Discovery of in vivo Chemical Probes for the Nervous System (R01 Clinical Trial Not Allowed) (PAR 27 081)

Discovery of in vivo Chemical Probes for the Nervous System (R01 Clinical Trial Not Allowed) (PAR 27 081) is sponsored by National Institutes of Health (NIH). This funding opportunity supports the discovery of in vivo chemical probes for the nervous system, which could have implications for understanding and treating neurological disorders.

PAR-27-081: Discovery of in vivo Chemical Probes for the Nervous System (R01 Clinical Trial Not Allowed) Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Eye Institute ( NEI ) National Institute on Drug Abuse ( NIDA ) National Institute of Mental Health ( NIMH ) Funding Opportunity Title Discovery of in vivo Chemical Probes for the Nervous System (R01 Clinical Trial Not Allowed) R01 Research Project Grant Check for any recent Notices of NIH Policy Changes that may impact application requirements.

Funding Opportunity Number (FON) Companion Funding Opportunity See Part 2, Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s) 93. 866, 93. 279, 93.

867, 93. 242 Funding Opportunity Purpose The purpose of this Notice of Funding Opportunity (NOFO) is to support investigators who have the interest and capability to join efforts for the discovery of in vivo chemical probes for novel brain targets. It is expected that applicants will have, in hand, the starting compounds (validated hits) for chemical optimization and bioassays for testing new analog compounds.

Through this NOFO, NIH wishes to stimulate research in: Discovery and development of novel, small molecules for their potential use in understanding biological processes relevant to the missions of National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), National Eye Institute (NEI), and/or National Institute on Aging (NIA) and Discovery and/or validation of novel, biological targets that will inform studies of brain disease mechanisms.

Emphasis will be placed on projects that provide new insight into important disease-related biological targets and biological processes. Funding Opportunity Goal(s) To encourage biomedical, social, and behavioral research and research training directed toward greater understanding of the aging process and the diseases, special problems, and needs of people as they age.

Open Date (Earliest Submission Date) The following table includes NIH standard due dates marked with an asterisk. Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) 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.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Use Grants. gov Workspace to prepare and submit your application and eRA Commons to track your application.

Part 1. Overview Information Part 2. Full Text of Announcement Section I.

Notice of 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.

Notice of Funding Opportunity Description Technological innovations in chemical synthesis, cheminformatics, structural biology, 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.

Through this Notice of Funding Opportunity (NOFO), NIMH, NIDA, NEI and/or NIA encourage applications to advance the discovery of small molecule chemical probes that would enable, by modulating the function of a novel biological target, mechanistic questions to be addressed in animal studies.

The NIH aims to stimulate research in 1) discovery and development of novel in vivo chemical probes for their potential use in understanding biological processes 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 brain disease mechanisms.

Emphasis will be placed on research that provides new insight into important disease-related biological targets and biological 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, to advance the successful development of in vivo chemical probes. Applicants to this NOFO should have, in hand, the starting compounds (validated hits) for chemical optimization and bioassays for testing new analog compounds.

The iterative bioassay and chemical optimization cycles may encompass: In vitro cellular and tissue activities (potency, selectivity assessment of on-target and off-target effects in cells, specificity, etc.). In vitro structural, physicochemical, and biochemical properties (solubility, stability, membrane permeability (Caco-2/MDR1-MDCK/PAMPA), protein binding, microsome stability, metabolite identification, CYP inhibition, etc.).

In vivo pharmacokinetics (PK) with absorption, distribution, metabolism, excretion (ADME) and toxicity. The above-mentioned areas of investigation are representative and not meant to be all-inclusive. The main emphasis of projects submitted under this NOFO should be on chemical probes development rather than drugs or therapeutic discovery, the latter of which are beyond the scope of this NOFO.

Applications Not Responsive to this NOFO. Applications on the following research topics are not responsive to this NOFO and will be withdrawn prior to review: Projects proposing the development of phenotypic chemical probes. Projects proposing the development of drugs or therapeutic discovery.

Projects seeking resources for later-stage drug development. Projects proposing extensive studies required for the preclinical or clinical development of candidate therapeutics, such as IND-directed toxicological testing and Good Manufacturing Practices (GMP) synthesis. See Section VIII.

Other Information for award authorities and regulations. Section II. Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO. Not Allowed: This NOFO only accepts applications that do not propose clinical trials.

Note: Applications may propose activities involving human subjects that are not deemed clinical trials. Need help determining whether you are doing a clinical trial? 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.

Application budgets are not limited but need to reflect the actual needs of the proposed project. The scope of the proposed project should determine the project period. The maximum project period is 5 years NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III.

