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

Research Objectives

In the last several years, pharmaceutical companies have shifted their focus away from psychiatric indications, due to the high failure rate of drug approvals, with many of the failures occurring in late stage development after significant funding and testing had occurred. Likewise, a handful of new Food and Drug Administration (FDA) approvals in the field of neuromodulation have also been offset by failed large-scale invasive and non-invasive brain stimulation trials and hesitancy by industry to invest in mental health treatments.

Given the high risk of failure for these Central Nervous System (CNS) intervention studies, there is a need to re-design early stage trials to incorporate objective measures that adequately test both the delivered dosage and the proposed mechanism of action of the intervention in humans and determine if the intervention target has been engaged and modulated. In response to these emergent issues, NIMH has developed this NOFO to encourage Exploratory/Developmental Phase II R33 grant applications that support early stage, novel pharmacologic and neuromodulatory device-based intervention studies that incorporate an experimental medicine approach to validate molecular/circuit-based targets and evaluate their association with neurophysiological/behavioral/clinical benefit, as measured through improvements in a symptom or a domain of clinical function.

In this approach, clinical studies should be designed so that even negative results will provide meaningful information: 1) Do dose-dependent pharmacologic/neuromodulatory device actions enable target engagement independent of side effects and potential safety issues?; and 2) if target engagement occurs, is a measurable change in function demonstrated (i.e., is clinical benefit observed as detected through functional domains or clinical measures)? If these results are not obtained, the molecular/circuit-based mechanism has not been validated and should not be pursued further.

This NOFO uses an Exploratory/Developmental Grant Phase II approach (R33) to manage the risk associated with these early-stage clinical studies, but does require a demonstration of the intervention's effect on the proposed mechanism of target engagement or site of action (intervention's molecular/circuit-based target) as preliminary data in the grant application. Specifically, the NOFO requires supporting data that demonstrates milestone-driven testing, refinement, and/or validation of the intervention's engagement with an empirically supported, measurable molecular/circuit-based target. This application will support clinical studies to confirm target engagement and assess the relationship between target engagement and changes in functional outcomes or clinical symptoms/functional domains. Results from the project should provide enough evidence to determine whether further development of the intervention is warranted. This NOFO strongly encourages the testing of interventions not previously approved/marketed for psychiatric disorders, including: 1) interventions in active development; 2) pharmacologic and/or neuromodulatory device interventions repurposed from approved/marketed non-CNS indications; 3) pharmacologic agents and/or neuromodulatory devices discontinued from development in the indication where they were originally developed (see http://www.ncats.nih.gov/ntu/assets/current for a list of examples provided through the NCATS 2020 Industry-Provided Assets), and 4) expanding uses of neuromodulatory devices to other indications and populations.

Studies testing multimodal interventions (e.g., a novel pharmacologic agent/device designed to augment a psychosocial intervention such as exposure therapy) are acceptable under this NOFO, as long as the pharmacologic agent or neuromodulatory device being tested is novel. A clear and careful description of the combination of therapies, and how the multitude of combination parameters will be assessed is expected to be included. This includes evaluating the dosage of each modality of the combination intervention.  Studies are expected to demonstrate how effects of the combined therapies on target engagement are positively synergistic (vs. negative or net-neutral), using appropriate control conditions (e.g., comparing the effects of the combined therapies relative to each monotherapy). For all combination therapies, applicants should follow all other guidance/requirements of the NOFO to which they are applying, including defining measures of target engagement and describing how they will test various doses/combinations. The rationale for the selection of doses/combinations being assessed should be well supported by empirical evidence (i.e., preliminary data, clinical and/or preclinical studies, or existing evidence from the literature).

For multimodal interventions in pediatric populations, a novel intervention should be paired with a previously established intervention. For drugs and neuromodulatory devices, an established intervention is defined through FDA approval/clearance of the intervention, for a specific indication, age range and dosing.

