Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Technological innovations in chemical synthesis, cheminformatics, and high throughput bioactivity and drug property assays have allowed rapid discovery of novel, small-molecule probes for the study of disease-related biological processes and mechanisms in academic environments. This provides an unprecedented opportunity for investigators to translate knowledge about diseases into tangible tools and to reshape their research frontier toward a cure. This Funding Opportunity Announcement (FOA) is to support investigators who have interest and capability to join efforts for the discovery of in vivo chemical probes. Applicants to this FOA should have in hand the starting compounds ( validated hits ) for chemical optimization and bioassays for testing new analog compounds.

Through this FOA, NIH aims to stimulate research in 1) discovery and development of novel in vivo chemical probes for their potential use in studying disease treatment relevant to the missions of the participating NIH Institutes, and 2) use of chemical probes to discover and/or validate novel biological targets that will inform studies of disease mechanisms. Emphasis will be placed on the research that provides 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 creates an opportunity for integrated research in biology and chemistry on structure-activity relationships (SAR) of novel compounds through an iterative and parallel optimization process, which ultimately allows the researchers to take a holistic approach and make rapid progress toward successful development of in vivo chemical probes. The iterative bioassay and chemical optimization cycles may encompass:

• In vitro cellular and tissue activities (potency, selectivity, specificity, etc.);
• In vitro structural, physicochemical, and biochemical properties (solubility, stability, membrane permeability, protein binding, microsome stability, metabolite identification, CYP inhibition, etc.);
• In vivo pharmacokinetics (PK) with absorption, distribution, metabolism, excretion (ADME) and toxicity;
• In vivo efficacy

The above-mentioned areas of investigation are representative and not meant to be all-inclusive. Investigators are encouraged to explore novel cost effective approaches to the discovery of in vivo chemical probes. Extensive studies required for the clinical development of candidate therapeutics, such as IND-directed toxicological testing and Good Manufacturing Practices (GMP) synthesis, are beyond the scope of this FOA.

The NIH NCATS Bridging Interventional Development Gaps Program (BrIDGs, http://www.ncats.nih.gov/research/reengineering/bridgs/bridgs.html), offers investigators access to preclinical development resources on a competitive basis, which include synthesis, formulation, pharmacokinetic and toxicology services in support of investigator-held Investigational New Drug (IND) applications to the Food and Drug Administration.

Note: Applicants are encouraged to take advantage of the resources provided by the NIH Clinical & Translational Science Awards (CTSAs) program, (http://www.ctsacentral.org/) to leverage resources for therapeutic discovery in areas described in this FOA. CTSA resources include, for example, core facilities, super computer centers, biostatistics, bioinformatics, community engagement network, tissue repositories, and animal models.

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 the 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) all assay data, (2) protocols for assays implemented, (3) the chemical structure of compounds tested in assays, and (4) synthetic protocols of chemicals.

NIMH: The NIMH is especially interested in applications proposing development of therapies aimed at novel molecular and clinical targets for the treatment of mental disorders, especially treatment-resistant depression, bipolar disorder, schizophrenia, PTSD, and autism spectrum disorder (see From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses). Studies aimed at the development of new ligands for targets where a high-quality probe or therapeutic already exists are generally of lower priority.

Investigators are strongly encouraged to discuss their research plans with NIMH Scientific/Research staff 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. Please see the NIH/NIMH Therapeutics Discovery web page for links to NIMH drug discovery FOAs: Drug Discovery for Nervous System Disorders PAR-13-048 (R01), PAR-13-049 (R21); National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction PAR-14-234 (U19) and PAR-14-184 (U01).

NIMH is particularly interested in the development and testing of novel interventions that target operationally defined, biologically linked functional domains whose disruption is hypothesized to drive functional deficits in mental disorders. For example, NIMH Research Domain Criteria (RDoC, http://www.nimh.nih.gov/research-priorities/rdoc/nimh-research-domain-criteria-rdoc.shtml ) constructs may inform mechanism-based hypotheses and the selection of interventions, outcome measures and clinical subjects. Intervention targets related to RDoC constructs are of interest for this FOA, but other, biologically relevant targets may be suitable as well, especially if they maximize the probability that subjects share the same mechanism of disorder.

Rigor of Data: Translating discoveries into evidence-based treatments is predicated on the existence of strong, well powered, adequately controlled, and replicated preclinical data. In addition, the value of such research is greatly enhanced when detailed information is made available about study design, execution, analysis and interpretation. Examples of critical elements for a well-designed study are summarized on the NIMH website (http://www.nimh.nih.gov/research-priorities/policies/enhancing-the-reliability-of-nimh-supported-research-through-rigorous-study-design-and-reporting.shtml). Please also see https://grants.nih.gov/grants/guide/notice-files/NOT-MH-14-004.html .

NCI: Validated hits that are pertinent to the mission of NCI should be justified in the application as relevant to cancer. The NCI is particularly interested in validated hits for targets that address unmet needs in the prevention, treatment, or diagnosis of cancer. Strategies that include testing of in vivo chemical probe activity in primary human tumor cells are encouraged. In vivo chemical probes 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 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 projects 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 Scientific/Research staff listed in this FOA prior to submitting an application.

