Part 1. Overview Information

Key Dates

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.

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this 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.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. 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.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
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

Purpose and Background

Through this Notice of Funding Opportunity, (NOFO), NIMH wishes to stimulate research in the discovery and development of novel screening assays for the discovery of validated hits that can be used in future drug discovery/development efforts for identifying potential drug candidates for the treatment of mental illness. 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.

Stages of discovery research covered by this NOFO include 1) assay development; 2) primary screen implementation to identify initial screening hits (high throughput target-focused screens, or moderate throughput screens); and 3) hit validation using a series of assays and initial medicinal chemistry inspection to prioritize the hit set.

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

• First, increased rigor in target identification is necessary. For instance, whether prior studies of the selected target were adequately controlled and powered are important considerations. Were cell lines verified, plasmids sequenced, and protein reagents tested for contaminants?
• Second, reproducibility of the proposed primary assay should be carefully considered because this assay is often the basis for assessing not only initial hits but also for iteratively assessing optimized hits during structure-activity relationship (SAR) studies. Development of primary screening assays that test a key biological function of the target of interest are likely to yield hits of increased relevance. In this respect, phenotypic screens have had a resurgence.
• Third, a hit validation scheme or critical path that includes orthogonal assay(s) to eliminate false positives, as well as a series of assays in diverse biological systems with diverse read-outs, particularly including assays that model human disease, is likely to yield hits of increased relevance.
• Fourth, the inclusion of skilled synthetic and/or medicinal chemists to assess the validity of the hit chemotypes to eliminate PAINS (pan-assay interference compounds) or other undesirable chemotypes.

Research Scope

Projects covered by the NOFO should focus on the following stages of the discovery research:

1) Assay development

2) Primary screen implementation

3) Hit validation

Areas to be considered for each stage are described below and given in greater detail in Section IV (Application and Submission Information, PHS 398 Research Plan).

1. Assay Development

This NOFO supports implementation of innovative biological, biophysical or cell-based assays for novel biological targets or processes relevant to mental disorders.Projects for assay development should emphasize the design and validation of creative approaches to assess biological and disease processes that have the potential to be used as starting points for chemical probes or drug development.

Proposed primary screening assays must be relevant to neuroscience research aimed at discovering pathological processes of psychiatric disorders and developing safer and more effective treatments. The NIMH is interested in applications proposing the development of therapies aimed at novel molecular targets for the treatment of psychiatric disorders, such as treatment-resistant depression, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), panic disorder, and autism spectrum disorders.

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

• Target-based biochemical or cellular assays that measure receptor-ligand binding, protein-protein interactions, activities of enzymes, ion channels, transporters, nuclear receptors, and other transcription factors, and other novel targets emerging from genetic, epigenomic, transcriptomic, proteomic, and metabolomic research in model systems and in human diseases
• Cell- or organism-based assays that detect phenotypic changes linked to the biological or disease process of interest

Assays may utilize any preparation which enables high throughput screening (HTS) or moderate throughput screening (MTS), including cell-free systems, cultured cells, induced pluripotent stem cells (iPSCs), organoids, organotypic brain slices, or model organisms (e.g., zebrafish, Caenorhabditis elegans (C. elegans) and Drosophila melanogaster), which adequately recapitulate important aspects of neuronal or glial function.

Phenotypes of interest may include, but are not limited to, dendritic morphology; axonal outgrowth; neuronal activity and plasticity; synaptic maturation or synaptic function; neuronal and/or glial signaling pathways; receptor function, trafficking, and/or localization; protein synthesis, sorting, interactions, and turnover; cell fate specification; or chromatin remodeling.

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

• Fluorescence, luminescence, absorbance
• Fluorescence resonance energy transfer (FRET)
• Time-resolved fluorescence resonance energy transfer (TR-FRET)
• Fluorescence polarization
• Flow cytometric measurements
• Fluorescence imaging
• Bioluminescence resonance energy transfer (BRET)
• AlphaScreen, scintillation proximity assay (SPA)
• Electrophysiology
• Biophysical measures

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

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

2. Primary Screen Implementation

Virtual Screening (VS)

This NOFO seeks to make use of large, publicly available databases of 3D protein structures, genomic, metabolomic, and proteomic data, and virtual small molecule libraries, combined with computational approaches to accelerate the discovery of novel and potential drug candidates based on specific molecular targets. Projects proposing the use of VS, either ligand-based screening or receptor-based screening, must collaborate with hit assay validation and medicinal chemistry experts for experimental testing of the proposed in silico hits.

