Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Mental Health (NIMH)

Funding Opportunity Title
Novel Assays to Address Translational Gaps in Treatment Development (UG3/UH3 Clinical Trial Optional)
Activity Code

UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement

Announcement Type
Reissue of PAR-19-214
Related Notices

NOT-OD-22-190 - Adjustments to NIH and AHRQ Grant Application Due Dates Between September 22 and September 30, 2022

Funding Opportunity Announcement (FOA) Number
PAR-22-169
Companion Funding Opportunity
PAR-22-170 , R01 Research Project
Assistance Listing Number(s)
93.242
Funding Opportunity Purpose

The goal of this initiative is to identify neurophysiological measures as potential assays for treatment development research. The Funding Opportunity Announcement (FOA) will support efforts to optimize and evaluate pharmacodynamic (PD) measures of neurophysiological processes that are disrupted within or across mental disorders in both healthy humans and in another species relevant to the therapeutic development pipeline. The initiative will support initial proof of concept studies aimed at identifying measures for potential development as preclinical assays for evaluating potential new drug and device therapies and their targets. Data may also reveal assay measures where performance is dissimilar between preclinical animal species and humans, thus establishing a firm basis for limiting speculative extrapolations of preclinical animal findings to humans. The ultimate goal of this FOA is to improve the efficiency of the therapeutic development process by identifying congruent measures as well as inconsistencies between the preclinical screening pipeline and clinical evaluation of new treatment candidates.

The objectives of the FOA will be accomplished by supporting partnerships among basic and translational neuroscientists who are committed to advancing the discovery of in vivo physiological measures as tools for target validation and therapeutic development. Groups will be tasked with developing and optimizing in vivo assays of brain processes in both animals and in healthy humans. Groups will evaluate assay performance across both species in response to pharmacologic manipulations. In this way, projects will reveal the potential of specific assays to translate from animals to humans, suggesting assays for further development as tools in the treatment development pipeline.

Key Dates

Posted Date
July 07, 2022
Open Date (Earliest Submission Date)
September 21, 2022
Letter of Intent Due Date(s)

30 days before the application due date.

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
October 21, 2022 October 21, 2022 Not Applicable March 2023 May 2023 July 2023
February 21, 2023 February 21, 2023 Not Applicable July 2023 October 2023 December 2023
June 21, 2023 June 21, 2023 Not Applicable November 2023 January 2024 April 2024
October 21, 2023 October 21, 2023 Not Applicable March 2024 May 2024 July 2024
February 21, 2024 February 21, 2024 Not Applicable July 2024 October 2024 December 2024
June 21, 2024 June 21, 2024 Not Applicable November 2024 January 2025 April 2025
October 21, 2024 October 21, 2024 Not Applicable March 2025 May 2025 July 2025
February 21, 2025 February 21, 2025 Not Applicable July 2025 October 2025 December 2025
June 20, 2025 June 20, 2025 Not Applicable November 2025 January 2026 April 2026

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.

Expiration Date
June 21, 2025
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

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.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The goal of this initiative is to identify neurophysiological measures as potential assays for treatment development research. The funding opportunity announcement (FOA) will support efforts to optimize and evaluate pharmacodynamic (PD) measures of neurophysiological processes that are disrupted within or across mental disorders in both healthy humans and in another species relevant to the therapeutic development pipeline.The initiative will support initial proof of concept studies aimed at identifying measures for potential development as preclinical assays for evaluating potential new drug and device therapies and their targets. Data may also reveal assay measures where performance is dissimilar between preclinical animal species and humans, thus establishing a firm basis for limiting speculative extrapolations of preclinical animal findings to humans. The ultimate practical goal of this FOA is to improve the efficiency of the therapeutic development process by identifying congruent measures as well as inconsistencies between the preclinical screening pipeline and clinical evaluation of new treatment candidates.

The objectives of the FOA will be accomplished by supporting partnerships among basic and translational neuroscientists who are committed to advancing the discovery of in vivo physiological measures as tools for target validation and therapeutic development. Groups will be tasked with developing and optimizing in vivo assays of brain processes in both animals and in healthy humans. Groups will evaluate assay performance across both species in response to specific pharmacologic manipulations. In this way, projects will reveal the potential of specific assays to translate from animals to humans, suggesting assays for further development as tools in the treatment development pipeline.