NIDA: NIDA is particularly interested in novel targets that may lead to the development of pharmacotherapeutics for drug addiction as well as novel targets for pharmacotherapeutics to treat chronic pain that are likely to have low addiction liability. NIDA is also interested in compounds that are selective for or against reported human genetic and epigenetic variants of known targets for drug addiction, where the variant is associated with risk for or protection against dependence or addiction. Projects that are further along in the medications development pipeline, may want to consider applying under PAR-11-109.

NIDCD: The NIDCD is interested in the development of chemical probes 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/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 at http://www.nidcd.nih.gov prior to submitting an application.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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

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

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

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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

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

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

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:

Enrique L. Michelotti, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443 5415
Email: Enrique.michelotti@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.

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: In the Research Strategy applicants must address the following topics as they pertain to the research project proposed:

1. Validated Hits. Various approaches may be adopted toward pursuing a validated hit, including high throughput screening (HTS) of a large collection of structurally diversified or privileged compounds, virtual screening, fragment-based screening, affinity-based compound library screening, and structure-based de novo design. For a hit compound to be accepted as the starting point of this program, it should have the following well-characterized properties:

• elicit a reproducible response in at least two assay types and also elicit a dose-response over a hundred-fold concentration range;
• be analytically validated in terms of integrity and purity (e.g., use of resynthesized powder sample of high purity in the preliminary assays);
• demonstrate adequate potency;
• possess a tractable starting point of chemical optimization with no obvious major chemical liabilities.

When possible, multiple series of scaffolds may be submitted for parallel optimization to enhance the likelihood of success of the project.

2. Assays. A cascade of in vitro and in vivo assays needs to be in place to efficiently test analog compounds derived from the submitted hits. The applicants are expected to perform in vitro and in vivo SAR assays related to their research fields. The in vitro SAR assays may include target-, pathway-, and phenotype-based assays. Some examples are: 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 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), electrophysiology, and varieties of biophysical readouts. Assays adaptable to microtiter plates (96-, 384-well plates) are advantageous in rapid generation of assay data to enhance SAR iteration efficiency.

The in vivo activity assays may be proof-of-concept assays using one, well-characterized animal species model. Recognizing that very few disease models are clinically validated, applicants are expected to present a convincing argument that the models selected, endpoints measured, and levels of activity observed are likely to be clinically relevant. These preclinical "proof-of-concept" studies must be sufficiently powered, controlled, and replicated to lend a high degree of confidence to the results.

3. Probe criteria. The application should (1) define the specific criteria that a compound must meet to be considered a probe for the project, and (2) provide a thorough literature and informatic analysis about prior art of chemical probes.

4. Critical path. The application should include a one-page flow diagram to outline all critical steps in sequential and/or parallel manners with appropriate benchmarks and timelines, including but not limited to iterative chemical optimization and bioassays to be implemented, alternative approach (e.g., computational docking) to ensure success of the probe discovery, in vivo pharmacokinetic/pharmacodynamic assays to characterize chemical probes, study of structure-activity relationships, assay and chemistry responsibilities of each party involved, etc.

5. Future plan. The application should also include a plan to briefly describe existing and potential follow-up assays to advance chemical probes in the future.

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 modification:

• 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) all assay data, (2) protocols for assays implemented, (3) the chemical structure of compounds tested in assays, and (4) synthetic protocols of chemicals.
• Applications should include a statement of willingness to deposit the aforementioned data to PubChem within the Data Sharing section of the application.

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.

Not Applicable

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

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

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 by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Applicants are required to follow our Post Submission Application Materials policy.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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 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/PI, 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 to carry out the assays and capable of advancing active compounds? Are the investigators reasonably knowledgeable and experienced to conduct chemical optimization efficiently in a cost effective manner?

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 project for a novel biological target or process? Does the application address whether or not known small molecule modulators are available for this biological target or process? Is there a need for better small molecule modulators against the target or process?

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 human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed? Has the biological activity of the hits been adequately characterized and validated by orthogonal assays? Are the biological and physicochemical qualities of the hits adequate as the starting material for in vivo probe development? Are the proposed assays adequate for the iterative study of structure-activity relationships? If so, are the proposed assay reagents and protocols in place and will they be readily implemented? Is the proposed chemical optimization approach adequate and efficient?

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 six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

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.

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) 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.

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

As part of the scientific peer review, all applications:

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

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

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: https://grants.nih.gov/support/index.html
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-945-7573
Email: GrantsInfo@nih.gov

Enrique L. Michelotti, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443 5415
Email: michelottiel@mail.nih.gov

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

Suzanne Forry, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5922
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

Chhanda Dutta, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-4161
Email: DuttaC@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, MD
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

Kristopher Bough, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-9800
Email: boughk@nida.nih.gov

Mary Custer, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-1164
Email: custerm@csr.nih.gov

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

Shane Woodward
National Cancer Institute (NCI)
Telephone: 301846-1017
E-mail: woodwars@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

Yinka Abu
National Institute on Drug Abuse (NIDA)
Telephone: 301-490-3203
Email: abuy@nida.nih.gov

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 Parts 74 and 92.