VS techniques may involve computational approaches that include, but are not limited to:

• Machine learning based QSAR (particularly deep learning methods)
• Innovative protein-ligand docking algorithms (e.g., evolutionary search methods)
• Similarity search methods
• Pharmacophore mapping methods

Moderate throughput screening (MTS) and high throughput screening (HTS)

Applicants are encouraged to collaborate with an experienced MTS or HTS facility. The screening facility may provide advice such as identification and selection of commercial MTS/HTS assay reagents, and suitable MTH/HTS assay format and readout. In addition, the screening facility may be able to aid in adapting assays to an HTS format (e.g.,1536-well or 384-well microplate) and performing a pilot screen of a small library of compounds. Further, the applicants are expected to seek advice from the screening laboratory about orthogonal assays to validate the screening hits.

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

Phenotypic and model organisms screening

In vivo whole organism assays (e.g., zebrafish, Caenorhabditis elegans (C. elegans) and Drosophila melanogaster) should only be proposed if they adequately recapitulate important aspects of neuronal or glial function and are needed to demonstrate the biological or physiological effects of validated hit compound(s).

Phenotypic screening should only be proposed if a target deconvolution is included in the application or there is a strong association between the mechanisms that drive the phenotypic assay, the preclinical disease model and the human disease.

3. Hit Validation

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.

Hits from a primary screen may be systematically assessed using a cascade of follow-up assays to remove false positives efficiently and effectively. Primary HTS assays typically generate hundreds to thousands of hits, many of which are false positives or are chemically intractable. Hits from smaller scale primary screens are also likely to generate false positives or chemically intractable molecules that require additional screens. Post-primary screening assays may include, but are not limited to:

• An assay that is essentially identical to the primary assay but with an orthogonal detection scheme (e.g., switching light detection mode or wavelength to avoid intrinsic compound interference);
• A target-minus assay (e.g., coupling enzymes in the absence of the assay target enzyme, parental cell line without the assay target protein, etc.);
• An assay that is different in biological context and process (e.g., protein functional assay vs. protein binding assay; RT-PCR or Western blot vs. reporter gene assay; cell-based assay vs. biochemical assay);
• Cytotoxicity assay;
• Target selectivity assay(s);
• Specificity assays to distinguish biological activities of chemical entities among orthologous targets across organism species through kingdoms (e.g., yeast vs. mammalian cell targets; parasite vs. host targets);
• Mode of action assays (e.g., allosteric vs. orthosteric; competitive vs. noncompetitive or uncompetitive); or
• Target identification assays.

Downstream assays may also include cellular and/or tissue models pertaining to the relevant physiology or pathophysiology, or to the mode and mechanism of action of the validated hits. In vivo whole organism assays (e.g., zebrafish, Caenorhabditis elegans (C. elegans) and Drosophila melanogaster) should only be proposed if they are needed to demonstrate the biological or physiological effects of validated hit compound(s).

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

The NIMH encourages applications proposing novel, clinically relevant targets with the goal of transforming target discovery into the therapeutic treatment of psychiatric disorders such as depression, bipolar disorder, schizophrenia, anxiety, panic disorder, autism spectrum disorders, etc. (see From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses). Proposed projects should be relevant to NIMH's mission of supporting basic science discoveries and translating these discoveries into new therapeutic interventions that will relieve the suffering of people with psychiatric disorders. Projects aimed at the discovery of in vivo chemical probes should consider applying to PAR-21-029. Projects aimed at the discovery of cell-based chemical probes should consider applying to PAR-21-028. Projects aimed at early stages of drug discovery and development should consider the Drug Discovery for Nervous System Disorders PAR-22-031 (R01) and PAR-22-032 (R21) or the National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction PAR-22-144 (U19) and PAR-22-143 (U01)

Small businesses should consider applications through the Small Business Innovation Research Program.

