Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Mental Health (NIMH)
National Cancer Institute (NCI)
National Eye Institute (NEI)
National Institute on Aging (NIA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute on Deafness and Other Communication Disorders (NIDCD)
National Institute on Drug Abuse (NIDA)
National Institute of General Medical Sciences (NIGMS)

Funding Opportunity Title

Solicitation of Assays for High Throughput Screening (HTS) to Discover Chemical Probes (R21)

Activity Code

R21 Exploratory/Developmental Research Grant

Announcement Type

New

Related Notices

  • May 30, 2013 (NOT-OD-13-074) - NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013.
  • March 4, 2013 - See Companions PAR-13-134 (X01) and PAR-13-135 (R03).
  • January 16, 2013 - See Notice NOT-MH-13-011. The purpose of this notice is to facilitate access for researchers to a screening laboratory to develop an High Throughput Screening (HTS) assay and thereby submit a grant application to this FOA.

Funding Opportunity Announcement (FOA) Number

PAR-12-059

Companion FOA

PAR-12-058, R01 Research Project Grant

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.242, 93.393, 93.394, 93.395, 93.396, 93.399, 93.867, 93.866, 93,273, 93.846, 93.865, 93.173, 93.279, 93.859, 93.273

FOA Purpose

This Funding Opportunity Announcement (FOA) encourages investigators to form collaborations with an established academic, nonprofit, or commercial high throughput screening (HTS) facility that has the requisite expertise and experience to implement HTS-ready assays for the discovery and development of small molecule chemical probes.

Through this FOA, NIH 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, and 2) discovery and/or validation of novel, biological targets that will inform studies of disease mechanisms.  Emphasis will be placed on assays that provide new insight into important disease targets and processes.

Key Dates
Posted Date

December 13, 2011

Open Date (Earliest Submission Date)

January 5, 2012

Letter of Intent Due Date

30 days prior to the anticipated application due date.

Application Due Date(s)

Standard dates apply, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Standard dates apply, by 5:00 PM local time of applicant organization.

Scientific Merit Review

Standard dates apply

Advisory Council Review

Standard dates apply

Earliest Start Date(s)

Standard dates apply

Expiration Date

September 8, 2014

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (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.


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Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Research Scope

Recent technological innovations in high throughput screening (HTS), chemical synthesis, and cheminformatics have allowed 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, http://www.slas.org/screeningFacilities/facilityList.cfm). This provides an unprecedented opportunity for investigators to translate knowledge about diseases into tangible tools for translational research.  This Funding Opportunity Announcement (FOA) is to support investigators to form collaboration with an academic, nonprofit, or commercial HTS screening facility that has the requisite expertise and experience to implement an HTS-ready assay for the discovery and development of small molecule chemical probes.  Through this FOA, we wish 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, and 2) discovery and/or validation of novel, biological targets that will inform studies of disease mechanisms. Emphasis will be placed on assays that provide new insight into important disease targets and processes. For example, applications may involve emerging therapeutic targets and mechanisms for the discovery of chemical probes that may lead to further development of therapeutics or provide insight into the biology of relevant diseases.

This program supports mainly the following two stages of discovery research:

1.  HTS implementation. The screening facility should have the capability to optimize and automate biochemical-, cellular-, or whole organism-based assays to screen a large library of compounds with adequate diversity and representation of chemical space. The projects submitted to this FOA are expected to already have an implementable HTS assay and a large collection of compounds to be screened. Some assay adaptation may be performed with the aim of optimizing parameters such as reagent preparation/consumption, assay readout, and automation in parallel or multiplex screening format. Such adaptation work will be accomplished through a joint effort between the assay submitting investigator and the screening facility responsible for implementing the assays. Some complementary research including biology-oriented chemical synthesis of screening compounds, virtual screening may also be conducted to improve the screening success likelihood.

HTS assay development is beyond the scope of the FOA. Investigators who are interested in the development of HTS assays are encouraged to apply under PA-10-213 - Development of Assays for High-Throughput screening for use in Probe and Pre-therapeutic Discovery (R01).

2.  Hit validation. When HTS is complete, fresh compound samples of initial hits will be selected (cherry-picked) for further confirmation. The investigators will implement secondary assays that are orthogonal to the primary assay to remove false positives. This provides additional verification that the hits are acting on the target/pathway of interest. In addition, the investigators will 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. Additional follow-up assays may also be conducted to characterize mode and mechanism of action of the validated hits.

