or developmental processes that provide insight into a disease.

Primary screening assays may be target-, pathway-, or phenotype-based. Some examples include:

• target-based biochemical or cellular assays that measure activities of enzymes, receptor-ligand binding, protein-protein interactions, ion channels, transporters, nuclear receptors, and other transcription factors, and other new targets emerging from genetic and proteomic research in model systems and in human diseases;
• cell- or organism-based assays that detect phenotypic changes that may involve unidentified molecular targets; and
• non-traditional targets of interest such as nucleic acids, protein folding, polymorphic gene products, post-transcriptional editing or gene splicing factors, and protein or RNA stabilizers.

Assay detection methods may include, but are not limited to:

• fluorescence, luminescence, absorbance;
• fluorescence resonance energy transfer (FRET);
• time-resolved fluorescence resonance energy transfer (TR-FRET);
• fluorescence polarization;
• flow cytometric measurements;
• fluorescence imaging;
• bioluminescence resonance energy transfer (BRET);
• AlphaScreen, scintillation proximity assay (SPA);
• electrophysiological assays, and;
• biophysical assays

In general, assays should adopt an adequate detection principle that results in the sensitive detection of even weak binders with expected low rates of false positives and false negatives. Complementary research including virtual screening may also be conducted to improve the likelihood of success and cost-effectiveness.

Instructions for the design and testing of a primary assay may be found in Section IV (Application and Submission Information, PHS 398 Research Plan).

2. Primary Screen Implementation

Applicants are encouraged to collaborate with an experienced screening facility, particularly if high throughput screening (HTS) is planned. The screening facility may provide advice such as identification and selection of commercial HTS assay reagents, and suitable HTS assay format and readout. In addition, the screening facility may be able to aid in adapting assays to an HTS format (e.g., 1536-well or 384-well microplate) and performing a pilot screen of a small library of compounds. Further, the researchers might seek advice from the screening laboratory about orthogonal assays to validate the screening hits, and about chemical improvement of the initial hits via a structure-activity relationship (SAR) study following hit validation.

Projects focusing on screen implementation are encouraged to provide preliminary data demonstrating that a primary screen has been developed, fully characterized, and tested in a pilot format. See Section IV for further details on expected information prior to the Primary Screen Implementation stage.

Other technical resources about assay development and screening include the online comprehensive guidebook (Assay Guidance Manual), assay protocols deposited on the PubChem BioAssay data base, ASSAY and Drug Development Technologies, a peer-reviewed bi-monthly journal, and SLAS Discovery.

3. Hit validation

Hits from a primary screen may be systematically assessed using a cascade of follow-up assays to efficiently and effectively remove false positives. Primary HTS assays typically generate hundreds to thousands of hits, many of which are false positives or are chemically intractable. Hits from smaller scale primary screens are also likely to generate false positives or chemically intractable molecules that require additional screens. Post-primary screening assays may include:

• an assay that is essentially identical to the primary assay but with an orthogonal detection scheme (e.g., switching light detection mode or wavelength to avoid intrinsic compound interference);
• a target-minus assay (e.g., coupling enzymes in the absence of the assay target enzyme, parental cell line without the assay target protein, etc.);
• an assay that is different in biological context and process (e.g., protein functional assay vs. protein binding assay; RT-PCR and Western assay vs. reporter gene assay; cell-based assay vs. biochemical assay);
• cytotoxicity assay;
• target selectivity assay(s);
• specificity assays to distinguish biological activities of chemical entities among orthologous targets across organism species through kingdoms (e.g., yeast vs. mammalian cell targets; parasite vs. host targets);
• mode of action assays (e.g., allosteric vs. orthosteric; competitive vs. non-competitive or uncompetitive); and;;
• target identification assays. The assays farther downstream may also include cellular and tissue models pertaining to the relevant physiology or pathophysiology, or to mode and mechanism of action of the validated hits. In vivo assays (e.g. whole animal models) should only be proposed if they are needed to demonstrate the biological or physiological effects of lead compound(s).

In addition, investigators should conduct advanced cheminformatics analysis and medicinal chemistry inspection to prioritize the hit set. It is expected that the investigators will test powder samples of hit compounds and commercially available analog compounds during the hit validation stage. Investigators should verify the structure of hits using a combination of analytical methods and, if possible, re-synthesis of select hits.

