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, optimize, and evaluate measures of neurophysiological processes that are disrupted within or across mental disorders and which can be assessed in animals and humans. The goal is to support further development of these measures as assays for evaluating potential new drug and device therapies and their targets. Data will also reveal assay measures where the performance between preclinical species and humans is dissimilar, thus establishing a firm basis for limiting speculative extrapolations of preclinical findings. Ultimately, the goal of this FOA is to improve the efficiency of the therapeutic development process by addressing 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 physiological measures as tools for target validation and therapeutic development. Groups will be tasked with building a target-engagement-linked-to-functional-brain-effect suite of assays with potential to translate from animals to humans and thus serve as a basis for selecting preclinical treatment candidates for further development and clinical testing. Towards this goal, the FOA will support development, optimization and evaluation of brain based assays in both preclinical species and in healthy humans and the evaluation of assay performance in response to carefully selected chemical, physiological, or behavioral manipulations.

Background and Research Objectives

The NIMH recently took steps to optimize the scientific value of its investment in clinical trials, redirecting the focus of early stage clinical trial support to studies that incorporate experimental medicine designs. Relevant to mental disorders, experimental medicine designs integrate biologically based brain measures into a trial to more directly define whether the intervention has sufficient activity at the appropriate molecular target or brain region to provide scientific support for a larger, more expensive later stage trial. Complementary to this effort, the Research Domains Criteria (RDoC) was developed as a framework to develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures that may span multiple disorders. By evaluating behavioral processes within the context of specific brain circuits and processes, RDoC has the potential to identify measures that can be incorporated in experimental medicine trial designs that evaluate links between targets, circuits and key functional domains in relation to clinical improvements.

The NIMH emphasis on experimental medicine in early phase trials requires an evaluation of the expected effects of any intervention on brain processes that are hypothesized to be key targets for impacting clinical function. Unfortunately, the types of brain based measures appropriate for the early trials are rarely included in the preclinical therapeutic development testing funnel. This lack of continuity of functional measures of target engagement across species contributes uncertainty in treatment development. 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), are poor predictors of the potential clinical efficacy of compounds that engage novel molecular targets.

The purpose of this FOA is to build a target-engagement-linked-to-functional-brain-effect suite of assays which translate from animals to humans as a basis for selecting preclinical treatment candidates for further development and clinical testing. Towards this goal, the FOA will support development, optimization and evaluation of in vivo CNS assays that measure particular brain functions that are evolutionarily conserved between certain animals and humans. Feasibility testing will compare the assays in preclinical species and healthy humans. The FOA will additionally support assessment of the performance (sensitivity) of brain based assays in both preclinical species and in healthy humans in response to carefully selected chemical, physiological, or behavioral manipulations. Assays should include quantitative, robust and reliable measures that tap into specific neurophysiological systems that are potentially impacted in mental disorders. 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 people.

The UH2/UH3 is a two stage phased innovation award. This FOA will support the planning and preliminary work needed to conduct an evaluation of the performance of assays with reasonable likelihood of shared conservation of physiology and brain circuitry across healthy human controls and a preclinical species likely to be incorporated into a therapeutic development pipeline. Projects will be milestone driven with an interim program review determining those projects advancing from the preparatory (UH2) to the assay testing (UH3) phase.

The initiative will support partnerships among basic and translational neuroscientists who are committed to advancing the discovery of translational physiological measures that may be used across preclinical development and into healthy human trials as tools for target validation and 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 focus on quantitative measures to assess neurophysiology/circuit activity that underlie or reflect domains of function that are potential treatment targets (e.g., cognitive function, impulsivity, and motivation, etc.).

Proposed projects may include:

• Development and testing of assays or measures that tap into fundamental, neurophysiological functions that are disrupted within or across mental disorders such as aspects of vigilance or attentional mechanisms contributing to cognition that can be objectively measured in animals and humans using brain imaging or neurophysiological measures such as spectral EEG to assess sleep spindles or magnetoencephalography (MEG). Innovative measures are encouraged.
  