Eligibility Information Higher Education Institutions - Includes all types Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education 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 (Other than Small Businesses) 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 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 Non-domestic (non-U.S.) Entities (Foreign Organizations) Foreign Organizations/International Collaborations Non-domestic (non-U.S.) Entities (Foreign Organizations) 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. NIH will no longer issue awards (i.e., new, renewal, or non-competing continuation) to domestic or foreign entities that involve foreign subawards/subcontracts.

All NIH-funded research involving foreign subawards/subcontracts must be submitted in response to a NOFO that is specifically designated for funded international collaborations. See NIH Grants Policy Statement 16. 8 Collaborative International Research Awards .

Applications involving foreign subawards/subcontracts submitted in response to this NOFO will be deemed noncompliant and will not be considered for funding.

This policy applies to all monetary international collaborations resulting in foreign subawards/subcontracts, however, it does not preclude unfunded international collaborations or foreign components , funding for foreign consultants, or procurement of unique equipment or supplies from foreign vendors.

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- 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.

Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2. 3. 9.

2 Electronically Submitted Applications for additional information. System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually . The renewal process may require as much time as the initial registration.

SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code. Foreign organizations must obtain a NATO Commercial and Government Entity (NCAGE) Code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.

gov registration process. The same UEI must be used for all registrations, as well as on the grant application. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.

gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants.

gov – Applicants must have an active 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.

All PD(s)/PI(s) must be registered with ORCID . The personal profile associated with the PD(s)/PI(s) eRA Commons account must be linked to a valid ORCID ID. For more information on linking an ORCID ID to an eRA Commons personal profile see the ORCID topic in our eRA Commons online help .

Eligible Individuals (Program Director/Principal Investigator) 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 their organization to develop an application for 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 How to Apply-Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

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 NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise (in this NOFO, in a policy notice , or other notice from NIH Guide for Grants and Contracts ). 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. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Cover Page Supplement All instructions in the How to Apply - Application Guide must be followed. All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions: Research Strategy : In the Research Strategy section, applicants should address the following topics as they pertain to the research project proposed: 1. Biological Target.

Address the novelty and significance of the biological target or biological process. Clearly describe any known small molecule modulators and the need for better small molecule modulators against the intended biological target or biological process. 2.

Validated Hits. Applicants to this NOFO should have, in hand, the starting compounds (validated hits) for chemical optimization and bioassays for testing new analog compounds. For purposes of this initiative, a hit is defined as a compound that has the desired activity in a compound screen and whose activity is confirmed upon retesting in orthogonal assays.

Various approaches using in silico , in vitro, ex vivo , or in vivo assays may be adopted toward pursuing a validated hit, including application of machine learning (ML) at each step of the hit discovery stage, spanning from hit identification to hit optimization, use of generative ML models in de-novo design of chemical structures with desired properties, ligand-based or structure-based virtual screening and computational hit expansion, high throughput screening (HTS) of a large collection of structurally diversified or privileged compounds, and use of ML in the design of new molecules employing phenotypic and high content screening data and assessing their potency, selectivity, and binding affinity, and use of ML models for predicting bioactivity and ADMET parameters of compounds.

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 orthogonal assay types and 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. demonstrate the adequate potential for selectivity. possess a tractable starting point of chemical optimization with no obvious major chemical liabilities.

To enhance the likelihood of success of the project, the parallel optimization of multiple validated hits is highly encouraged. 3. 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 v itro 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 other omics 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 the rapid generation of assay data to enhance SAR iteration efficiency. Demonstrate that the proposed assays are adequate for the iterative study of structure-activity relationships and that the proposed assay reagents and protocols are in place and will be readily implemented.

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. 4. Probe criteria.

(1) Define the specific criteria that a compound must meet to be considered a probe for the project, (2) provide thorough literature and informatics analysis of any known small molecule probe for the intended biological target or biological process, and (3) provide evidence that the validated hit to be optimized is engaging its target in vivo . 5. Critical path.

Include a 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 the success of the probe discovery, in vivo pharmacokinetic/pharmacodynamic assays to characterize chemical probes, the study of structure-activity relationships, assay and chemistry responsibilities of each party involved.

6. Future plan. 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 as provided in the How to Apply - Application Guide . All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions: A Data Management and Sharing Plan (DMS Plan) is required for any NIH-funded or conducted research that will generate scientific data.

Applicants must submit the DMS Plan at the time of application using the NIH DMS Plan Format Page. The DMS Plan must address the elements in the structured format should not exceed two (2) pages. Where the DMS Plan Format Page requires a “Yes or No” response, no additional narrative is allowed.