4. Hit-to-lead Optimization

Screening campaigns may yield validated hits that can be further optimized via medicinal chemistry. For chemical optimization projects, applicants should have a validated chemical hit as the starting point. The validated hit should have the following properties: (i) elicit a reproducible response in at least two assay types, and elicit a dose-response over a hundred-fold concentration range; (ii) be analytically validated in terms of integrity and purity (e.g., use of resynthesized powder sample of high purity in the preliminary assays); (iii) demonstrate adequate potency; and (iv) possess a tractable starting point of chemical optimization with no obvious major chemical liabilities. Investigators should implement SAR assays that measure target engagement, target selectivity, and functional assays quantifying biological activity or immunomodulation of the analogs. Physiochemistry, in vitro Absorption, Distribution, Metabolism, and Excretion (ADME) and biophysical characterization of derived analogs are strongly encouraged for this stage. If applicable, in vivo activity assays can be proposed in appropriate animal models that adequately reflect the disease being studied (for instance, the complexity of the host immune system for cancer immunotherapy studies).

Institute Interests

NCI: Assays and screens pertinent to the mission of NCI should be justified in the application as relevant to cancer. Of interest to NCI are assays and screens to identify or evaluate small molecules for use in elucidating molecular, cellular, or in vivo mechanisms or processes of probable or known importance in cancer biology, and for use in developing strategies for cancer prevention, diagnosis, treatment or clinical monitoring of treatment. Discovery of small-molecule probes, preventive or therapeutic drug leads, or imaging agent leads are of interest. NCI encourages projects focusing on small molecules that specifically target pediatric fusion oncoproteins or that address novel targets in small cell lung cancer or pancreatic cancer or that address immunotherapy of cancer. Small molecules that impact known immune checkpoint inhibitor pathways are of interest as well as small molecules that address emerging pathways involved in immune-mediated control of cancer. Leads identified through this FOA may be appropriate for entry in the NCI Experimental Therapeutic Program (NExT). Applicants may also find the NCI Developmental Therapeutics Program resources to be helpful.

NIDCD: The NIDCD is interested in the development of high throughput screens (HTS) to assess and validate putative novel, or small molecules that have potential therapeutic value in the treatment, protection or prevention of communication disorders, including hearing, balance, smell/taste, voice, speech, and language. Applications could include, but are not limited to, improved HTS towards the identification of clinically-relevant candidate therapeutics or biological targets that might lead to clinical relevancy in hearing/balance areas of otoprotection, regeneration, otitis media, tinnitus, and normal/abnormal development; chemosensory abnormalities such as they relate to serious diseases of obesity, diabetes, Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis; disorders involving voice speech, language, including swallowing, aphasia or dysarthria, and laryngeal replacement. Potential applicants are encouraged to review the NIDCD mission (see http://www.nidcd.nih.gov) prior to submitting an application.

NIMH: The NIMH is especially interested in applications for novel, clinically-relevant targets with the goal of transforming target discovery into the therapeutic treatment of mental disorders such as depressive disorder, bipolar disorder, schizophrenia, anxiety disorders, panic disorder, autism, etc. (see From Discovery to Cure:Accelerating the Development of New and Personalized Interventions for Mental Illnesses). Proposed projects should be relevant to NIMH's mission of supporting basic science discoveries and translating these discoveries into new therapeutic interventions that will relieve the suffering of people with mental disorders. Investigators who are interested in developing novel and robust assays to reveal changes in neuronal and/or glial function may apply to PAR-18-505. Projects aimed at the discovery of in vivo chemical probes should consider applying to PAR-17-336. Projects aimed at the discovery of cell-based chemical probes should consider applying to PAR-17-335. Projects aimed at early stages of drug discovery and development should consider the Drug Discovery for Nervous System Disorders PAR-19-147 (R01) and PAR-19-146 (R21), National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction PAR-20-119 (U19) and PAR-20-118 (U01). Details on these and additional funding opportunity announcements and therapeutic discovery resources are listed on the NIH/NIMH Therapeutics Discovery Research webpage. Further information on NIMH research priorities can be found in the NIMH Strategic Plan,Strategic Research Priorities, and Interventions Workgroup Report. Applicants are strongly encouraged to discuss applications with NIMH staff listed in Section VII - Agency Contact(s) Scientific/Research Contacts prior to submission to determine alignment of the planned studies with NIMH priorities and to assess whether this or other NIMH funding opportunities are most appropriate.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign 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) 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 to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active 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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will 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)

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

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

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

The letter of intent should be sent to:

Suzanne Forry, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5922
Email: forryscs@mail.nih.gov

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.

R&R or Modular Budget

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: Applicants should address the following topics as they pertain to the research project proposed:

• Significance: Applicants should address why the chosen target or pathway is significant for the proposed chemical probe/drug discovery project, and whether the probe will provide new insight into important disease targets and processes. Preliminary data or published information demonstrating the significance of the target or pathway should be included. Any existing modulators for the target should be mentioned, and a rationale for doing additional development of small molecules that address the target should be delineated.
• Innovation: Innovative aspects of studying the proposed target or pathway, and of the proposed assay(s) and screening scheme should be highlighted.
• Approach: Applicants are highly encouraged to define the scope of the proposed research project via the drug discovery stages outlined in Section I and to propose a timeline and budget in keeping with the scope. Preliminary data are required to substantiate the proposed scope. For instance, if a project for HTS through hit validation is proposed (Stages 2 and 3), preliminary data should address the topics mentioned below under Assay Development, as appropriate to the project. The application should include a flow diagram to outline all critical steps in sequential and/or parallel manners with appropriate benchmarks and timelines for whichever stage(s) of discovery are proposed.