  
• Development and testing of highly tractable task-based behavioral 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 use of behavioral paradigms that are already commonly used cross species (e.g., fear conditioning) must include novel measures of underlying neuronal processes to be responsive to this FOA.

1. The UH2 Preparatory Testing and Prioritization Phase (Stage 1) for this FOA supports milestone-driven planning and prioritization of assay optimization and evaluation of the measures that can be implemented in both animals and humans. For examples, some assay measures that are already developed in animals will need to be adapted for humans while other assays may need to be back translated from humans to the preclinical species. This stage also supports the collection of preliminary data needed to address feasibility and to optimize parameters for the cross species evaluation.

UH2 projects that have met 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 that tap into mental health relevant brain processes (e.g., neural plasticity, cognitive or affect regulatory processes, impulsivity) and neural circuit activity. Studies will also evaluate 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.), data collected in this phase will assess the degree of cross species coherence of performance of the measures. Examples of the types of manipulations appropriate for this phase include, but are not limited to:

• An 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 sleep spindles on plasticity

Expected outcomes include the identification of promising measures for further development as tools for assessing the biology of the therapeutic target or approach 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 methods in both animals and humans into assays for use in the therapeutic development pipeline. Ideally, the most promising 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 provide 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.

Projects Not Responsive to this Announcement Include:

• Development or inclusion of preclinical models "of" mental disorder syndromes or diagnoses including gene or environmental models.
• Behavioral assays without inclusion of measures of relevant brain processes and/or neural circuits.
• Broad batteries of behavioral tests.
• Invasive manipulations that cannot feasibly be performed in healthy humans.

Please see the NIH/NIMH Therapeutics Discovery web page for links to other NIMH drug discovery FOAs: Drug Discovery for Nervous System Disorders PAR-13-048, National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction PAR-13-086 (U19) and PAR-13-087 (UM1). 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).

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.

Milestones

Because novel translational assay development and evaluation in the UH2 phase are likely to be high risk, it is anticipated that there may be attrition as projects move through the cross species assay optimization phase (UH2). Milestones will be required as quantifiable measures of success that can be used for go/no-go decision making and should have quantitative criteria associated with them (see Section IV.2 for details).

Technical Assistance Teleconference

Technical Assistance teleconferences will be held for potential applicants on Thursday February 12, 2015 from 12:00pm 1:00 pm EST and Thursday February 26, 2015, from 3:00 pm- 4:00 pm EST. The dial in number is 866-755-6381 and participant code is 8833299. NIH staff will be available to answer questions related to this FOA. Questions gathered via email and on these technical assistance calls as well as their responses can be found at: FAQ website. Applicants are strongly encouraged to refer to the FAQs available on the NIMH Therapeutics Development Website.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The letter of intent should be sent to:

Lois Winsky, Ph.D.
Telephone: 301-443-5288
Fax: 301-402-4740
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 detailed 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 UH2 phase or the UH3 phase. The UH2 and UH3 cannot be funded in the same fiscal year.

The UH2/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 UH2 and UH3 phases. All applications are required to include both UH2 and UH3 phases.

Research Strategy: Organize the Research Strategy in the subsections identified below.

Applicants should describe both the UH2 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 be meaningful regardless of outcome.
• Describe how the results will add value to a therapeutic development pipeline.
• Describe how the proposed work has the potential to be more widely adopted in a therapeutic discovery and development pipeline.

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 or in clinical neuroscience research or drug trials, explain why the proposed approach would be expected to provide important new information or a benefit over existing measures.
• Comment on the novelty of proposed assays.

Approach: This section should cover the application as a whole as well as the UH2 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 and with potential clinical benefit if corrected.
• 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.
• 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, assays, and endpoints for all studies.
• If assays will require optimization, explain the goal of the optimization and strategies for addressing barriers that may arise in the course of optimization in one or both species.
• Include a detailed Results and Interpretation section for both the UH2 and UH3 phases that outlines how results will be evaluated.
• Explain how lack of concurrence of the measures cross species may be informative to the research community.

