Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

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

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

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

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

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

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

Although many promising novel therapeutic targets for treating psychiatric disorders have been discovered in recent years, the translation into effective treatments has been unacceptably slow. For those interventions advancing to clinical testing, the success rate of new drug and device approvals for psychiatric disorders has been poor, with candidates often failing in late stage clinical trials after significant investment. In too many cases, the reasons for trial failures remain unclear but might include, for example, inadequate target engagement, patient heterogeneity, unfavorable drug characteristics (toxicity, poor target engagement, sub-optimal pharmacokinetic (PK)/pharmacodynamics (PD) parameters), or inappropriate biological targets for the disorder. This situation has contributed to the decrease in industry’s investment in psychiatric drug development and enlarged the “valley of death” for therapeutic development overall.

The NIMH and NIH provide funding support and research resources to facilitate drug development. Drug discovery and the development of novel medications for psychiatric disorders are supported through several avenues (see NIH/NIMH Therapeutics Discovery Research). A report of the National Advisory Mental Health Council’s Workgroup ,(see https://www.nimh.nih.gov/about/advisory-boards-and-groups/namhc), evaluated NIMH’s portfolio, and funding opportunities/resources for drug discovery/development in light of the current trend of pharmaceutical companies and venture capital to decrease their investments in clinical trials for central nervous system (CNS) disorders. One of the recommendations of this workgroup was for NIMH to invest in early stage clinical trials of novel Agents that act on novel molecular pathways (receptors, enzymes, second messengers, etc.) that are not targeted with currently available psychiatric drugs, and that have a strong justification as a novel mechanism for the treatment of psychiatric disorders. In addition, a recommendation was made that such trials include biological measures to assess target engagement in the brain and evaluate the Agent’s mechanism of action in humans. The incorporation of these additional measures into early stage trials is intended to provide very early signs of potential failure or success of the Agent and help inform whether further later stage trials should be considered.

The NIMH is also interested in encouraging the field of neuromodulation and neurostimulation devices for mental health conditions. Therefore, this NOFO also supports early stage testing of novel neuromodulation and neurostimulation devices (invasive or non-invasive) through FIH and EFS trials. As in pharmacologic studies, NIMH expects that objective CNS measures of the device’s action on the brain be included in the trial. In general, a digital therapeutic proposed as a sole intervention (not being tested as a multimodal therapy with either a pharmacologic or neuromodulatory device) would not be appropriate for this NOFO.

Research Objectives

The intent of this NOFO is to test new mechanism of action interventions (defined as investigational drugs, drug candidates, rescued or repurposed drugs, or neuromodulatory devices) in early stage trials (i.e., FIH, EFS, Phase Ib, and Phase II/PoC studies) using experimental medicine approaches to address unmet medical need for the treatment of psychiatric disorders. For this NOFO, Phase Ib and Phase II/PoC trials are defined as follows: Phase Ib trials are defined as studies usually conducted in the target patient population to establish feasibility (e.g., target engagement, PK/PD, optimal dosing of the Agent) for a future Phase II/PoC. Phase II/PoC trials are defined as studies designed to explore new hypotheses and to assess whether the Agent demonstrates an early signal of efficacy in the targeted patient population. In addition to clinical benefit, Phase II/PoC trials also include assessments of safety, tolerability, and PK/PD response of the Agent. Strategies to inform the selection of patients for Phase II/PoC studies of the novel candidate Agent (e.g., approaches to segment or enrich subjects for inclusion in the trial) are strongly encouraged. Note: Since many CNS targets lack high affinity PET ligands for use in testing receptor occupancy of novel drugs, PET studies are not required. Rather, CNS functional measures such as fMRI, EEG should be proposed to infer target engagement.   

For this NOFO, FIH and EFS are defined as small clinical investigations of a device early in development, typically before the device design has been finalized, for a specific indication (e.g., innovative device with initial pre-clinical safety data or marketed device for a novel clinical application). It may be used to evaluate the device design concept with respect to initial clinical safety and device functionality in a small number of subjects (generally fewer than 10 initial subjects) when this information cannot practically be obtained through additional nonclinical assessments or appropriate nonclinical tests are unavailable (see Investigational Device Exemptions (IDEs) for Early Feasiblity medical Device Clinical Studies, Including Certain First in Human (FIH) Studies. Target engagement and initial efficacy should be evaluated along with device safety.