Background

The NIMH Strategic Plan for Research outlines research priorities for transforming the understanding and treatment of mental illnesses. The plan includes two cross-cutting themes which are directly relevant to the goals of this Funding Opportunity – Transforming Diagnostics and Accelerating Therapeutics. A core component of the Transforming Diagnostics theme is the Research Domains Criteria (RDoC) project. RDoC has grown into a significant effort for the NIMH that frees investigators from the current symptom-based diagnostic categories (i.e., Diagnostic and Statistical Manual, DSM) and encourages clinical researchers to study dimensions of observable behavior and neurobiological measures that may span multiple disorders. As outlined in NOT-MH-19-053, basic neuroscientists are encouraged to address molecular and neural mechanisms underlying specific domains of mental function, rather than creating animal models of diseases. Relevant to the Accelerating Therapeutics theme, NIMH has shifted its clinical trials portfolio toward studies with defined targets and milestones. The Institute’s experimental medicine approach seeks trials that will address the clinical assessment of the mechanism of action of the therapeutic treatment, providing a foundation for building specific treatment strategies. 

Implementation of experimental medicine designs in early phase trials of novel treatments for mental disorders requires a demonstration that the proposed intervention engages the target sufficiently to evaluate target-mediated effects on brain processes and clinical outcomes. In this context, ‘target’ refers to the brain signaling system, circuit, or physiological process the therapeutic strategy aims to correct as a means of improving function across mental disorders. The RDoC effort has the potential to identify measures that can be incorporated in experimental medicine trial designs to evaluate links between targets, circuits, and key functional domains in relation to clinical improvements. However, the potential success of the emerging clinical efforts is diluted by the lack of reciprocal efforts to develop assays of neural processes in the preclinical species. This lack of continuity of functional measures of target engagement between the preclinical species selected for use in treatment development and evaluation of effects in humans contributes uncertainty to an already risky pipeline of treatment development for mental disorders. For example, it is not surprising that commonly used preclinical behavioral assays whose original value was based on their ability to detect certain classes of compounds (e.g., the Porsolt swim test to identify serotonin uptake inhibitors as antidepressants), are poor predictors of the potential clinical efficacy of compounds that engage novel molecular targets.

Research Objectives

The purpose of this FOA is to address the translational divide between preclinical and clinical measures implemented in the treatment development pipeline for mental disorders by supporting the construction of a suite of in vivo functional brain assays that evaluate measures for translational predictive value. Towards this goal, the FOA will support the identification, development, optimization, and evaluation of in vivo CNS assays that measure brain functions that are evolutionarily conserved between the selected animal species and humans. The FOA will additionally support assessment of the performance (test-retest reliability, sensitivity) of brain-based assays in both the preclinical species and in healthy humans in response to carefully selected pharmacologic-based dose response pharmacokinetic (PK)/PD assessment. Assays will aim to identify quantitative, robust, and reliable measures that tap into specific neurophysiological systems that are potentially impacted in mental disorders such as neural plasticity, cognitive or affective regulatory processes, or impulsivity. The manipulations will provide a critical first evaluation of how the measure performs in the context of the therapeutic development pipeline spanning from the preclinical species to humans.

Proposed assay measures are expected to have a reasonable likelihood of shared conservation of physiology and brain circuitry across healthy human controls and preclinical species. While there is a risk that measures of some brain processes may be difficult to optimize for cross-species evaluation or may not show coherence between species, this risk is managed by the UG3/UH3 mechanism, a two-stage phased innovation cooperative agreement award. The UG3 phase supports the planning and preliminary studies needed to conduct an evaluation of the performance of assays in both species in the UH3 phase. Projects will be milestone driven with an administrative review by internal NIMH staff to identify UG3 projects attaining milestones and demonstrating feasibility of assays in both species for advancement to the assay testing (UH3) phase. The cooperative agreement mechanism allows for greater involvement of NIMH staff in these projects, including suggesting external advisors and providing opportunities for multiple FOA awardee groups to interact and share data. Should multiple UG3/UH3 awards be issued, it is expected that the groups will meet annually as a consortium to share updates on progress, to troubleshoot, and to outline strategies for disseminating data.

While it is understood that many protocols and the data generated will be at an early proof-of-concept stage, a central goal of this FOA is to contribute to building a more robust, experimentally based therapeutic development pipeline for mental disorders. Regardless of study outcomes, it is expected that experimental protocols and data generated through both the UG3 and UH3 phases of this FOA will be made available to the research community as a valuable source of information regarding relationships between animal assay results and human data no later than within one year of completion of the studies.  

The initiative will support partnerships among basic and translational neuroscientists who are committed to the discovery of translational physiological measures that may be used across preclinical development and that have the highest potential to be advanced into healthy human trials as tools for use in phase 1 or phase 2 therapeutics development.