Details on these and additional funding opportunity announcements and therapeutic discovery resources are listed on the NIH/NIMH Therapeutics Discovery Research webpage. Further information on NIMH research priorities can be found in the NIMH Strategic Plan, Strategic Research Priorities, and Interventions Workgroup Report. Applicants are strongly encouraged to discuss potential applications with NIMH staff listed in Section VII - Agency Contact(s), Scientific/Research Contacts prior to submission to determine the alignment of the planned studies with NIMH priorities and to assess whether this or other NIMH funding opportunities are most appropriate.

Applications Nonresponsive to This NOFO

The following studies will be considered non-responsive for this announcement and will not be reviewed:

• Assays focusing on targets or/and approaches that have been extensively studied
• Implementation of structure-activity relationship (SAR) assays
• In vitro Absorption, Distribution, Metabolism, and Excretion (ADME) assays
• Proposing in silico hits without experimental validation
• In vivo rodent activity assays
• Lack of verification of the chemical structures of hit compounds using a combination of analytical methods

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Government

• 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.

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • 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 registration; 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.

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. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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

2. Cost Sharing

This NOFO 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.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 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 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 SF424 (R&R) Application Guide except where instructed in this notice of funding opportunity 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.

Letter of Intent

Not Applicable

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 NOFO.

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

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

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

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

R&R or Modular Budget

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

R&R Subaward Budget

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

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

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

Research Strategy: Address the following topics as they pertain to the research project proposed:

Significance: Address why the chosen target or pathway is significant for the proposed chemical hit discovery project, and whether the hit(s) will provide new insight into important disease targets and processes. Preliminary data or published information demonstrating the significance of the target or pathway should be included. Any existing modulators for the target should be mentioned, and a rationale for additional discovery and/or development of small molecules that address the target should be delineated.

Innovation: Innovative aspects of studying the proposed target or pathway and of the proposed assay(s) and screening scheme should be highlighted.

Investigators: Describe investigators' knowledge and experience in biological targets, pathways, and disease areas, and in performing the discovery research stages proposed.

Approach: Define the scope of the proposed research project via the three drug discovery research stages outlined in Section I. Include a flow diagram outlining all critical steps in sequential and/or parallel manners with appropriate benchmarks and timelines for the stage(s) of discovery research proposed. The application should include the following topics in the research plan:

1) Assay Development: An explanation of the scale of the proposed assay campaign (i.e., low-, moderate- or high-throughput), reproducibility of the primary screening assay and reproducibility and robustness of the primary screening assay in a low-to-moderate throughput setting. Define experiments to test the predictability and reproducibility of responses to known compounds or other control conditions and a clear threshold between positive and negative responses.

2) Primary Screen Implementation: Preliminary data on the primary screening assay performance as tested in a small-scale pilot screen, a discussion of the following parameters: anticipated number of hits; feasibility of assessing hits (particularly large numbers); test concentrations; cut-off concentration; reagent availability; equipment used in configuring the assay; strategy to characterize initial active compounds, and a rationale for the size and selection of the library of compounds to be screened regardless of the scale of the screen.

3) Hit Validation: a rationale for the chosen hit validation scheme, considering the number of hits from the primary screen, anticipated false positives inherent in the primary assay format, and/or necessary assays to test the biology or physiology of the target, availability, and suitability of secondary and counter-screen assays as appropriate for the scale of the screening campaign or plans to develop and characterize them, a definition of the specific criteria that a compound must meet to be considered a validated hit, a plan to conduct advanced cheminformatic analysis and medicinal chemistry inspection to prioritize the hit set, confirmation of hit compound structures by testing powder samples and commercially available analog compounds and resynthesis of selected hits, a description of the desired properties of validated hit series, including structures and preliminary data if available and the criteria for disqualifying a hit series from further optimization and selection of back up series.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R& R ) Application Guide.