The overall objective of this NOFO is to facilitate rapid collection of data to "de-risk" novel mechanism of action investigational drugs or devices, rescued, or repurposed drugs for use in psychiatric disorders, in order to attract private funding for further clinical development and FDA approval of the intervention. In addition to the adult FIH, EFS, Phase Ib, and Phase II/PoC studies, support is also available for novel, first in children intervention testing in pediatric populations (i.e., first exposure in children or first in pediatric indication).

A key aspect of this NOFO is the formation of collaborative partnerships between the biomedical researchers and biotechnology or industry partners to facilitate psychiatric drug and device development. In cases where the Phase II/PoC studies are successful, it is anticipated that the biotechnology or pharmaceutical company partner will pursue further clinical development of the intervention whenever feasible.

The NOFO will support stand-alone FIH, EFS, Phase Ib or Phase II/PoC studies or a combination of these, with rigorous milestone-based go/no-go decisions to progress from one study to the next if multiple trials are proposed.

Pharmacologic Agents: For pharmacological Agents, the duration of the project must be appropriate for the proposed project with a target goal of one year for completion of a FIH, up to two years for a Phase Ib study and three years for a Phase II/PoC study (4-5 years for applications to complete both phases). Applicants should consider the current state of research activities when planning the application to ensure sufficient time is requested to complete the study. FIH studies should assess Agent: 1) safety and tolerability, 2) target engagement and 3) pharmacological effects on relevant circuits or systems. Data resulting from FIH studies and Phase Ib trials in the target patient population are expected to determine optimal clinical dosing and to establish feasibility for further testing in Phase II/PoC and efficacy trials. Agents must be sufficiently potent and selective for critical evaluation of target engagement and brain exposure. The Agent/indication (if successful) should have a major, not merely incremental, impact on unmet medical needs in psychiatric disorders.

Phase II/PoC studies must assess the clinical efficacy signal of novel Agents using pharmacologically-based dosing, with validation of target engagement and exposure in brain, and must include biological measures of impact of the Agent on clinically relevant physiological systems to assess the link between hypothesized drug mechanism/target and clinical effect. Phase II/PoC studies must be sufficiently powered to assess Agent impact (magnitude and duration of target modulation) on a physiological process that is associated with the clinical outcome measure (e.g., cognition, social function) and an outcome measure to assess clinical benefit must be included.

Neuromodulatory devices: This NOFO also supports FIH and EFS trials for novel neuromodulatory medical devices as defined by Section 201(h) of the Food, Drug, and Cosmetic Act, with the intended use of treating or preventing mental illness. FIH/EFS studies should evaluate both safety and early signs of clinical efficacy of device interventions, both of which can inform future device development.  For devices, the same experimental medicine strategy is expected to demonstrate that CNS stimulation produces a dose dependent CNS effect under regulatory safety considerations for devices. The experimental medicine approach requires that neuromodulatory devices demonstrate target engagement via neural activity changes. Neural activity can be assessed by means of EEG, fMRI, or a variety of other electrophysiological or neuroimaging modalities. The dose dependent CNS effect should be explored, and target engagement should be optimized throughout the study to inform future interventional study parameters. Information required for device studies is included in the “Research Strategy” section below.

The duration and budget of the device trial(s) must be appropriate for the proposed project, with a maximum of four years. For the purpose of this NOFO, both FIH and EFS device studies are comparable studies and generally include up to 10 subjects for studies in adults. Details regarding the regulatory status of the device must be included in the application. Information regarding the FDA regulatory approval process for obtaining an investigational device exemption (IDE) in FIH/EFS studies can be found at: https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279103. Documentation of nonsignificant risk (NSR) determination from the FDA must be submitted for device studies that do not require an IDE.