Potential applicants are strongly encouraged to read the Frequently Asked Questions (FAQs) for this FOA and to contact NIMH Scientific/Research Contact(s) prior to preparing an application.

Research Scope

This FOA will support the phased development of in vivo assays to address translational gaps in treatment development for mental disorders. Support will be provided for assay development efforts that propose quantitative measures to assess alterations in neurophysiology/circuit activity that contribute to or reflect clinically relevant domains of function (e.g., cognitive function, impulsivity, motivation, etc.).

Proposed projects may include:

  • Development and testing of in vivo measures that tap into fundamental processes that are disrupted within or across mental disorders such as aspects of vigilance, neural plasticity, reward processing, or attentional mechanisms contributing to cognition and/or affect regulation, that can be objectively measured in both live animals and humans using brain imaging or neurophysiological measures such as spectral EEG or MEG to assess brain rhythms with different frequencies. Innovative measures are encouraged.
  • Development and testing of highly tractable behavioral paradigms as assays that may serve as proxies of neural circuit activity linked to a specific functional domain in both humans and animals. For example, the CNTRICS program identified constructs across six cognitive systems relevant to schizophrenia and selected tasks from cognitive neuroscience that measure the constructs and the CNTRACS initiative extended those measures (goal maintenance, relational encoding, gain control, visual integration). Such studies should combine behavioral and physiological measures (for example, tracking changes in forebrain oscillations during performance). Since the goal is to build innovation and address translational gaps, the inclusion of behavioral paradigms that are already commonly used cross species (e.g., fear conditioning) must incorporate novel measures of underlying neuronal processes.

See the NIH/NIMH Therapeutics Discovery web page for links to other NIMH drug discovery FOAs: Drug Discovery for Nervous System Disorders PAR-19-147 (R01) and PAR-19-146 (R21), National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Substance Use Disorders, or Alcohol Disorder PAR-20-119 (U19) and PAR-20-118 (U01). Note the related FOAs titled Understanding and Modifying Temporal Dynamics of Coordinated Neural Activity, PAR-21-175 (R01) and PAR-21-176 (R21).

The UG3/UH3 is a two-phased mechanism. Each phase is milestone driven and only those projects attaining the UG3 milestones have the potential to progress to the UH3 phase. The UG3 phase supports feasibility testing and optimization of measures in animals and humans. The UH3 phase supports parallel testing of the measures in both animals and humans in response to pharmacologic dose ranging PK/PD studies to evaluate the performance, sensitivity, and coherence of measures across species.

1. The UG3 Preparatory Testing and Prioritization Phase (Stage 1) for this FOA supports milestone-driven optimization of testing and prioritization of measures that tap into mental health relevant brain processes (e.g., neural plasticity, cognitive or affect regulatory processes, impulsivity) and neural circuit activity as assays in both animals and humans. For example, some assay measures that are already developed in the animal species selected will need to be adapted for humans while other assays may need to be back-translated from humans to the preclinical species. Other measures in this phase may need to be optimized in both species. Studies are expected to be performed in live animals and humans and not in cell culture, post mortem, or in vitro preparations. The only exception would be the allowance of a small number of limited studies in the UG3 phase aimed at identifying pharmacologic dose levels of the manipulations to be used in the UH3 phase for equivalent target engagement across species. 

UG3 projects are milestone driven and include go-no-go criteria for each assay that will be used to determine whether assays are sufficiently optimized and methodologically equated across species. UG3 assays that meet the scientific milestones and feasibility requirements may be eligible for transition to the UH3 stage pending NIH administrative review, availability of funds, and programmatic balance.

2. The UH3 Measure Evaluation Phase (Stage 2) will support milestone-driven evaluation of measures optimized in the UG3 phase by examining the effects of FDA-approved pharmacologic drugs selected based on demonstrated action on the circuit/brain process, in both humans and the preclinical species in parallel. By employing a dose ranging PK/PD study design, where dosing is chosen for comparable potency across species, data collected in this phase will assess the degree of cross species coherence of performance of the measures as assays.

Expected outcomes include the identification of promising measures for further development as tools for assessing the biological effects of novel therapeutic candidates across preclinical and healthy human studies. Data will also identify measures that differ in performance between preclinical species and humans, thus establishing a firm basis for limiting speculations about the potential clinical significance of preclinical assay data. Although only preclinical and healthy human studies would be supported by this FOA, the emphasis is on developing (PK/PD) measures that will ultimately be useful for the evaluation of novel therapeutic mechanisms in phase 1 or 2 studies in patients with mental disorders.