For the purpose of this NOFO, the following data generated or developed under this NOFO are expected to be released to PubChem , consistent with achieving the goals of this program: (2) protocols for assays implemented, (3) the chemical structure of compounds tested in assays, and (4) synthetic protocols of chemicals.

To advance the goal of advancing research through widespread data sharing among researchers, investigators funded by NIMH under this NOFO are expected to share those data via the National Institute of Mental Health Data Archive (NDA; see NOT-MH-23-100 ).

Established by the NIH, NDA is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, tools, and supporting documentation. NDA links data across research projects through its Global Unique Identifier (GUID) and Data Dictionary technology. Investigators funded under this NOFO are expected to use these technologies to submit data to NDA.

To accomplish this objective, it will be important to formulate a) an enrollment strategy that will obtain the information necessary to generate a GUID for each participant, and b) a budget strategy that will cover the costs of data submission.

The NDA website provides two tools to help investigators develop appropriate strategies: 1) t he NDA Data Submission Cost Model which offers a customizable Excel worksheet that includes tasks and hours for the Program Director/Principal Investigator and Data Manager to budget for data sharing; and 2) plain language text to be considered in your informed consent available from the NDA's Data Contribution page .

Investigators are expected to certify the quality of all data generated by grants funded under this NOFO prior to submission to NDA and review their data for accuracy after submission.

Submission of descriptive/raw data is expected semi-annually (every January 15 and July 15); submission of all other data is expected at the time of publication, or prior to the end of the grant, whichever occurs first (see NDA Sharing Regimen for more information); Investigators are expected to share results, positive and negative, specific to the cohorts and outcome measures studied.

For more guidance on submitting data to NDA, refer to the NDA Data Management and Sharing Plan on the NDA website . NDA staff will work with investigators to help them submit data types not yet defined in the NDA Data Dictionary . Appendix: Only limited Appendix materials are allowed.

Follow all instructions for the Appendix as described in the How to Apply - Application Guide . No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide , with the following additional instructions: If you answered “Yes” to the question “Are Human Subjects Involved?

” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record. Study Record: PHS Human Subjects and Clinical Trials Information All instructions in the How to Apply - Application Guide must be followed.

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How to Apply- Application Guide must be followed. PHS Assignment Request Form All instructions in the How to Apply- Application Guide must be followed.

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement , and procedures for foreign organizations described throughout the How to Apply- Application Guide. 3. Unique Entity Identifier and System for Award Management (SAM) See Part 2.

Section III. 1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants. gov 4.

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

When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day. Organizations must submit applications to Grants. gov (the online portal to find and apply for grants across all Federal agencies).

Applicants must then complete the submission process by tracking the status of the application in the eRA Commons , NIH’s electronic system for grants administration. NIH and Grants. gov systems check the application against many of the application instructions upon submission.

Errors must be corrected and a changed/corrected application must be submitted to Grants. gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2. 3. 9.

2 Electronically Submitted Applications . 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 How to Apply-Application Guide .

5. Intergovernmental Review (E. O.

12372) 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 Section 7.

9. 1 Selected Items of Cost. 7.

Other Submission Requirements and Information Applications must be submitted electronically following the instructions described in the How to Apply – Application Guide . Paper applications will not be accepted. Applicants must complete all required registrations before the application due date.

Section III. Eligibility Information contains information about registration. For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide .

If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII. All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form .

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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply – Application Guide . See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200. 113 and NIH Grants Policy Statement Section 4.

1. 35 . Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.

hhs. gov . Post Submission Materials Applicants are required to follow the instructions for post-submission materials, as described in the policy Section V.

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. Factor 1.

Importance of the Research (Significance and Innovation) Evaluate the importance of the proposed research in the context of current scientific challenges and opportunities, either for advancing knowledge within the field, or more broadly. Assess whether the application addresses an important gap in knowledge in the field, would solve a critical problem, or create a valuable conceptual or technical advance.

Evaluate the rationale for undertaking the study, the rigor of the scientific background for the work (e.g., prior literature and/or preliminary data) and whether the scientific background justifies the proposed study. Evaluate the extent to which innovation influences the importance of undertaking the proposed research.

Note that while technical or conceptual innovation can influence the importance of the proposed research, a project that is not applying novel concepts or approaches may be of critical importance for the field. Evaluate whether the proposed work applies novel concepts, methods or technologies or uses existing concepts, methods, technologies in novel ways, to enhance the overall impact of the project.

Evaluate how well the goals are defined