A substantial amount of screening campaigns may yield validated hits that can be further optimized via medicinal chemistry work. However, extensive medicinal chemistry optimization is beyond the scope of the FOA.  Investigators of a successful screening project are encouraged to consider further funding opportunities that would support medicinal chemistry optimization of the validated hits, i.e., PAR-12-060 or other funding opportunities as listed below in the section "Institute Interests."

Technical Prerequisites

1.  Compound collection. A large library of compounds should be used for HTS to cover adequate chemical space. In certain cases, it may be advantageous to utilize focused libraries of compounds with specific considerations for the assay targets, privileged scaffolds, representative diversity sets, drug repurposing, and/or the ease of follow-up synthetic chemistry for SAR expansion. The compounds in such a collection are expected to be maintained under strict storage conditions and meet a set of quality control restrictions on purity, solubility, a number of reactive groups, and compound size.

2.  Primary HTS assay. Assays developed for HTS may be target-, pathway-, and phenotype-based assays. Some examples include: a) target-based biochemical or cellular assays that measure activities of enzymes, receptor-ligand bindings, 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; b) cell- or organism-based assays that detect phenotypic changes that may involve unidentified molecular targets; and c) non-traditional targets of interest such as nucleic acids, protein folding, polymorphic gene products, post-transcriptional editing or splicing of gene products, and protein or RNA stabilization. The assay detection methods may include 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 assay, biophysical assay, etc. In general, the proposed HTS assay should adopt an adequate detection principle that results in a sensitive detection of even weak binders with expected low rates of false positives and false negatives. Assays that require only addition of reagents (i.e., mix and measure or homogeneous assays) and endpoint measurements are preferable. Assays that require long-time kinetic recordings, high content imaging, multiple washing and aspiration steps, whole organism preparations, reagents of exceedingly high cost, and radioactive materials may be re-configured using alternative assay technologies to simplify the process.

The application is expected to include preliminary data on the primary assay performance most often in microtiter plate format (96-, 384- and 1536-well plates).  A scatter plot obtained from a pilot screen of a small collection of structurally diverse small molecules (e.g., NIH Clinical Collection at http://www.nihclinicalcollection.com/, LOPAC1280 at http://www.sigmaaldrich.com/chemistry/drug-discovery/validation-libraries.html, etc.) may provide an overview of the assay performance. An acceptable lower limit of Z’ factor is 0.5 that corresponds to a combination of Signal-to-Basal Ratio (S/B) of 4 with a Coefficient of Variation (CV) of 10%. 

3.  Follow-up assay.  A cascade of follow-up assays need to be in place to efficiently and effectively remove false positives because the primary HTS assay may typically generate hundreds to thousands of hits, of which most may be false positives or chemically intractable. The post-HTS follow-up assays include:  a) an assay that is essentially an HTS assay with orthogonal detection scheme (e.g., switching light detection mode or wavelength to avoid intrinsic compound interference); b) 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.); c) 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, etc.); d) cytotoxicity assay; (e) target selectivity assays; (f) 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); (g) mode of action assays (e.g., allosteric vs. orthosteric, competitive vs. noncompetitive or uncompetitive); and (h) target identification assays. The assays farther downstream may also include cellular and tissue models pertaining to the relevant physiology or pathophysiology.

Programmatic Management of the Screening Project

A Chemical Probe Development Plan (CPDP) should be developed at the beginning of the project based on the awarded research application by a team composed of the screening staff, the assay submitter, and an NIH program staff. The CPDP outlines the projected probe development path and predicts appropriate benchmarks and timelines. Importantly, the CPDP defines the specific criteria that a compound must meet to be considered a probe for the project. The CPDP discussion should include discussion of prior art of chemical probes, probe definition, assay responsibilities, hit selection criteria, planned follow-up assays, structure-activity relationships of bioactive compounds, and a flowchart to summarize critical path to the probe discovery.

Since an important goal of the NIH is to rapidly disseminate new and important information, awardees will work together with the NIH PubChem staff to ensure fidelity of the data (http://pubchem.ncbi.nlm.nih.gov). Awardees will submit annual Progress Report to summarize the project progress and data generated in primary HTS assays and follow-up assays.

NIH program staff will review the success of the screening campaign based on the Progress Report and the PubChem data to determine feasibility of advancing the project.