The overall goal is to transform experimental protocols in both animals and humans into assays for use in the therapeutic development pipeline. Ideally, the most promising in vivo assays have the potential to be standardized and adapted for broader use across laboratories. This effort will build towards a critical understanding of the predictive value of assays as applied across preclinical species and humans. The effort will also begin to build critical measures of analytical performance (sensitivity, specificity, precision, stability, and reproducibility) that may be used to set standards for replication and verification of assay findings and to advance promising biomarkers and targets to clinical applications in subsequent projects.

Experimental Rigor: Translating discoveries into evidence-based treatments is predicated on the existence of strong, well-powered, adequately controlled, and replicated preclinical and clinical data. In addition, the value of such research is greatly enhanced when detailed information is made available about study design, execution, analysis, and interpretation. Examples of critical elements are outlined in section IV.2 and detailed in NOT-OD-15-103 as well as NIMH guidelines. As per NOT-OD-15-102, it is expected that animal and human studies will include both males and females.

Milestones

Because novel translational assay development and evaluation in the UG3 phase are likely to be high risk, it is anticipated that there will be attrition of some projects after the assay optimization phase (UG3). Objective milestones of success and go/no-go rules for assay progression will be required and both should have quantitative criteria associated with them (see Section IV.2 for details).

The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring (NOT-MH-19-027). The application’s PHS Human Subjects and Clinical Trials Information, including the Data and Safety Monitoring Plan, should reflect the policies and guidance in this notice. Plans for the protection of research participants and data and safety monitoring will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations.

Applications Not Responsive to this FOA

The following will be considered not responsive and will not be reviewed:

  • Development or inclusion of animal models "of" mental disorders. Projects should adhere to recommendations in NOT-MH-19-053, NIMH’s Considerations Regarding the Use of Animal Neurobehavioral Approaches in Basic and Pre-clinical Studies, as well as the Recommendations of the NAMHC Workgroup on Genomics.
  • Behavioral assays without the inclusion of measures of associated brain processes and/or neural circuits.
  • Broad batteries of behavioral tests or clinical battery testing.
  • Invasive manipulations that cannot feasibly be performed in healthy humans.
  • Cell culture, post-mortem, or in vitro assay measures in either species.
  • Mechanistic studies of brain systems testing hypotheses about their role underlying functional domains, pathophysiology of disease, or treatment response.
  • Studies aimed at clinical testing of novel therapeutics or therapeutics discovery.

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

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

Application Types Allowed
New
Resubmission

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Clinical Trial?

Optional: Accepting applications that either propose or do not propose clinical trial(s).

Funds Available and Anticipated Number of Awards

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

Award Budget
Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period

The UG3 period may be 1 to 3 years, the UH3 period may not exceed 3 years. The total duration of the UG3 and UH3 phases may not exceed 5 years. 

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

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)
  • Eligible Agencies of the Federal Government

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)
Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 

Required Registrations

Applicant organizations

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. SAM registrations prior to fall 2021 were updated to include a UEI. For applications due on or after January 25, 2022, the UEI must be provided on the application forms (e.g., FORMS-G); the same UEI must be used for all registrations, as well as on the grant application.
  • eRA Commons - Once the unique organization identifier (UEI after April 2022) is established, organizations can register with eRA Commons in tandem with completing their full SAM and 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.

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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

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 FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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 funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

The letter of intent should be sent to:

Email: nimhreferral@mail.nih.gov

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

For this specific FOA, the Research Strategy is limited to 15 pages.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

The biosketches should clearly describe the role of all key personnel along with a description of the specific expertise each contributes towards the assay development and testing across species.

R&R Budget

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

Budget Justification: For each budget year, indicate if the requested budget is for the UG3 phase or the UH3 phase. The UG3 and UH3 cannot be funded in the same fiscal year.

The UG3/UH3 budget may include travel costs for one or two trips per year to attend meetings of the cooperative group.

It is expected that the PD/PI or each PD/PI on a multiple PD/PI application will dedicate at least 15% level of effort (1.8 calendar months) to managing the project.

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: Provide the overall goals for the entire application. The Specific Aims section should include distinct Aims for the UG3 and UH3 phases. All applications are required to include both UG3 and UH3 phases.

Research Strategy: Organize the Research Strategy in the subsections identified below, addressing all specific points below.

Applicants should describe both the UG3 phase and the UH3 phase within these subsections as described, including milestones.