Detailed guidelines for the four stages are as follows:

1) Assay development: To increase the overall likelihood of a successful assay development project, applicants should include the following topics in the research plan:

• Explanation of the scale of the proposed assay campaign (i.e. low-, moderate- or high-throughput), in keeping with the selected target. If available, include preliminary data supporting the choice of the primary screening assay for the specific target.
• Reproducibility of the primary screening assay in a low-to-moderate throughput setting. If the goal is to perform a high-throughput screen, the research plan should include experiments to test whether the primary assay is sufficiently reproducible and robust for adaptation to an automated, high-throughput screening approach using a diverse and significant number of compounds (e.g., a collection of FDA-approved drugs or other bioactive molecules). Possible considerations when designing and characterizing a primary screening assay include effects of time, temperature and protein concentration; tolerance to the effect of DMSO at 0.1-1%; and reproducibility between plates and day-to-day experiments. Additional considerations for HTS are simplicity of the readout and ability for the primary assay to be miniaturized into formats such as 96-, 384-, or 1536-well automated screens.
• Experiments to test predictability and reproducibility of responses to known compounds or other control conditions and a clear threshold between positive and negative responses. In general, an acceptable lower limit of Z factor is 0.5 for a robust single-concentration HTS that corresponds to a combination of Signal-to-Basal Ratio (S/B) of 4 with a Coefficient of Variation (CV) of 10%. Assay robustness will improve if multiple compound test concentrations or kinetic recordings are used in HTS.
• Availability of reagents necessary to perform the screen, such as enzyme indicators, chemicals necessary for reagent readout, and the capacity to generate sufficient reaction substrates (DNA, RNA, protein, or enzyme substrates).
• If achievable, pilot screening for target validation from a small compound library (e.g., LOPAC1280), or other bioactive molecules should be performed as a highly desirable validation step for translation of the assay to HTS. Alternatively, dose-ranging studies for a limited set of agents having known interaction with the proposed target should be proposed. The intent of this characterization is to demonstrate the ability of the assay to pharmacologically distinguish structurally diverse compounds.

2) Primary Screen implementation: Applications to perform a screen of any scale should include preliminary data to address the topics described above in the Assay Development section. In addition, the topics mentioned under Screen Implementation in Section I should be considered when writing the Approach section. Specifically, applications are expected to include:

• Preliminary data on the primary screening assay performance as tested in a small-scale pilot screen, including a scatter plot with a Z factor above 0.5 (see Assay Development section above).
• Discussion of the following parameters: anticipated number of hits; feasibility of assessing hits (particularly large numbers); test concentrations; cut-off concentration; reagent availability; equipment used in configuring the assay; strategy to characterize initial active compounds.
• A rationale for the size and selection of the library of compounds to be screened regardless of the scale of the screen. In certain cases, it may be advantageous to utilize focused libraries of compounds with specific consideration of assay targets, known bioactivities, privileged scaffolds, representative diversity sets, drug repurposing, and/or the ease of follow-up synthetic chemistry for SAR expansion. The compounds should be maintained under strict storage conditions and meet a set of quality control restrictions on solubility, the number of reactive groups, and compound size.

3) Hit validation: The Approach section of the grant application is expected to include the following:

• A clear rationale for the chosen hit validation scheme, considering the number of hits from the primary screen, anticipated false positives inherent in the primary assay format, and/or necessary assays to test the biology or physiology of the target.
• Availability and suitability of secondary and counter-screen assays as appropriate for the scale of the screening campaign or plans to develop and characterize them. Preliminary data demonstrating feasibility of hit validation assays will strengthen the application.
• Definition of the specific criteria that a compound must meet to be considered a probe or pre-therapeutic lead for the project.
• A plan to conduct advanced cheminformatics analysis and medicinal chemistry inspection to prioritize the hit set.
• If hit identification and validation is the goal of the proposed project, it is expected that investigators will confirm hit compounds by testing powder samples and commercially available analog compounds. If commercial analogs are available, investigators may propose preliminary SAR studies. Investigators should verify the structure of hits using a combination of analytical methods and, if possible, perform re-synthesis of select hits.

4) Hit-to-lead optimization: For hit-to-lead optimization projects, a cascade of in vitro and/or in vivo assays should be in place to efficiently test analog compounds derived from validated hits. The SAR assays may include target-, pathway-, and phenotype-based assays that are relevant to the target.