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

To advance the goal of advancing research through widespread data sharing among researchers, investigators funded under this Notice of Funding Opportunity (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) the 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 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.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

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

Foreign Institutions

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

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

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

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile 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 SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

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

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

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

NIMH expects investigators for this funding announcement to collect Common Data Elements (CDEs) for mental health human subjects research. Unless NIMH stipulates otherwise during the negotiation of the terms and conditions of a grant award, this Notice applies to all grant applications involving human research participants. The necessary funds for collecting and submitting these CDE data from all research participants to the NIMH Data Archive (NDA) should be included in the requested budget. A cost estimator (https://nda.nih.gov/ndarpublicweb/Documents/NDA_Data_Submission_Costs.xlsx) is available to facilitate the calculation of these costs. NIMH may seek further information regarding CDEs prior to award. Additional information about CDEs can be found at the NIMH webpage on Data Sharing for Applicants and Awardees.

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

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

Overall Impact

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).

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? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this NOFO:

• How well does the application justify the important and well-defined goals for the use of hit compounds, either as research tools or for therapeutic development?
• If the goal is to develop hit compounds as research tools, how well does the application describe the potential of the hits to provide a new insight into important disease targets and processes? If compounds exist for the proposed target, how convincing is the rationale for additional discovery research?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance, and organizational structure appropriate for the project?

Specific to this NOFO:

• Examine the adequacy of the investigators' knowledge and experience in the biological target, pathway, disease area and ability to perform the discovery research stages proposed?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Specific to this NOFO:

• How well does the application describe the novelty of the biological target or pathway for the proposed disease being studied?
• Examine the novelty of the proposed assay design, compound screening scheme, and/or hit structures?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this NOFO:

• How well does the application describe the proposed timeline consistency with the scale and stages of discovery research proposed in the Aims? How well does the application describe the preliminary data supporting the stages of discovery research proposed in the Aims?
• How well does the application define the scope of the proposed research project via the drug discovery stages outlined in Section I? How well does the application delineate the flow diagram outlining all critical steps in sequential and/or parallel manners with appropriate benchmarks and timelines for whichever stage(s) of discovery are proposed?

Specifically for each stage:

1) Assay Development:

• How appropriate is the scale of the proposed assay campaign (i.e., low-, moderate- or high-throughput) for the selected target? How well does the application address the reproducibility of the primary screening assay, the reproducibility and robustness of the primary assay in an automated, MHT or HTS approach, and the predictability and reproducibility of known compounds responses?

2) Primary screen implementation:

• How well does the application address the inclusion of the preliminary data on the primary screening assay performance as tested in a small-scale pilot screen?
• How well does the application address the inclusion of a discussion on the anticipated number of hits; feasibility of assessing hits: test concentrations; cut-off concentration; reagent availability; equipment used in configuring the assay; strategy to characterize initial active compounds?
• How well does the application describe and sufficiently justify the rationale for the size and selection of the library of compounds to be screened, regardless of the scale of the screen?

3) Hit validation:

• How well does the application describe the rationale for the chosen hit validation scheme, considering the number of hits from the primary screen, anticipated false positives inherent in the primary assay format, and/or necessary assays to test the biology or physiology of the target?
• How well does the application describe the availability and suitability of the secondary and counter-screen assays?
• How well does the application describe the definition of the specific criteria that a compound must meet to be considered a validated hit?
• To what extent does the application provide an adequate plan to conduct advanced cheminformatic analysis and medicinal chemistry inspection to prioritize the hit set?
• How well does the application justify the confirmation of the structure of the hit compounds by testing powder samples and/or commercially available analog compounds and by re-synthesis of select hits?
• How well does the application present a description of the desired properties of validated hit series?
• How well does the application describe the criteria for disqualifying a hit series from further optimization and selection of back up series?

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 score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals 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 Accepted

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 Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

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

2. Review and Selection Process

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

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

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

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 NOFO. 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.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

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 recipient's business official.

Recipients 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 NOFO will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federal wide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a condition of receiving the grant, to administer programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity, The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. See https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

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

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.

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

• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Not Applicable

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

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

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

Section VII. Agency Contacts

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

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

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Enrique Michelotti, PhD
National Institute of Mental Health (NIMH)
Telephone: 301-443-5415
Email: [email protected]

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

Heather Weiss
National Institute of Mental Health (NIMH)
Telephone: 301-443-4415
Email: [email protected]

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.