Significance:

  • Discuss how the proposed measures of neurophysiological processes address a translational gap.
  • Provide justification as to why the proposed measures are clinically relevant.
  • Describe how the study findings will advance the field regardless of outcome.

Innovation:

  • Explain how the project offers a novel approach to evaluating potential new treatments for mental disorders.
  • If similar measures are common practice in either a preclinical treatment development pathway, clinical neuroscience research, or clinical trials, explain how the proposed approach provides important new information or a benefit over existing measures.

Approach: This section should cover the application as a whole as well as the UG3 and UH3 phases with the appropriate headers within the text.

Overall Approach:

  • Justify the choice of measures, including a brief description of evidence that the measures have potential to either directly or indirectly assess activity or function within the same targeted circuits or physiological processes in both the preclinical species and humans.
  • Include discussion of evidence indicating how the planned measures and pharmacologic drugs are relevant to key neural circuits/processes that are disrupted in mental disorders.
  • Provide evidence of feasibility to perform the measurements and manipulations in both preclinical species and humans.
  • Explain the rationale behind the choice of preclinical species.
  • If assays will require optimization, explain what aspects require optimization, why, and how potential roadblocks as well as strategies for addressing the barriers that may arise in the course of optimization in one or both species.
  • Provide the rationale for the selection of manipulations that will be used to perturb the measures and thus evaluate the performance, reliability, and sensitivity of the measures in both species. Include the rationale for the dosing ranges planned for the UH3 phase in both species along with evidence of similar potency, if known (e.g., selection of drug doses with similar receptor occupancy across species, for example).
  • Include a detailed Results and Interpretation section for both the UG3 and UH3 phases that outlines how results will be quantitatively evaluated.
  • For each assay proposed, provide quantitative criteria and operational definitions of results that would indicate coherence between species. Explain how results will be communicated with the research community regardless of outcome.

Preparatory Testing and Prioritization Stage (UG3): All supported projects will begin with a UG3-funded preparatory phase to identify measures and manipulations to be evaluated in the testing phase (UH3).

  • Describe the research team's approach toward selecting, planning and prioritizing assays for optimization and evaluation in both humans and a preclinical species.
  • Provide the goals and rationale for all requisite preliminary studies planned for this phase.
  • Provide sufficient detail regarding how preliminary data presented in the application were collected and how planned studies are required to extend these data, to prioritize measures, optimize parameters or level of perturbations, and evaluate the feasibility of the assays.
  • Clearly describe studies to be performed in this phase and how results will contribute towards the selection of assays for cross-species evaluation in the UH3 phase. It is recommended that, to the extent feasible, multiple measures be included for optimization in the UG3 phase to maximize the potential for advancement of some assays to the UH3 evaluation phase.
  • Describe the explicit go and no-go criteria for each measure that will be used to determine if it will be advanced to full evaluation in both species in the UH3 stage.  If there is more than one type of measurement included in an assay, such as behavior and physiology, outline a strategy for determining the degree to which the measures must co-vary for the task to progress. Indicate how assay stability and precision will be assessed. It is not sufficient to indicate that the best match across tasks would go forward to full evaluation in the UH3 phase.
  • If applicable, provide details of UG3 phase studies aimed at optimizing the pharmacologic challenge for cross species comparisons in the UH3. The pharmacologic testing and measures should be either the same in both species or, if there are necessary procedural differences across species, evidence should be provided to justify direct comparisons based on comparable physiological effects.
  • Describe explicit go and no-go criteria for inclusion of manipulations in the UH3 phase where optimization is required in the UG3 phase.

Describe plans for annual in person (travel permitting) Steering Committee meetings among key personnel, NIH project scientists. The initial meeting should prioritize two-three measure/manipulation sets for cross species evaluation and to identify and plan preliminary studies within the timeframe of the UG3. The second meeting should review new data, summarize the UG3 activities, and prepare a refined UH3 plan for conducting the comparative studies. At least monthly teleconferences are expected during the intervening months of UG3 support. The Steering Committee should include outside expert advisors.

For the Measure Evaluation Phase (UH3): Based on the successful conduct of the UG3 and approval by the  NIMH, the awardee will be provided with additional years of support through the UH3. The award of the UH3 phase will depend on the strength of the evidence, rationale, and plan for evaluating primary and back up measures in animals and humans including: a) evidence that the measures are robust and reliable, b) preliminary evidence that the assays are sensitive to pharmacologic testing, and c) demonstration of equivalent intensity or dose effect in animals and humans of the drug levels proposed.

The UH3 period will support the performance of the experiments outlined in the original application and refined during the UG3 phase. Support for each year will be milestone driven with the expectation that at least one measure evaluation can be completed in both species in each year of support.