Applications Not Responsive to this NOFO include:

Studies that are not responsive to this NOFO will not be reviewed include the following:

• Non-human animal studies.
• The testing of established or well-studied Agents for the treatment of psychiatric disorders.
• Applications that propose to test pharmacological or neuromodulatory device-based interventions where there are studies already completed or underway to test them in that population and with the same target. Applicants should check ClinicalTrials.gov to determine if the project they are considering is innovative or not.
• Applications that do not list the status of FDA regulatory oversight (e.g., Investigational New Drug (IND)/Investigational Device Exemption (IDE) status or Nonsignificant risk (NSR) determination status).
• Pharmacologic studies that do not include a functional CNS PD readout and plasma drug levels.
• Pediatric pharmacologic studies that do not include a pediatric pharmacologist and a pediatric psychopharmacologist. 
• Neuromodulatory device studies that lack:
  1. Thorough description of all device settings and algorithms that would enable precise replication of the methods using units/metrics appropriate to the specific device being studied (e.g. stimulation parameters in the case of electromagnetic devices, or processing algorithms in the case of neurofeedback or closed-loop systems)
  2. Individualized modeling, and where appropriate, measurement, of the strength and distribution of the dose received by the individual subject, using methods appropriate to the specific device being studied in the case of devices that apply energy to the head or body (i.e. realistic head modeling of the electric field induced in the brain by electromagnetic devices)
  3. Specific contextual information regarding brain state when the dose is delivered. For multimodal/combined interventions, this includes when each intervention is delivered with respect to the other.
  4. Clear description of the sham/control condition that will be used.
  5. Description of neuronavigation procedures indicating how individual patient anatomy will guide stimulation.
  6. Applications whose scope of work does not include the objective measurement of molecular/circuit-based target engagement, the choice of which is supported by empirical evidence of its potential relationship in the functional domain(s) or symptoms, and of its potential to address an unmet therapeutic need.

To fully evaluate the study's scientific validity and the safety implications for participants, studies involving human participation must include information on any planned or reasonably anticipated co-enrollment for participants in this study, including any studies participants are actively participating in at enrollment or any reasonably anticipated co-enrollment in additional studies during participation in the present study. 

Other Considerations

Overall, the goal for all trials funded under this NOFO is to "de-risk" novel mechanism of action investigational drugs or devices in order to attract private funding for further clinical development as FDA-approved treatments. These studies will: 1) accelerate the testing of new therapeutics for psychiatric disorders, 2) facilitate the validation of biological targets for therapeutic development, and 3) provide data assessing the relationship between clinical measures and biological indicators (mechanistic or PD biomarkers) of effect.

It is expected that successful applications will likely include multi-disciplinary teams of scientists with appropriate expertise for experimental evaluation and the clinical development of novel treatments. Scientists from both academia and biotechnology or pharmaceutical/device industry are encouraged to participate on the project. As an example, while an academic institution may be submitting the application, the company would be providing the therapeutic, input on trial design, and therapeutic know-how into the project. It is anticipated that the interaction of academic and non-profit research institutions with NIH and pharmaceutical/device industry will facilitate timely clinical evaluation and development of novel therapeutics. Applicants should outline proposed plans for further development of promising clinical candidates that are tested in the FIH, EFS, Phase Ib, and/or Phase II/PoC studies through this program.

It is required that Contract Research Organizations (CROs) or Clinical and Translational Science Awards (CTSAs) or equivalent with expertise in managing regulatory quality clinical trials and with expertise in the age range and intervention type, participate in managing the trials.

Given the diversity of expertise needed to conduct pediatric drug trials, it is required that a pediatric pharmacologist and a pediatric psychopharmacologist would jointly participate. 

For information on NIMH’s interest in pediatric pharmacological clinical trials, as well as the requirements, goals, and priorities of pediatric drug trials please see: "Notice of NIMH's Interest to Highlight High-Priority Pediatric Pharmacologic Trial Research Areas" (NOT-MH-17-039).