Data Sharing

A goal of the program is to further research advancements across the scientific community as rapidly as possible.  This will require synergies that can be achieved through broad sharing of research efforts in a collaborative and cooperative research environment.  It will take the combined resources of researchers in the public and private sectors many years to use small molecule probes to characterize the biology of genes and proteins of interest, cellular processes, and disease processes, and then to use that information to develop products and other approaches that will improve public health. The open sharing of data, research tools, and resources will not only encourage scientific rigor in probe discovery process, but also lead more rapidly to the identification and validation of novel targets for drug discovery, and will facilitate more rapid development of therapeutics by both the private and public sectors, with resulting benefits to public health, especially for rare and neglected disorders. In order to reap the maximum benefit from this program, assay data, assay protocols, and chemical structures of compounds tested will be made publicly available.

For the purpose of this FOA, the following data generated or developed under this FOA are expected to be released to PubChem, consistent with achieving the goals of this program: (1) primary assay data from high throughput screening (HTS), (2) data generated in the follow-up assays, (3) protocols for assays implemented, and (4) the chemical structure of compounds tested.

Applications in response to this FOA should include a statement of willingness to deposit the aforementioned data to PubChem within the Data Sharing section of the application. 

Project Oversight

Projects awarded under this FOA are subject to oversight and review by each of the following entities.

The participating NIH ICs will be responsible for making the award according to their respective missions to support basic and clinical research. For each awarded research project, the participating IC will delegate a program staff to join meeting discussions on the Chemical Probe Development Plan and participate in coordination of the screening project.

NIH PROJECT TEAM. The NIH Project Team composed of the participating IC staff will serve as the governing body that oversees the data deposition to PubChem.

Institute Interests

NIMH:  The NIMH is especially interested in applications for novel, clinically-relevant targets with the goal of transforming target discovery into therapeutic treatment of mental disorders such as depressive disorder, bipolar disorder, schizophrenia, anxiety disorders, panic disorder, and autism, etc.  Proposed projects should be relevant to NIMHs mission of supporting basic science discoveries and translating these discoveries into new therapeutic interventions that will relieve the suffering of people with mental disorders.  NIMH encourages cross-disciplinary collaboration among NIMH-funded existing research, such as Psychopharmacology, Neuropharmacology, Molecular Pharmacology Research, and Genetic Basis of Mental Disorders Programs.  In case a screening campaign yields promising bioactive hits, investigators are encouraged to consider the following funding opportunities: Drug Discovery for Nervous System Disorders PAR-10-001, PAR-10-002, and Optimization of Small Molecule Probes for the Nervous System PAR-09-251.

NCI:  High throughput screens that are pertinent to the mission of NCI should be justified in the application as relevant to cancer.  The NCI is interested in high throughput screens intended to identify small molecules for use in elucidating molecular, cellular, or in vivo mechanisms or processes of probable or known importance to cancer biology, and for use in developing strategies for cancer prevention, diagnosis, treatment or clinical monitoring of treatment.  Screens may be biochemical, cellular or model organism-based.  High throughput screens for targets that address unmet needs in cancer prevention, treatment or diagnosis are encouraged.  Validated hits identified by HTS may be appropriate for entry in the NCI Experimental Therapeutics Program (NExT) for further development to clinical candidate status and testing in clinical trial.  See http://next.cancer.gov/ for the NExT application process.  Applicants may also find the NCI Developmental Therapeutics Program (http://dtp.nci.nih.gov) resources to be helpful.

NEI:  The NEI is especially interested in applications to develop novel, clinically-relevant targets, which can be transformed into therapeutics for treatment of visual diseases and disorders.  Appropriate research areas include, but are not limited to, inflammatory, vascular, and degenerative diseases of the eye, such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma, ocular infections, corneal wound healing, and dry eye syndrome.  Proposed projects should be relevant to NEI’s mission of supporting basic science discoveries and translating these discoveries into new therapeutic interventions that will lead to sight-saving treatments, reduce visual impairment and blindness, and improve the quality of life for people of all ages.

NIA:  NIA is interested in HTS assays and chemical probes that are relevant to the process of normal aging (including normal cognitive aging) and age-related diseases and conditions in a variety of tissues. Examples include  Mild Cognitive Impairment (MCI), Alzheimer’s disease and other dementias of aging, progeroid syndromes, osteoporosis, sarcopenia, and other age–related changes that occur during the human lifespan. NIA is particularly interested in assays and chemical probes that will be useful in identifying new therapeutic targets and, novel therapeutic and imaging agents. NIA is also interested in assays to screen for compounds that affect protective factors or processes that may contribute to slowing or reversing the progression of age-related adverse molecular, biochemical, genetic, cellular, or physiological changes that contribute to multiple age-related diseases, and which hence could contribute to longer health span.