  • Describe explicit criteria for prioritizing assays, how they could be used in therapeutics development, and manipulations to be selected for progression from the UG3 phase to the UH3 phase in both species.   
  • Detail the experimental approach to evaluate the measures in both humans and the preclinical species in parallel. Outline where experimental details will rely on completion of UG3 studies.
  • Provide the rationale for the choice of drug(s), dose ranges to be tested to modify activity of the neural circuits or behavioral readouts in both species. Outline strategies and/or evidence to assure comparable degrees of effects of the pharmacologic challenge across species.
  • Describe plans for data analysis and interpretation including an operational, objective definition of coherence of measures between species as go and no-go criteria for further measure development or implementation in a therapeutic discovery pipeline. Include plans for analyzing PK/PD relationships for each species.
  • Outline plans for at least one in person (travel permitting) Steering Committee meeting and five or more interim meeting update teleconferences each year.
  • Describe procedures that will be included for evaluating assay reliability. Include plans for evaluating test-retest stability either in the funded project period or in future studies.

Milestones:

The clarity and completeness of the UG3/UH3 application with regard to specific goals and feasibility milestones are critical. Separate milestones should be proposed for the UG3 and UH3 phases. The milestones should be unambiguous, quantifiable, and scientifically justified to allow NIMH staff to assess progress. The UG3 phase milestones should include a timeline for completion of all preliminary studies needed to move the measure evaluation to the UH3 phase, as well as plans for publication or sharing of assay results regardless of outcome.  UH3 milestones should include plans for evaluating a minimum of one assay measure in both species per year. These milestones are distinct from the go/no-go criteria for measures, manipulations, and assays.

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.

  • All applications, regardless of the amount of direct costs requested for any one year, must include a Data Sharing Plan.

While it is understood that many protocols and the data generated will be at an early proof-of-concept stage, a central goal of this FOA is to contribute to building a more robust, experimentally based therapeutic development pipeline for mental disorders. Regardless of study outcomes or publication status, the experimental protocols and data generated through this FOA will be valuable to the research community by indicating assays with variable levels of potential predictive value in cross species comparisons.

Accordingly, applicants are expected to include a detailed Data and Experimental Protocol sharing plan that specifies how data will be shared and who will be responsible for managing sharing of all protocols and data, consistent with achieving the goals of this program. At a minimum, plans should include annual submission of raw and summary data on their website, through PubChem or some other venue. Human data from the UH3 phase are expected to be submitted to the appropriate NIMH Data Archive database and detailed in NOT-MH-19-033.

Data sharing plans must include items from the list below:

  • The expected schedule for data sharing
  • The format of the dataset
  • The documentation to be provided with the dataset
  • Whether any analytic tools also will be provided
  • Whether a data-sharing agreement will be required. If so, consider including:
    • A brief description of such an agreement
    • Criteria for deciding who can receive the data
    • Whether or not any conditions will be placed on their use
    • The mode of data sharing (e.g., the PI could handle data sharing by mailing a disk or posting data on their institutional or personal website, or the data sharing could be handled through a data archive or enclave).
      • Investigators choosing to handle their own data sharing may wish to enter into a data-sharing agreement.

Applicants must include the following key elements:

  • Description of how protocols and data will be shared as well as schedule/timeline for sharing data. At a minimum, plans are expected to include annual submission of raw and summary data.
  • Description of project management of protocol and data sharing.

To advance the goal of advancing research through widespread data sharing among researchers, investigators funded under this FOA are expected to share those data via the National Institute of Mental Health Data Archive (NDA; see NOT-MH-19-033). 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 FOA 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 web site 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 FOA 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. The NDA Data Sharing Plan is available for review 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 SF424 (R&R) Application Guide.
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 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.

PHS Assignment Request Form

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential fieldof 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 FOA for information on registration requirements.

The applicant organization must ensure that the unique entity identifier (UEI) provided on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, 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 has released expectations for collecting common data elements when an application involves human research participants. Details can be found at NOT-MH-20-067 and the NIMH webpage on Data Sharing for Applicants and Awardees.

Post Submission Materials

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.