All drugs/devices to be tested must have passed Phase I/EFS safety studies (in healthy or patient populations). In addition, responsive pediatric applications must be testing drugs that have already been approved for use in pediatric populations in non-psychiatric indications and are now being repositioned. Applications to conduct First in Human testing of new chemical entities or trials of novel first-in-children pharmacological agents or federal regulated devices designed for brain stimulation in pediatric populations (i.e., first exposure in children or first in pediatric indication) should instead apply to PAR-25-180, "First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01)". Applications that combine industry and academic effort into the design and management of the trial should also apply to PAR-25-180. Applications focused on clinical trials to establish the effectiveness of interventions where efficacy has already been demonstrated, and to test hypotheses regarding moderators, mediators, and mechanisms of action of these interventions should be directed to PAR-25-177 "Full-Scale Hybrid Effectiveness-Implementation Trials for Mental Health Interventions (R01 Clinical Trial Required)", or PAR-25-178 "Pilot Hybrid Effectiveness-Implementation Trials for Mental Health Interventions (R01 Clinical Trial Required)" or their subsequent reissuances. Applicants focused on device-based interventions including but not limited to behavioral, cognitive, interpersonal, and device-based (both invasive/surgically implanted as well as noninvasive/transcranial) approaches or a combination thereof are encouraged to apply to “Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders (R01)”, PAR-25-179.

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. 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.

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.

R33 Applications

Pilot studies supported by this NOFO should be powered for testing the link between the degree of the intervention's target engagement and functional outcomes in a patient population. It is not expected that projects would be powered for efficacy. In addition to the aims of testing safety and measuring target engagement, functional/symptoms will be measured and evaluated for how they associate with target engagement. Specific activities may also include: 1) evaluating how the molecular/circuit-based target relates to biomarkers/measures of brain function and domains of functions, as well as symptom/functional measures; 2) further testing of the intervention's feasibility, safety, and acceptability; 3) evaluating the feasibility of recruitment, randomization (if appropriate), retention, assessments, and reporting of adverse events; and 4) developing target engagement, brain functional and symptom/functional measures.

The results of the project should inform a decision about whether the intervention has the potential to substantially improve functional/symptom outcomes, including evidence of safety, tolerability; alter CNS physiology; and strength of the association between target engagement and change in symptoms/function.

Preliminary Data

For this NOFO, preliminary data need to include positive results that demonstrate the molecular/circuit-based target can be modulated by varying the dose or stimulation exposure in clinical studies. If sufficient preliminary data are not included, then this NOFO is not appropriate. Target modulation needs to be measured objectively and may assess intervention effects at the molecular, circuit, neural oscillatory, or system level (i.e., target engagement), and may also include a preliminary assessment of symptoms/domains if an acute study is not feasible due to a safety need for incremental dosing. The specific activities included in the preliminary study will depend on the type of intervention under study and its stage of development. Generally, these activities include: 1) objective measures of the molecular/circuit-based target and hypothesized mechanism of action (including ratio of target versus non-target activity); 2) evidence that the measure(s) of target engagement can be reliably and validly manipulated in a dose-dependent fashion); 3) demonstration of adequate target engagement with established dose selection or stimulus range; and 4) feasibility data to indicate that an adequate dose range for the intervention can be applied in the selected human population with good safety and tolerability.

Additional information for specific intervention types:

Neuromodulatory devices: This NOFO supports 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. Clear measures of target engagement for device studies should be included. Regions of interest must be rigorously defined, and statistical tests should be prespecified. Valid control/sham conditions should be included. Dose ranging studies (e.g., two stimulation paradigms compared) may be utilized, but if there is a strong case for why only one dose in comparison to control/sham is needed, this information should be clearly justified, and NIMH program staff and reviewers will determine appropriateness. Each condition tested should be sufficiently powered to inform the aims (go/no go decisions for future testing).

For neuromodulatory devices, 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 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 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.

A figure must be provided demonstrating this head modeling, including labeled axes on figure legends/scale bars and demarcating a threshold for activation, when relevant. If multiple targets are proposed, models should be provided to demonstrate stimulation capabilities at each site (if individualized targets are to be used, models covering multiple general targets may be used).

Additionally, individualized targeting should be used throughout the proposed application, not just for the example figure.