Prior to award, it is expected that an IND or IDE be in place with the FDA for the proposed intervention (for studies not determined to be NSR). In addition, there should be documentation verifying the full participation of the pharmaceutical or biotechnology partner for rescue/repurpose studies and sufficient Agent/device supply to complete the study, and additional required documentation (e.g., confidential disclosure agreements (CDAs), collaborative research agreements (CRAs), licensing agreements). Timelines for submission of all documentation are critical for this project. It is expected that such documentation would be initiated early in the process of developing the application. Lack of appropriate documentation at the time of award could influence funding decisions.

For multisite trials, site number should take into consideration potential variability of biomarker measures across sites, and ways to mitigate variability. The larger the number of sites, the greater the risk of variability. Strong subject recruitment is expected in these trials due to shortened timelines allowed for conducting the trials. Therefore, the recruitment plan provided in the application package will be included in the Notice of award and monitored closely.

The testing of established or well-studied Agents for the treatment of psychiatric disorders is not the focus of this NOFO. Such applications would be considered of very low priority. Established device-based interventions for treatment of psychiatric disorders via novel mechanisms that are reasonably expected to provide new clinically meaningful therapeutic options or substantially improve the benefit-risk profile of a treatment are acceptable. Only FIH, EFS, Phase Ib, and Phase II/PoC studies of novel interventions on the regulatory path are appropriate for this announcement. Please refer to www.clinicaltrials.gov for a listing of Agents/mechanisms of action that are currently in development in order to determine if the trial(s) is: 1) relevant to the proposed work, and could help inform the design of the U01 application; or 2) may be duplicative of the proposed application and therefore limit the innovation in the proposed application. Relevant trials should be acknowledged in the application.

Applicants are strongly encouraged to contact the relevant Scientific/Research Contact listed in Section VII of this NOFO to determine: 1) if the proposed intervention/mechanism of action and clinical indication would be considered a priority for NIMH; and 2) if this, or other clinical trials NOFOs, may be more appropriate for the proposed work.

Information about the mission, Strategic Plan, and research interests of the NIMH can be found on the NIMH website. Applicants are also strongly encouraged to review the information on Support for Clinical Trials at NIMH and the NIMH webpage on clinical research.

The NIMH is committed to enhancing the reliability of NIMH-supported research through rigorous study design and reporting (NOT-MH-14-004).

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

• Eligible Agencies of the Federal Government - Including the NIH Intramural Program
• 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 Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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

It is required that CROs or CTSAs or similar groups with expertise in managing regulatory quality clinical trials and with expertise in the age range and intervention type, participate in managing the trials. For pediatric drug trials, the application must include the joint participation of a pediatric pharmacologist and pediatric psychiatrist, as multiple PD/PIs. 

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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]  

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply- Application Guide must be followed.

For all trials, it is required that Contract Research Organizations (CROs) or CTSAs, or equivalent with expertise in the age range, intervention type, and type of study (e.g. FIH) conduct the trials..

SF424(R&R) Other Project Information

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed.

R&R or Modular Budget

All instructions in the How to Apply- Application Guide must be followed.

R&R Subaward Budget

All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply- Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

Research Strategy: Applications must include the following items:

Design FIH pharmacological and EFS device trials to assess: 1) safety and tolerability and 2) early evidence of target engagement.

Pharmacologic Agents: For FIH, Phase Ib, and Phase II/PoC pharmacological studies, include a clear description of the approach for determining pharmacological dose/response relationships and target engagement of the drug candidate. Beyond these requirements, Phase II/PoC studies should present a compelling scientific rationale for the biological measures (mechanistic biomarkers) used to assess the link between hypothesized drug mechanism/target and clinical effect.

FIH trials should also assess Agent pharmacological effects on relevant circuits or systems. Data resulting from FIH studies and Phase Ib trials in the target patient population are expected to determine optimal clinical dosing and to establish feasibility for further testing in Phase II/PoC and efficacy trials. Agents must be sufficiently potent and selective for critical evaluation of target engagement and brain exposure. The Agent/indication (if successful) should have a major, not merely incremental, impact on unmet medical needs in psychiatric disorders, and justified in the application.