For this particular announcement, note the following:

  • Evaluation of the approach should emphasize the biological rationale and, the degree to which the planned experiments contribute towards building innovative and useful preclinical assays and approaches in a therapeutic development pipeline through evaluation of the coherence of measures between the preclinical species and healthy humans.
  • Very few, if any, measures currently have sufficient evidence of shared physiology between preclinical species and humans. As such, it is expected that groups will have limited preliminary data.
  • Risk is expected; it is anticipated that this inherent risk will be managed through the use of the two phase mechanism. Projects should be evaluated relative to expectations for their proposed entry stage, when assessing risk.
  • The goal of this FOA is practical, to evaluate the coherence of physiological measures between humans and a preclinical species. The expected outcome from this FOA is the identification of 1) in vivo measures with some potential to serve as preclinical assays in therapeutic development based on coherence of measures between animals and humans, and 2) in vivo measures demonstrating a lack of coherence between animals and humans which should indicate the need for caution in interpreting preclinical results using similar assays. Thus, both positive and negative outcomes of well controlled, rigorous studies will be valuable.
  • The purpose of the pharmacologic dose ranging study in the UH3 phase is solely to evaluate the performance of the assays, not to address mechanistic hypotheses or test novel therapeutic targets.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the PD measure for future trials investigating novel pharmacologic agents is unwarranted.

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 FOA:

Do the proposed measures of neurophysiological processes adequately address a translational gap? Is adequate justification provided as to why the proposed measures are clinically relevant? Are study findings likely to advance the field regardless of outcome?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

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 FOA:

Does the investigative team have the breadth of expertise to perform all of the planned experiments in both humans and a preclinical species?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

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 FOA:

Does the project offer a novel approach to evaluating potential new treatments for mental disorders?

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

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 FOA:

Evaluation of the approach should emphasize the biological rationale, the ability of the planned experiments to contribute towards building innovative and useful preclinical assays and approaches in a therapeutic development pipeline. Areas of particular importance include:

  • How directly will proposed studies modify the circuits under investigation and record effects on circuit activity? How effectively will the experiments evaluate relationships between brain activity changes and physiological/behavioral assay measures?
  • How well justified is the choice of neurophysiological and/or behavioral measures in terms of 1) relevance to functional deficits in humans with mental illnesses and 2) feasibility to perform the measure in animals and in humans?
  • How strong is the rationale that supports conservation of brain processes and circuitry underlying the measures across humans and the preclinical species? How likely are the proposed experiments to provide the data necessary to determine whether the brain processes under study will allow direct comparison with humans?
  • How clear and well-justified are proposed go/no go decisions for further measure development and implementation in a therapeutic discovery pipeline?
  • For phase 2 studies, to what extent is the proposed design appropriate for the choice of drug, including dose range, route, PK sampling, and timing of the intervention in relation to testing? To what extent is the proposed dose selection based on brain target engagement measures such as receptor occupancy? To what extent are the proposed measurements based on known drug Cmax? How effectively will the proposed experiments test the involvement of hypothesized circuits in driving the physiological/behavioral assay measures?
  • Do the data sharing plans address how the applicants will ensure broad availability of data and protocols and provide a timeline for sharing, consistent with achieving the goals of this program?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

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?

Specific to this FOA:

Are the facilities sufficient to support the conduct of studies in the selected animal species and humans?

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

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.

Timelines and Milestones

Are the UG3 and UH3 milestones unambiguous, quantifiable, and scientifically justified to allow program staff to assess progress? Do the UG3 phase milestones include a timeline for completion of all preliminary studies needed to move the measure evaluation to the UH3 phase, as well as plans for publication or sharing of assay results regardless of outcome? Do the UH3 milestones include plans for evaluating a minimum of one assay measure in both species per year?

Study Timeline

Specific to applications involving clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Sharing Model Organisms; and (2)  Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by NIMH 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. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Mental Health Council. 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 FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

The NIMH has published policies and guidance for investigators regarding human research protection, data and safety monitoring, Independent Safety Monitors and Data and Safety Monitoring Boards, reportable events, and participant recruitment monitoring (NOT-MH-19-027). The application’s PHS Human Subjects and Clinical Trials Information should reflect the manner in which these policies will be implemented for each study record. These plans will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations. The NIMH will expect clinical trials to be conducted in accordance with these policies including, but not limited to: timely registration to ClinicalTrials.gov, submission of review determinations from the clinical trial’s data and safety monitoring entity (at least annually), timely submission of reportable events as prescribed, and establishment of recruitment milestones and progress reporting.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all 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.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

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:

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 must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identify, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and 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 FOA.