Preparatory Testing and Prioritization Stage (UH2): All supported projects will begin with a UH2-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 to evaluate 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 should be identified for prioritization and testing in the UH3 phase to optimize potential for advancement to the UH3 assay comparison phase.
• Provide details regarding any preliminary studies to be conducted in this phase aimed at optimizing the perturbation for cross species comparisons. The manipulations and measures should be either the same in both species or, if there are necessary procedural differences across species, evidence should be cited to justify direct comparisons based on comparable physiological effects.
• Describe the go/no-go criteria for advancement of a measure or manipulation to full evaluation in both species in the UH3 stage.
• Suggest alternate approaches should the pilot work not support advancement to more formal measure testing in the UH3 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, to identify any preliminary studies needed to prioritize the evaluation of measures, and to create an action plan for collecting this data within the timeframe of the UH2. The second meeting will be to review new data, summarize the planning phase activities, and to prepare and submit a refined UH3 plan for conducting the comparative studies. At least monthly teleconferences are expected during the intervening months of UH2 support. The inclusion of outside expert advisors is encouraged.

For the Measure Evaluation Phase (UH3): Based on the successful conduct of the UH2, the PD/PI 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 lead and back up measures based on a) links to specific biology with evidence of conservation of neural circuitry across the species to be examined, b) the demonstrated ability to evaluate measures across both species, c) evidence that the measures are robust and reliable across species, and d) preliminary evidence that the measure can be modified in one or both species.

The UH3 period will support the performance of the experiments outlined in the original application and refined during the UH2 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.

• Detail how UH2 results will contribute toward the selection and evaluation of assay measures 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 UH2 studies.
• Provide rationale for the choice and levels or doses of perturbation (manipulation) used to modify activity of the neural circuit and test the measures including all strategies used to assure comparable degree of effects of the manipulation across species.
• 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.
• Include sufficient details to allow reviewers to evaluate the rigor of the experimental design. Describe the study design in detail, 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. Describe rationale for levels of the purturbation to be evaluated such as dose, route, and timing of intervetion in relation to testing. Describe plans for data analysis and interpretation including what would constitute a go/no go decision for further measure development or implementation in a therapeutic discovery pipeline.

Milestones:

The clarity and completeness of the UH2/UH3 application with regard to specific goals and feasibility milestones are critical. Separate milestones should be proposed for the UH2 and UH3 phases. The milestones should be unambiguous, quantifiable, and scientifically justified to allow program staff to assess progress. The UH2 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. Include in UH3 milestones, plans for evaluating a minimum of one assay measure in both species per year.

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 modifications:

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 Data and Experimental Protocol sharing plan, 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.

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

All applications 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.

Applicant 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.
• Detailed plans on how data will be made broadly available
• 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 conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

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 and responsiveness by NIMH, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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, the ability of the planned experiments to contribute towards building innovative and useful preclinical assays and approaches in a therapeutic development pipeline including unbiased evaluation the potential coherence of measures between preclinical and healthy human controls.
• Very few, if any, measures currently have sufficient evidence of parallel physiology between preclinical species and humans. As such, preliminary data is expected to be limited.
• 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.

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

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

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

What is the likelihood that completion of the research objectives will lead to a novel assay that allows for more biologically linked prediction of effects from preclinical species to humans?

Is there potential utility of the measure in drug discovery efforts?

Will lack of concurrence of the measures be informative to the research community?

Does the assay measure assess a brain process of relevance to mental disorders (i.e., is there a reasonable chance that the assay measure could show a difference in patients with mental disorders)?

Is a strong rationale or is evidence provided to support the choice of manipulation for evaluating the performance of the assay measure?

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

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 the potential for developing a novel approach to evaluating potential new treatments for mental disorders?

If successful, would the proposed approach be expected to provide important new information or a benefit over existing preclinical/clinical measures?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? 