Neuromodulatory devices: For FIH/EFS device studies, the clinical impact and feasibility should be clearly defined. Describe the current state of knowledge of the etiology, clinical characteristics, and current and projected prevalence of the proposed disease indication where appropriate. Briefly discuss available alternatives, their limitations, and how the proposed project would provide benefits over existing therapies or diagnostics, regardless of therapeutic class (i.e., agents and devices). Identify one or more clinically meaningful device outcome measures based on input from both clinicians and patients. Discuss how the proposed project relates to therapy or diagnostic development efforts underway in academia and industry, including both agents and devices. Explain the rationale for the minimally acceptable and ideal results. Briefly comment on the feasibility of conducting clinical trials toward these goals (e.g., availability of clinical trial networks).

All aspects of dose should be thoroughly defined, modeled, and where appropriate, measured, including its spatial and temporal components, as well as the context of its administration. The exact means of modeling and/or measurement will depend on the form of energy delivered by the device, or the approach’s intended impact on brain function as in the case of MRI-neurofeedback interventions.  Note that 'dose' includes all aspects of the delivered dose and the received dose. Delivered dose refers to the specifications of the parameter settings on the neuromodulatory device (e.g. temporal parameters of pulse shape, pulse trains, duty cycle, etc.), the specifications of the means of application (e.g. coil, electrodes, transducer, neuroimaging paradigm specifications and processing algorithms in the case of MRI-neurofeedback, etc.), the contextual aspects of when and how the dose is administered (e.g. brain state at time of delivery, phase of endogenous oscillations, simultaneous or sequential engagement in a task or psychosocial intervention, etc.).  The received dose refers to the specifications of the dose received by each individual, which includes the strength and spatial distribution of the energy once it enters the individual’s brain (e.g., where in the brain the energy is deposited, and its amplitude at each location). Characterization of the spatial aspects of received dose for brain stimulation devices should use realistic head modeling to simulate the amplitude of the electric field induced or other form of energy applied across the brain and should evaluate the degree of target to non-target stimulation.

For multimodal/combined interventions, include clear description of when each intervention is delivered with respect to the other.

In the Overall Plan, include:

• A clear description of the device and method of neuromodulation.
• A compelling rationale that the mode of neuromodulation will have a direct effect on brain regions of interest (characterization of the spatial aspects of delivered dose using realistic head modeling).
• A plan for testing the target engagement/neural stimulation of a target brain region by means of neuroimaging/neurophysiology such as EEG, fMRI, MEG, or other devices.
• A plan for testing and describing dose/response characteristics of the delivered dose.
• A description of the temporal and spatial characteristics of the stimulation parameter space.
• A clearly stated device testing timeline that includes practical, achievable goals in support of the proposed clinical study.
• Anticipated risks in the device testing process, including potential needs for design changes, and mitigations based on initial test results.
• Clinical considerations including, but not limited to, description of the tools and process for device insertion and method for evaluating the functional integrity of the device. This plan will often involve collaboration between the investigators, clinical researchers, and may include the participation of private-sector companies.
• A discussion of why the target population is an appropriate group to address the hypotheses.
• A description of any planned or reasonably anticipated co-enrollment for participants in this study, if applicable. Information may include but is not limited to:
  • Assessment and justification for permitting or excluding co-enrollment.
  • Ethical implications and the risks, burdens, and benefits of co-enrollment to the participants and the scientific validity of the study.
  • Confirmation that anticipated co-enrollment is included in the protocol provided to the IRB, FDA (if applicable), and the DSMB (if applicable).
  • Actions taken to ensure participants are fully informed about the risks, burdens, and benefits that may result from co-enrollment in the studies.
  • Actions taken to reduce potential confusion about the differentiation between clinical care and research or individual research studies (for example, consider who conducts the informed consent).
  • Mitigative actions taken to address concerns or risks that may arise from co-enrollment? (e.g., adjustments to exclusion criteria).