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.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipientsis anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipientsfor the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

The PD(s)/PI(s) will have primary authority and responsibility to define objectives and approaches and to plan and conduct the proposed research. She/he will assume responsibility and accountability to the applicant organization and to the NIMH for performance and proper conduct of all research supported in the cooperative agreement, including any NIH intramural component, if applicable, in accordance with the Terms and Conditions of Award. The PD(s)/PI(s) will be a member of the Steering Committee (SC). Intramural research scientists participating as collaborators have the same rights and responsibilities as other members of the SC (see below for Participation of NIH Intramural Scientists).

The Recipient Institution and/or PD(s)/PI(s) Institution will retain primary custody of and have primary rights to data as specified under the data and research resource sharing plans (described above). The Government, via the NIMH Project Scientist(s), will have access to data generated under this cooperative agreement and may periodically review the data consistent with current DHHS, PHS, and NIH policies. Timely publication of major findings by the PD/PI and grant investigators is encouraged. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NIMH support, including the assigned cooperative agreement award number. The PD(s)/PI(s) may invite external scientist(s) to serve as advisors on the SC post grant submission and review, as needed, and in consultation with the NIH Program Official and NIH Project Scientist(s).

Each annual progress report will describe progress toward achieving milestones submitted prior to award.

NIH extramural staff members have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The Project Scientist(s) interacts scientifically with the PD/PIs and other SC members and may provide appropriate assistance, including assisting in research planning, suggesting studies within the scope of the research team's objectives and research activities, presenting experimental findings to the SC from published sources or from relevant contract projects, participating in the design of experiments agreed to by the SC, participating in the analysis of results, suggesting external experts as consultants, and advising in management and technical performance. The Project Scientist(s) will be a member(s) of the Steering Committee. However, the total membership by NIH staff will not exceed one-third (1/3) of the membership of the Steering Committee. In all cases, the role of NIMH will be to assist and facilitate and not to direct activities. For matters requiring a vote, NIH staff will have one vote.

The NIH Project Scientist retains the option to consult with non-NIH experts in the field in evaluating progress in achieving milestones.

Additionally, an NIMH Program Official will be responsible for the normal scientific and programmatic stewardship of the award, including monitoring implementation of data and research resource sharing plans and will be named in the award notice.

Areas of Joint Responsibility include:

Should more than one UG3/UH3 be funded, the Groups will be federated through a Consortium Committee composed of the PD(s)/PI(s) and additional project leader from each Group, NIMH Project Scientist(s), and NIMH Program Official (as a non-voting member). The Consortium Committee members will meet annually in person or by teleconference to review progress and identify emerging opportunities for strategic partnerships. The Consortium Committee will select, by majority vote, a Chair from among the PD(s)/PI(s) for a one-year term. The Consortium Committee Chair, who will be responsible for organizing the meeting and preparing concise proceedings or minutes (two to four pages) which will be delivered to the members of the Group within 2 weeks of the meeting.

Steering Committee:

A governing Steering Committee composed of the PD(s)/PI(s) and all other key personnel, NIH Project Scientist(s), and NIH Program Official (as a non-voting member) will be established in each cooperative agreement to assist in monitoring and developing the scientific content and direction of the program.

The Steering Committee members will meet periodically to review and monitor progress, plan and design research activities, and establish priorities. Meetings will occur as monthly teleconferences with one in person meeting over the course of the UG3 phase and include at least one in-person (if travel is permitted) and 5 teleconferences each year over the course of the UH3 phase. The PI(s)/PD(s) will be responsible for scheduling the time and place (in person or by video or audio teleconference) and for preparing concise proceedings or minutes (two or three pages) which will be delivered to the members of the SC within 2 weeks of the meeting.

The principal end products of SC activities for NIMH are expected to include: 1) the identification and prioritization of measures and manipulations to be evaluated in humans and a preclinical species, 2) planning and evaluation of data required to support full evaluation of measures and manipulations, and 3) analyses and dissemination of study results.

It is expected that novel assays, experimental protocols, and data generated through both the UG3 and UH3 phases of this FOA will be made widely available to the research community as a valuable source of information.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will include: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. 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 FOAs 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.

Application Submission Contacts

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

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

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

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

Scientific/Research Contact(s)

Jamie Driscoll
National Institute of Mental Health (NIMH)
Telephone: 301-443-5288
Email: jdrisco1@mail.nih.gov

Sofiya Hupalo, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-3752
Email: hupalos2@mail.nih.gov

Peer Review Contact(s)

Nick Gaiano, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-3420
Email: nick.gaiano@nih.gov

Financial/Grants Management Contact(s)

Heather Weiss
National Institute of Mental Health (NIMH)
Telephone: 301-443-4415
Email: weissh@mail.nih.gov

Section VIII. Other Information

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

Authority and Regulations

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

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