Required Application Instructions

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

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Purpose

The overall goal of this initiative is to identify neurophysiological measures as potential assays for treatment development research. The FOA will support efforts to optimize and evaluate 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 will also reveal assay measures where the performance between preclinical animal species and humans is dissimilar, 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 coherence of measures and inconsistencies between the preclinical screening pipeline and clinical evaluation of new treatment candidates and thereby hasten the development of more effective treatments for mental disorders.

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 chemical, physiological, or behavioral 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 FOA, 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. Similarly, 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. In contrast to previous studies that looked only for statistical differences in efficacy, the Institute’s new experimental medicine approach seeks trials that will address the mechanisms of disorders, 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 component of a therapeutic development testing funnel. 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 and the evaluation of the 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 particular brain functions that are evolutionarily conserved between the selected animal species and humans. The FOA will additionally support assessment of the performance (sensitivity) of brain based assays in both the preclinical species and in healthy humans in response to carefully selected pharmacological, physiological, or behavioral manipulations. 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 reasonable likelihood of shared conservation of physiology and brain circuitry across healthy human controls and a 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 component allows for greater involvement of NIMH staff in the conduct of the 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 therapeutic 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, and motivation, etc.).

Proposed projects may include:

• Development and testing of in vivo neurophysiological 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 http://cntrics.ucdavis.edu/index.shtml. 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.

Projects Out of Scope for this Announcement Include:

• Development or inclusion of animal models "of" mental disorders. Only healthy wildtype animals should be included
• Behavioral assays without 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
• Hypothesis testing (e.g., mechanistic studies of brain systems underlying functional domains, pathophysiology of disease, or treatment response)
• Studies aimed at clinical testing of therapeutics or therapeutic discovery

Please see the NIH/NIMH Therapeutics Discovery web page for links to other NIMH drug discovery FOAs: Drug Discovery for Nervous System Disorders PAR-16-041 (R01) and PAR-16-042 (R21), National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction PAR-14-234 (U19) and PAR-14-184 (U01). Please also note the related FOAs titled Temporal Dynamics of Neurophysiological Patterns as Potential Targets for Treating Cognitive Deficits in Brain Disorders PAR-14-153 (R01) and PAR-14-158 (R21).

The UG3/UH3 is a two phased mechanism. Each phase is milestone driven and only those projects attaining the UG3 milestones have 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 variations of a manipulation as a way 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 levels (e.g., doses) 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 second 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 manipulations in both humans and the preclinical species in parallel. By employing the same manipulation at more than one level (dose, intensity, duration, etc.), where levels are 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. Examples of the types of manipulations appropriate for this phase include, but are not limited to:

• An FDA approved medication that targets a circuit critical to the measure
• A chemical challenge such as lactate or CO2 to engage hypervigilance
• Transcranial magnetic stimulation (TMS) to modify cortical circuits underlying specific learning processes
• Alterations in reward contingencies to modify striatal circuits
• A noise distractor manipulation to assess the impact of different brain rhythms on plasticity

The purpose of the manipulations is solely to evaluate the performance of the assays, not to address mechanistic hypotheses or test novel therapeutic targets.

Expected outcomes include the identification of promising measures for further development as tools for assessing 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 measures that will ultimately be useful for the evaluation of novel therapeutic mechanisms 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 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.

Rigor of Data: 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 the 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).

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The letter of intent should be sent to:
Email: [email protected]

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

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

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

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

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

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

Roles of all key personnel should be clearly described along with a description of the specific expertise each contributes towards the assay development and testing across species.

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.

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

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

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

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 types of measures are already in 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/manipulations 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 levels of the manipulation planned for the UH3 phase in both species along with evidence of similar potency (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 manipulation (perturbation) for cross species comparisons in the UH3. The manipulations 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 Steering Committee meetings among key personnel, NIH project scientists. A first meeting will be to 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 will be to 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 inclusion of outside expert advisors is encouraged.

For the Measure Evaluation Phase (UH3): Based on the successful conduct of the UG3 and approval by 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 the manipulation, and c) demonstration of equivalent intensity or dose effect in animals and humans of the manipulation levels proposed for the UH3 evaluation.

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 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 and levels, timing, and/or doses of perturbation (manipulation) used to modify activity of the neural circuits in both species. Outline strategies and/or evidence to assure comparable degrees of effects of the manipulations 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.
• Outline plans for at least one in person 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 program 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, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address 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 ad detailed in NOT-MH-15-012.

Key Elements that should be considered when developing such data sharing plan are detailed at: https://grants.nih.gov/grants/sharing_key_elements_data_sharing_plan.pdf.

Applicants are expected to 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.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a 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: All instructions in the SF424 (R&R) Application Guide must be followed.

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

Foreign (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.

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

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

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NIH program staff 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.

NIMH encourages 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.

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

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

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. Earlier-stage projects are aimed at addressing the risk for later-stage projects. 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 manipulation/perturbation in the UH3 phase is solely to evaluate the performance of the assays, not to address mechanistic hypotheses or test novel therapeutic targets.