Clearly articulate what the next step will be in device development assuming a successful outcome of the clinical study and justify the outcome metrics for the proposed clinical study in terms of quantifiable minimum-success criteria necessary to enable this next step.

All interventions: NIMH is specifically interested in novel molecular or circuit-based targets (for drugs) and circuit-based targets (for brain stimulation devices) and how they relate to functional domains or symptom(s) of mental disorders as opposed to broad diagnostic categories in which not all subjects may share the same underlying disease process. The goals of the Phase II/ PoC trials are to determine that the Agent modulates the target/mechanism and shows potential for efficacy in the proposed disease population, thereby building scientific data to "de-risk" the further clinical development of the Agent for a new therapeutic use that has not previously been explored.For all interventions, subject selection must be well justified and would ideally ensure the individuals have the abnormality in the CNS pathway being studied; objective, biological measures should be used when feasible for subject selection. Healthy subjects can be included, if appropriate. Phase II/PoC studies should incorporate FDA-accepted clinical outcome measures to assess potential efficacy in addition to the biological measures. NIMH Research Domain Criteria (RDoC) principles and constructs should, as appropriate, inform subject eligibility or stratification, identification of intervention targets, and/or selection of outcome measures. Inclusion of biomarkers in the design of the study is expected, when appropriate: e.g., the inclusion of PK/PD biomarkers to assess target engagement, brain exposure and functional pharmacological activity of the Agent or the use of molecular markers of disease, pharmacogenomics, or other biomarkers as patient selection strategies. 

Letters of Support

Include a letter of support from the private sector partner providing the investigational drug, drug candidate, or device for the proposed studies, if a partner is proposed.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

Other Plan(s): 

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions:

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

To advance the goal of advancing research through widespread data sharing among researchers, investigators funded by NIMH under this NOFO are expected to share those data via the National Institute of Mental Health Data Archive (NDA; see NOT-MH-23-100). Established by the NIH, NDA is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, tools, and supporting documentation. NDA links data across research projects through its Global Unique Identifier (GUID) and Data Dictionary technology. Investigators funded under this NOFO are expected to use these technologies to submit data to NDA.

To accomplish this objective, it will be important to formulate a) an enrollment strategy that will obtain the information necessary to generate a GUID for each participant, and b) a budget strategy that will cover the costs of data submission. The NDA website provides two tools to help investigators develop appropriate strategies: 1) the NDA Data Submission Cost Model which offers a customizable Excel worksheet that includes tasks and hours for the Program Director/Principal Investigator and Data Manager to budget for data sharing; and 2) plain language text to be considered in your informed consent available from the NDA's Data Contribution page. Investigators are expected to certify the quality of all data generated by grants funded under this NOFO prior to submission to NDA and review their data for accuracy after submission. Submission of descriptive/raw data is expected semi-annually (every January 15 and July 15); submission of all other data is expected at the time of publication, or prior to the end of the grant, whichever occurs first (see NDA Sharing Regimen for more information); Investigators are expected to share results, positive and negative, specific to the cohorts and outcome measures studied.For more guidance on submitting data to NDA, refer to the NDA Data Management and Sharing Plan on the NDA website. NDA staff will work with investigators to help them submit data types not yet defined in the NDA Data Dictionary. 

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

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

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply- Application Guide must be followed.

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

A plan for robust subject recruitment must be included that addresses the shorter trial duration. Failure to maintain the planned recruitment rate could result in trial termination.

The application must include a clear description of the procedures to avoid bias in the allocation of subjects to treatment and in assessment of outcomes; and subject follow-up procedures.

2.7 Study Timeline

The timeline should address reaching important study milestones such as: 1) obtaining IRB approval and regulatory clearance for the protocol, 2) establishing agreements with participating industry partners, 3) obtaining adequate supply of the investigational Agent or device, 4) finalizing the study procedures and training participating clinical site staff, and 5) enrolling 25%, 50%, 75% and 100% of the sample size.