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed? Is the choice of measures well justified, does the PD/PI present a solid rationale to support possible conservation of brain processes and circuitry underlying the measures across humans and the preclinical species?

Is the measure of potential clinical relevance?

Do the proposed measures have potential to either directly or indirectly assess activity or function within targeted circuits in both the preclinical species and humans?

Is there a strong rationale for the choice of manipulations that will be used to perturb the measures, including any evidence for direct and selective circuit-mediated effects?

Is the manipulation safe and feasible in both species?

Is there a strong rationale behind the choice of preclinical species, assays, and endpoints for all studies?

Are the human subjects' enrollment and exclusion criteria appropriate and well matched to the preclinical design?

Are appropriate, evaluative go/no go decision-making points and quantitative milestones provided and clearly defined? Are the milestones feasible and quantifiable? Are definitive go/no-go milestone studies appropriately powered and are statistical analyses clearly described?

Are the criteria outlined for advancement of a measure to full evaluation in both species sufficiently rigorous to allow rejection of misaligned measures? In other words, will both positive and negative results be informative?

Is the research sufficiently powered to evaluate effects of manipulations in both species, and are other aspects of data rigor adequately addressed?

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 both species?

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.

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 five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Not Applicable

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 Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

Is the applicant’s data and protocol sharing plan adequate? Are plans outlined for disseminating results regardless of outcome?

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.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. 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. 

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

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 SC members 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/PI 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).

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 SC 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, 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 the data and research resource sharing plans and will be named in the award notice.

Areas of Joint Responsibility include:

Steering Committee:

A governing Steering Committee composed of the PD(s)/PI(s) and 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 UH2 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.

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.

Intellectual Property and Patent Rights for New Chemical Entities

It is possible that novel assay measures will generate intellectual property in the form of novel tools, approaches and instrumentation for facilitating therapeutic development as a result of the support of this FOA.

Successful applicants are required to supply the following confidential materials to the NIMH Program Officials assigned in the Notice of Grant Award.

1. Each applicant team must provide a detailed description of the approach to be used for handling intellectual property and for licensing where appropriate, in particular where the invention may involve investigators from more than one institution. Procedures must be described for resolution of legal problems should they arise. Your attention is drawn to the NIH Extramural Technology Transfer Policies and Documents [http://grants.nih.gov/grants/intell-property.htm].

2. A formal statement of Intellectual Property among all research team members (key personnel) and their institutions as well as a detailed description of procedures to be followed for resolution of legal problems which may develop, must be signed and dated by the organizational official authorized to enter into intellectual property arrangements for all key personnel and member institutions. The signed agreement must be submitted prior to award to the appropriate NIMH staff listed in the Notice of Grant Award.

3. Prior to the award, the PD/PI must provide a signed statement of acceptance of the participation of NIMH staff during performance of the award as outlined under "NIH Staff Responsibilities" in Section VI.2.A - Cooperative Agreement Terms and Conditions of Award.

4. Prior to the award, NIMH Program staff will contact the applicant to discuss the proposed milestones and any concerns noted by the review panel or NIMH Program staff.  A final set of milestones must be submitted by the PD/PI. These milestones will be specified in the Notice of Award

Note: Do NOT submit documents 1-3 above with the application. However, awards will not be made until these documents are received and approved by NIMH.

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.

Progress towards achievement of the final set of milestones will be evaluated by NIMH Program staff.  NIMH Program staff may consult as necessary with independent consultants with relevant expertise. If justified, future year milestones may be revised based on data and information obtained during the previous project period. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued. 

UH2/UH3 transition

An administrative review will be conducted by NIMH program staff to decide which projects will advance from the UH2 phase to the UH3 phase.

In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NIMH portfolio balance and program priorities, competitive landscape, and availability of funds.

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: [email protected]

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

David Armstrong, Ph.D.
National Institute of Mental Health
Telephone: 301-443-3534
Email: [email protected]

Terri Jarosik
National Institute of Mental Health
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 Parts 74 and 92.