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).

For this particular announcement, note the following: 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 intervention is unwarranted or lead to new avenues of scientific investigation.

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.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? 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?

Do the proposed measures of neurophysiological processes 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 proposing 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 the trial needed to advance scientific understanding?

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?

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 proposing 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?

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?

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

In addition, for applications proposing 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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the 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 children, justified in terms of the scientific goals and research strategy proposed?

Overall Approach:

• Is adequate justification provided for the choice of measures, including 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?
• Is it feasible to perform the measurements and manipulations in both the preclinical species and humans?
• Is the rationale for choice of preclinical species clear?
• If assays will require optimization, are the optimization goals clear as well as the approach and strategies for addressing barriers that may arise in the course of optimization in one or both species?
• Is a clear rationale provided 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? Is rationale also provided for selection of the levels of the manipulation planned for the UH3 phase in both species along with evidence of similar potency (e.g., selection of drug doses with similar receptor occupancy across species, for example)?
• Is a detailed Results and Interpretation section included for both the UG3 and UH3 phases that outlines how results will be quantitatively evaluated?
• For each assay proposed, have quantitative criteria and operational definitions of results that would indicate coherence between species been identified? Has a strategy been outlined for disseminating results 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).

• Is the research team's approach toward selecting, planning and prioritizing assays for optimization and evaluation in both humans and the preclinical species clear?
• Are the goals and rationale for all requisite preliminary studies planned for this phase clear?
• Are sufficient details provided 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?
• Is there a clear description of 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?
• Are explicit go and no-go criteria for progression of each measure for advanced to full evaluation in both species in the UH3 stage identified? If there is more than one type of measurement included in an assay, such as behavior and physiology, is a strategy outlined for determining the degree to which the measures must co-vary for the task to progress? Is an approach identified for assessing assay stability and precision?
• If applicable, are the details of UG3 phase studies aimed at optimizing the manipulations (perturbations) for cross species comparisons in the UH3 clearly outlined? Are the manipulations and measures the same in both species or, if there are necessary procedural differences across species, is evidence provided to justify direct comparisons based on comparable physiological effects?
• Are explicit go and no-go criteria identified for inclusion of manipulations in the UH3 phase where optimization is required in the UG3 phase?

For the Measure Evaluation Phase (UH3): Based on the successful conduct of the UG3 and approval by NIMH program, the grant recipient will be provided with additional years of support through the UH3.

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.

• Are explicit criteria provided for prioritizing assays and manipulations for progression from the UG3 phase to the UH3 phase in both species?
• Is a clear experimental approach identified for evaluating the measures in both humans and the preclinical species in parallel? Are the experimental details that will rely on completion of UG3 studies clearly identified?
• Is a solid rationale provided for the choice and levels, timing, and/or doses of perturbation (manipulation) used to modify activity of the neural circuits in both species? Are strategies and/or evidence provided to assure a comparable degree of effects of the manipulation across species?
• Are adequate plans provided for data analysis and interpretation including operational, objective definitions of coherence of measures between species as go and no-go criteria for further measure development or implementation in a therapeutic discovery pipeline?
• Are procedures included for evaluating assay reliability? Are plans for evaluating test-retest stability indicated, either in the funded project period or in future studies?
• Are sufficient experimental design details provided to evaluate the rigor of the study design including the strain, age, and sex of animals, inclusion and exclusion criteria for healthy humans, power analyses and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization for both the animal and human studies?

In addition, for applications proposing clinical trials: Does the application adequately address the following, if applicable:

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?

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?

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?

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

In addition, for applications proposing 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?

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 separate milestones proposed for the UG3 and UH3 phases? Are the 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?

Specific to applications proposing 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)?

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

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

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

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.

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.

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.

Not Applicable

Not Applicable

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.

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.

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).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS)

Is the applicant’s data and protocol sharing plan adequate, and appropriate and consistent with achieving the goals of the program? Are plans outlined for disseminating results regardless of outcome appropriate?

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.

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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:

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

Applications will be assigned 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.
• Adequacy of data and protocol sharing plans as appropriate.

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.

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

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

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

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

Additionally, ICs may specify any special reporting requirements for the proposed clinical trial to be included under IC-specific terms and conditions in the NoA. For example: If the proposed clinical trial has elevated risks, ICs may require closer programmatic monitoring and it may be necessary to require the awardee to provide more frequent information and data as a term of the award (e.g., to clarify issues, address and evaluate concerns, provide documentation). All additional communications and information related to programmatic monitoring must be documented and incorporated into the official project file. 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 of all trials whether required under the law or not. For more information, see http://grants.nig.gov/ClinicalTrials_fdaaa/.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee 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).

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. 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. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), 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 awardees is 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 awardees for 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 Awardee 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.

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 1 in-person 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.

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

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

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

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Lois Winsky, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-5288
Email: [email protected]

Nick Gaiano, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-3420
Email: [email protected]

Terri Jarosik
National Institute of Mental Health (NIMH)
Telephone: 301-443-3858
Email: [email protected]

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

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