The timeline should include a plan for decision-making regarding the identification and evaluation of promising drug candidates or devices for development. All applications must include clearly-specified, well-defined milestones, go/no go decision points, and timelines for assessing progress. In addition, if the proposed research includes plans for FIH/EFS with progression to Phase Ib or Phase II/PoC studies in patients, specific milestones and go/no-go criteria should be described for assessing the appropriateness of advancing to Phase 1b or Phase II/PoC studies in patients.

Section 3 - Protection and Monitoring Plan

Section 3.5 Overall Structure of Study Team

For device testing, include descriptions of the organization of the study and how the trial will be managed, the role of any internal and external committees (e.g., executive committee, endpoint adjudication committee), and the responsibilities and oversight of any central laboratories/reading centers or resource centers.

Section 4 - Protocol Synopsis

4.2 Outcome Measures

For FIH/EFS device studies, include one or more clinically meaningful device outcomes measures along with a strong rationale for the measures.

4.3 Statistical Design and Power

Statistical methods must be proposed that are appropriately matched to the study design. Sample size, power calculations, and plans for analyses, data management, and quality control must be included.

4.5 Will the study use an FDA-regulated intervention?

4.5.a. If yes, describe the availability of Investigational Product (IP) and IND/IDE status

The application must include the status of all regulatory clearances necessary to conduct the proposed trial (e.g., status of the IND/IDE). The application should include evidence of contact with appropriate U.S. regulatory bodies (e.g., FDA in the form of Pre-submission meetings and IDE submission).  Documentation of NSR determination from the FDA should be submitted for device studies that do not require an IDE. IRB approval is not required at the time of application submission, but is required prior to funding, so NIMH encourages investigators to begin this process as early as possible.

Delayed Onset Study

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

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

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

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

Information on the submission process and a definition of on-time submission are provided in the How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

Applications Involving the NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as co-investigators in accord with the Terms and Conditions provided in this Notice of Funding Opportunity (NOFO). Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

Use of Common Data Elements in NIH-funded Research

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

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

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply Application Guide. Paper applications will not be accepted.

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

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

Videos are not allowed as post-submission material.

Section V. Application Review Information

1. Criteria

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

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

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

As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.

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.

2. Review and Selection Process

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

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

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

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

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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

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

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

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

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

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

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and 
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

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 2 CFR Part 200, 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 recipients 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 recipients for the project, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

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

• Define objectives, approaches, and to plan and conduct the proposed research and assume responsibility and accountability to the applicant organization and to the NIMH for performance and proper conduct of all research supported in this initiative, in accordance with the Terms and Conditions of Award.
• Provide interim progress updates when requested by NIMH.
• Provide leadership in thoughts, ideas, and actions, working with the Steering Committee for the cooperative agreement.
• Coordinate and attend at least monthly U01 meetings. The PD/PIs will be responsible for preparing concise proceedings or minutes (one to two pages), which will be delivered to all members within one week of the meeting.
• Attend and participate in in-person and/or virtual meetings amongst the PIs awarded under this initiative with the frequency determined by the Steering Committee.
• Accept close interaction with, and participation of, a NIMH Project Scientist in the U01 Steering Committee (SC).
• Communicate and publish major findings in a timely manner. Publication or oral presentation of work done under this agreement will be accompanied by an appropriate acknowledgment of NIMH support, including the assigned cooperative agreement award number.
• Share data and resources generated under this project with the scientific community, as permitted by law, in a timely manner and as directed under the applicable NIMH and NIH policies sharing policies.
• PD(s)/PI(s) agree to participate in the cooperative research program, including serving on the Steering Committee as a voting member, participating in Steering Committee in person and virtual meetings, adhering to Steering Committee policies and decisions, and accepting the participation and assistance of NIMH staff in accordance with the guidelines described under Cooperative Agreement Terms and Conditions of Award: NIH Responsibilities.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

The role of the NIMH Project Scientist will be to facilitate and not to direct the activities. It is anticipated that the NIMH Project Scientist will offer advisory input. The NIMH Project Scientist will:

• Provide guidance and support in the design of research activities.
• Serve as a resource for protocol design and development.
• Advise in the development of the protocol.
• Advise in management and technical performance.
• Participate as a voting member in the Steering Committee (SC). Regardless of the number of Project Scientists, NIH will only have one vote.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