Applicants are expected to include the following in the Approach section:

(i) description of the properties of validated hit series including structures, and preliminary data if available.

(ii) definition of specific criteria that a compound must meet to be considered a drug lead or chemical probe that may include target specificity profile, potency, solubility, permeability and/or other properties as appropriate;

(iii) specification of assays or methodologies to define critical components in the iterative hit-to-lead process including SAR assays, medicinal chemistry capacity, drug design strategy, in vitro ADME profiling, preliminary in vitro toxicity testing, target engagement, biophysical and physicochemical characterizations, and/or in vivo pharmacokinetic and pharmacodynamic characterization as appropriate to the stage of the process;

(iv) availability of SAR assays and rationale for assay selection including the relevance of the assays to the disease (e.g., in vivo assays for anti-cancer immunomodulation) and assay validation;

(v) criteria for disqualifying a hit series for further optimization and selection of back up series; and

(vi) if achievable, exploration of the mechanism of action for hits obtained from pathway- or phenotype-based screening assays.

Critical path: The application should include a flow diagram to outline all critical steps in sequential and/or parallel manners with appropriate benchmarks and timelines for whichever stage(s) of discovery are proposed. The flow diagram may include, but is not limited to: the primary assay to be implemented or previously implemented, alternative assay or approach (e.g., computational docking) to ensure success of the screening, hit selection criteria, cheminformatic analysis, chemical tractability assessment, all follow-up assays to validate screening hits or leads, SAR, and assay responsibilities of each party involved in the project.

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.

The following modifications also apply:

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

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

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

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

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

4. Submission Dates and Times

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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile 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.

Requests of $500,000 or more for direct costs in any year

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

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

Section V. Application Review Information

1. Criteria

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

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

Specific for this FOA: Are there important and well-defined goals for the use of chemical probes, either as research tools or for therapeutics development? If the goal is to develop chemical probes as research tools, will the probes provide new insight into important disease targets and processes? If compounds exist for the proposed target, is a convincing rationale provided for doing additional discovery research?

Investigator(s)

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?

Specific for this FOA: Are the investigators knowledgeable and experienced about the biological target, pathway, and disease area? Are the investigators knowledgeable and experienced to perform the discovery research stages proposed?

Innovation

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?

Specific for this FOA: Is a novel biological target or pathway for the proposed disease being studied? Are the assay design, compound screening scheme, and/or hit-to-lead strategies innovative?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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?

Specific for this FOA:Is a critical path diagram included that outlines all critical steps in sequential and/or parallel manners with appropriate benchmarks and timelines for whichever stage(s) of discovery are proposed? Is the proposed timeline consistent with the scale and stage(s) of discovery research proposed in the Aims? Do the preliminary data support the stage(s) of discovery research proposed in the Aims?

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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Environment

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.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the 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 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.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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 individuals of all ages (including children and older adults) 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.

Vertebrate Animals

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.

Biohazards

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.

Resubmissions

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.

Renewals

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

Revisions

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.

Applications from Foreign Organizations

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.

Select Agent Research

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).

Resource Sharing Plans

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).

Authentication of Key Biological and/or Chemical Resources:

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.

Budget and Period of Support

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

2. Review and Selection Process

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

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

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

• 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.

3. Anticipated Announcement and Award Dates

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

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.

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

2. Administrative and National Policy Requirements

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 laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides 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/fact-sheet-guidance/index.html and https://www.lep.gov. 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 https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

• 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.

• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/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.

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.

Not Applicable

3. Reporting

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

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

Section VII. Agency Contacts

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

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

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-637-3015

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

National Cancer Institute (NCI), for projects not involving cancer immunotherapy
Suzanne Forry, Ph.D.
Telephone: 240-276-5922
Email: forryscs@mail.nih.gov

National Cancer Institute (NCI), for projects that involve immunotherapy
Connie Sommers, Ph.D.
Telephone: 240-276-7187
Email: sommersc@mail.nih.gov

National Institute on Deafness and Other Communication Disorders (NIDCD)
Nancy L. Freeman, Ph.D.
Telephone: 301-402-3458
Email: FreemanN@mail.NIH.gov

National Institute of Mental Health (NIMH)
Yong Yao, Ph.D.
Telephone: 301-443-6102
Email: yyao@mail.nih.gov

Vinod Charles, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-496-2236
Email: charlesvi@mail.nih.gov

Shane Woodward
National Cancer Institute (NCI)
Telephone: 240-276-6303
Email:Woodwars@mail.nih.gov

Christopher Myers
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-435-0713
Email:myersc@mail.nih.gov

Terri Jarosik
National Institute of Mental Health (NIMH)
Telephone: 301-443-3858
Email:tjarosik@mail.nih.gov

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.