NIAAA:  NIAAA is interested in applications for novel clinically-relevant targets with the goal of transforming target discovery into treatment of alcohol dependence.  NIAAA is also interested in as the development of novel ligands to be used as tools for investigating biological processes contributing to alcohol dependence. Alcohol dependence is a complex disorder involving many neurotransmitter receptors and transporters, ion channels, neuromodulators, hormones, and intracellular signaling networks. This provides a number of potential target sites for which new pharmaceutical agents may be developed.  Examples of interest include:  effectors of opioid, glutamate, GABA, cannabinoid, and adenosine receptors, modulators of neuropeptide systems (e.g., NPY, CRF, substance P, orexin), agents that alter signal transduction pathways (such as protein kinase effectors, protein phosphatase inhibitors, G-protein regulators and calcium signaling disruptors), and modulators of neuroimmune and neuroinflammatory pathways. In case a screening campaign yields promising bioactive hits, investigators are encouraged to consider the following funding opportunities: Drug Discovery for Nervous System Disorders PAR-10-001, PAR-10-002; Optimization of Small Molecule Probes for the Nervous System PAR-09-251.

NIAMS:  NIAMS is interested in discovery and development of novel small molecules that can be used to treat diseases or understand disease mechanisms in the areas of arthritis and musculoskeletal and skin diseases.  Potential applicants are encouraged to review the NIAMS mission (http://www.niams.nih.gov/About_Us/Mission_and_Purpose/mission.asp) and the NIAMS long-range plan (http://www.niams.nih.gov/About_Us/Mission_and_Purpose/long_range.asp) for more information.

NICHD:  NICHD is interested in high throughput screening that will lead to discovery of chemical probes of developmental targets relevant to pregnancy and pediatric-related conditions. Potential applicants are encouraged to review the NICHD mission http://www.nichd.nih.gov/about/overview/mission/ and vision http://www.nichd.nih.gov/vision/ and to contact NICHD program listed on this FOA prior to submitting an application.

NIDA:  NIDA is particularly interested in assays for novel targets that may lead to the development of pharmacotherapeutics for drug addiction and/or chronic pain.  NIDA is also interested in assays to identify compounds that are selective for or against reported human genetic or epigenetic variants of known targets for drug addiction, where the variant is associated with risk for or protection against dependence or addiction.  In case a screening campaign yields promising bioactive hits, investigators are encouraged to consider the following funding opportunities: Drug Discovery for Nervous System Disorders PAR-10-001, PAR-10-002; Optimization of Small Molecule Probes for the Nervous System PAR-09-251.

NIDCD:  The NIDCD is interested in the development of high throughput screens to assess and identify putative analogs that might 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, identification of clinically-relevant targets that might lead to translatable therapeutics in hearing/balance areas of otoprotection, regeneration, otitis media, tinnitus, and normal/abonormal 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 http://www.nidcd.nih.gov prior to submitting an application.

NIGMS: The NIGMS welcomes assays that are relevant to the Institute's mission: basic scientific research that increases understanding of life processes and lays the foundation for more applied advances in disease diagnosis, treatment, and prevention. NIGMS-funded researchers seek to answer important scientific questions in fields such as cell biology, biophysics, genetics, developmental biology, pharmacology, physiology, biological chemistry, bioinformatics, computational biology, selected aspects of the behavioral sciences, and specific cross-cutting clinical areas that affect multiple organ systems.

Section II. Award Information
Funding Instrument

Grant

Application Types Allowed

New
Resubmission
Revision

The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications.

Award Budget

The total project period for an application submitted in response to this funding opportunity may not exceed two years. Total direct costs are limited to $275,000 over an R21 two-year period for each award, with no more than $200,000 in direct costs allowed in any single year, to cover costs associated with HTS and post-HTS follow-up assays.

To prevent budget overlap, applicants who will access assay and chemistry resources at an MLPCN center or other funded resources, may only request a budget to cover costs outside the funded resources.

Award Project Period

The total project period for an application submitted in response to this funding opportunity may not exceed 2 years.

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.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

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.

Required Registrations

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

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 PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (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

Number of Applications

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

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed. Resubmission applications may be submitted, according to the NIH Policy on Resubmission Applications from the SF 424 (R&R) Application Guide.   

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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:

The letter of intent should be sent to:

Yong Yao, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7175, MSC 9641
Bethesda, MD 20892-9641
Telephone:  (301) 443-6102
Email:  yyao@mail.nih.gov

Required and Optional Components

The forms package associated with this FOA includes all applicable components, mandatory and optional.  Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Page Limitations

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

PHS 398 Research Plan Component

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

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modifications:

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.