The NIMH Program Official will:

• Provide the normal scientific and programmatic stewardship of the award, including programmatic monitoring of the overall project.
• Prior to award, negotiate the final Resource Sharing Plan and Data Management and Sharing (DMS) Plan, and the milestones to ensure that the goals of the project are being met.
• Monitor Milestones and data sharing.
• Approve modifications to the research plan and/or study protocol(s), in consultation with the SC, based on emerging data and/or other issues that impact progress of the project.
• Reserve the right to obtain periodic external peer review and recommend reviewers for an assessment of progress and achievement of milestones and deliverables.
• Monitor performance and compliance with NIH procedures.
• May attend SC meetings as a non-voting observer.

Areas of Joint Responsibility

• Steering Committee: A governing Steering Committee composed of the PD/PI(s), key research scientists, collaborators or consultants, outside experts, and the NIH Project Scientist(s) will be established in the U01 to assist in monitoring and developing the scientific content and direction of the program. When included in the Steering Committee, outside experts are chosen by the PD/PI(s) in consultation with the NIH Project Scientist and Program Official. Each named member of the Steering Committee will have one vote.
• Coordination and facilitation of interactions among the recipients under this initiative.
• Facilitation of collaboration with other NIMH-supported research resources.
• Assist in avoiding unwarranted duplication of effort with other NIH efforts.
• Schedule and organize an in-person and virtual meetings for the purpose of dissemination of ideas and encouragement of scientific collaboration. The frequency of these meetings (annual, semi-annual, etc.) will be determined by the Steering Committee, who will be responsible for scheduling the time and place and for preparing concise proceedings or minutes (action items and one-two page summary) which will be delivered to the members of the Committee within 2 weeks of the meeting.

A governing Steering Committee composed of the PD(s)/PI(s), a CRO lead or CTSA, or equivalent lead (as applicable), key personnel and NIMH Project Scientist(s), will be established to assist in monitoring and developing the scientific content and direction of the program. The total membership by NIMH 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, participate in deliberations, and facilitate discussion and not to direct activities.

Steering Committee will serve as the governing board for recipients. All recipients under this initiative program are bound by the policies and procedures developed by the Steering Committee; adoption of such policies and procedures requires a majority vote. Recipients under this NOFO will be required to accept and implement policies approved by the Steering Committee.

Membership in the Steering Committee will include the PD(s)/PI(s) of each U01 award, or a designated representative in the case of Multiple PD/PI award. Each representative will have one vote.

The NIMH Project Scientist(s) will be a voting member of the Steering Committee. If there is more than one project scientist, NIMH will be allowed only one vote. 

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 have three members: 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 recipient. This special dispute resolution procedure does not alter the recipient'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 

Prior to award, AOR will confirm that an intellectual property agreement, in accordance with NIH GPS and the Bayh-Dole Act, has been signed by all parties and includes an appropriate dispute resolution. 

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

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

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

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

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

Questions about FIH and Phase I studies of novel therapeutic drug candidates should be directed to:

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

Questions about PoC studies for novel therapeutics drug candidates for psychiatric disorders in adult populations should be directed to:

Jonathan Sabbagh, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-594-2557
Email: [email protected]

Questions about FIH or EFS studies for devices for psychiatric disorders in adult populations should be directed to:

Jessica Tilghman, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-0439
Email: [email protected]

Questions about FIH or EFS multimodal/combination therapies for psychiatric disorders in adult populations should be directed to:

Lizzy Ankudowich, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-480-8187
Email: [email protected]

Questions about PoC studies for novel therapeutic drug candidates or devices for psychiatric disorders in children and adolescents (first exposure in children or first in pediatric indication), or in adults with early developmental onset disorders including Tourette Syndrome, Attention Deficit Disorder, and Autism Spectrum Disorder should be directed to:

Margaret Grabb, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-3563
Email: [email protected]

Nicholas 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]

Section VIII. Other Information

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

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