Foreign Institutions

Foreign (non-US) 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. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application 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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. 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.   

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF 424 (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.

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 SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD(s)/PI(s) Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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 Central Contractor Registration (CCR). 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 by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1. Criteria

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.

Overall Impact

Reviewers will provide an overall impact/priority 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).

Scored Review Criteria

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? 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 there important and well-defined goals for the use of chemical probes identified with the proposed assays, either as research tools or for therapeutics development? 

Investigator(s)    

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?  Are the investigators reasonably knowledgeable and experienced about the biological target area of science? Are the investigators reasonably knowledgeable and experienced about assay implementation and the process of screening compound libraries? Are the investigators reasonably knowledgeable and experienced to conduct follow-up assays to validate screening hits? Are the investigators reasonably knowledgeable to examine non-specific chemical reactivity and interference of compounds?

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?  Is this assay project for a novel biological target or cellular process? Does the application address whether or not there are known small molecule modulators available for this biological target? Is there a need for better small molecule modulators against the target or cellular process? Will the innovation in assay design and compound assembly lead to better success likelihood of the screening?  

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? 

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Is the compound library adequate for screening? Is the HTS assay well designed to minimize false positives and false negatives? Is there sufficient preliminary data to support assay readiness for HTS? Is there an assay performance parameter calculated, such as Z'-factor? Is the assay reproducible? Are non-commercial reagents required for this assay? If so, how are they characterized for purity and activity, and are they readily available? Are there adequate data and plan for secondary and tertiary follow-up assays to evaluate active compounds identified in the primary assays?

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?      

Additional Review Criteria

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/priority 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 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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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

Not Applicable.

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.

Additional Review Considerations

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/priority 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) Genome Wide Association Studies (GWAS).

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),, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate National Advisory Council or Board. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons

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

Section VI. Award Administration Information

1. Award Notices

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 the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) 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. 

Section VII. Agency Contacts

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

Application Submission Contacts

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

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

Suzanne Forry-Schaudies, Ph.D.
National Cancer Institute (NCI)
Telephone:  (301) 435-9147
Email:  forryscs@mail.nih.gov

Jerome Wujek, Ph.D.
National Eye Institute (NEI)
Telephone:  (301) 451-2020
Email:  wujekjer@nei.nih.gov

Larry Refolo, Ph.D.
National Institute on Aging (NIA)
Telephone:  (301) 496-9350
Email:  refolol@mail.nih.gov

Max Guo, Ph.D.
National Institute on Aging (NIA)
Telephone:  301-401-7747
Email:  qmguo@mail.nih.gov

Changhai Cui, PhD
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-1678
Email:changhai.cui@nih.gov

Amanda Boyce, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone:  (301) 594-5585
Email:  boycea@mail.nih.gov

Katerina Tsilou, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone:  (301) 496-6287
Email:  tsiloue@mail.nih.gov

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

Joni Rutter, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone:  (301) 435-0298
Email:  jrutter@nida.nih.gov

Miles A. Fabian, Ph.D.
National Institute of General Medical Sciences (NIGMS)
Telephone:  (301) 594-3827
Email:  fabianm@nigms.nih.gov

Peer Review Contact(s)

J. Thomas Peterson, Ph.D.
Center for Scientific Review (CSR)
Telephone:  (301) 408-9694  
Email:  petersonjt@csr.nih.gov

Financial/Grants Management Contact(s)

Rebecca Claycamp, M.S., CRA
National Institute of Mental Health (NIMH)
Telephone:  (301) 443-2811
Email:  rclaycam@mail.nih.gov

William Darby
National Eye Institute (NEI)
Telephone:  (301) 451-2020
Email:  wwd@nei.nih.gov

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: (301) 443-4704
Email:  jfox@mail.nih.gov

Melinda Nelson
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone:  (301) 435-5278
Email:  nelsonm@mail.nih.gov

Bryan S. Clark, M.B.A
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: (301) 435-6975
Email: clarkb1@mail.nih.gov

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

Cheryl Nathaniel
National Institute on Drug Abuse (NIDA)
Telephone:  (202) 526-0108
Email:  nathanic@nida.nih.gov

Lisa A Moeller
National Institute of General Medical Sciences (NIGMS)
Telephone:  (301) 594-3914
Email:  moellerl@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.

Authority and Regulations

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 Parts 74 and 92.


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