Each subject should be given individualized stimulation that matches unique aspects of their anatomy. Characterization of temporal elements of dosage should specify pulse shape, pulse direction, frequency, train duration, inter-train interval, etc. Characterization of the context of delivered dosage should specify brain state at time of administration, engagement in on-line or off-line cognitive/behavioral therapies, social context of device delivery, concomitant pharmacological intervention, etc. Evaluation of target engagement should use on-line (e.g., TMS/fMRI interleaving, TCS-EEG, TMS-PET, DBS-EEG) or off-line (PET, fMRI/rsfcMRI, MRS) approaches, depending on the nature of the spatial anatomical and/or neural oscillatory targets.

Focus should be placed on identifying the neuromodulatory paradigm (including the spatial, temporal, and contextual features) that most effectively results in a CNS modification, based on the proposed mechanism of action of the intervention to improve symptoms/domains. Subjects randomized should be the patient population (not healthy controls). Careful attention should be paid to time-course of action. In the event of rapidly acting interventions, where clinical change is expected acutely during administration (as in the case of intra-operative stimulation with DBS), it is necessary to use outcome measures that are sensitive to rapid clinical change (e.g., neurocognitive task performance, quantification of behavioral/speech/facial measures).

Additionally, sham/control--stimulus comparators must be included. In the event that a sham is used, demonstration not only of adequate masking procedures but also lack of biological action that would exert CNS effects must be provided. In the event of implanted neurostimulators, blinded discontinuation designs may be particularly useful.

Pharmacological interventions: The preliminary data must include a functional CNS pharmacodynamic (PD) readout that assessed target engagement, as well as plasma drug levels (which can be compared to existing pharmacokinetic (PK) data). The PD readout may be based on acute dosing and if appropriate, may be tested in healthy controls or in patients. Evaluation of target engagement in the preliminary study phase can be achieved using a range of measures, including neurophysiological, fMRI, and PET. It should be noted that there is a hierarchy of target engagement “proof”, with measures most proximate to the molecular event preferred (e.g. receptor occupancy), when available. Studies to adapt pharmacologic interventions to pediatric populations should be directed to PAR-25-180, "First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01)". Studies of multi-target drugs or dietary supplements will be considered only if the study design can provide non-ambiguous results about all the CNS targets of interest.

Preliminary data should include evaluation of safety and determination of an optimal dose/stimulus range to inform the R33 design by assessing dose-response with respect to PK, if appropriate, and a functional CNS PD readout of target engagement. Adequate functional target engagement, in relationship to PK and dosing must be a key criterion to determine if an R33 grant is warranted.

Applications must list the FDA regulatory oversight (e.g., IND/IDE) status or Non-significant risk (NSR) determination status.

Applications Not Responsive to this NOFO

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

• 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.
• 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).
• Non-human animal studies.
• Applications that lack preliminary data on the proposed measure of target engagement. 
• Applications that propose to test pharmacological or device-based interventions where there are studies already 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.
• Pharmacologic studies that lack inclusion of a functional CNS PD readout and evaluation of plasma drug levels.
• 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 application.

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

Applicants are strongly encouraged to consult with NIMH staff when developing plans for an application (see Agency Contacts, Section VII). This early contact will provide an opportunity to clarify NIMH policies and guidelines and discuss whether the proposed project is consistent with NIMH program priorities.

Applicants are encouraged to leverage existing resources and infrastructure, such as those provided by institutions with Clinical and Translational Science Awards (CTSAs) and/or other existing consortia/networks to promote efficient cross-disciplinary collaborations.

Applicants are encouraged to work with contract research organizations (CROs) or CTSAs or similar groups with expertise in managing regulatory quality clinical trials and with expertise in the age range and intervention type proposed.

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

Effective prevention and treatment of mental illness have the potential to reduce morbidity and mortality associated with intentional injury (i.e., suicide attempts and deaths, see: www.suicide-research-agenda.org). Lack of attention to the assessment of these outcomes has limited our understanding regarding the degree to which effective mental health interventions might offer prophylaxis. Where feasible and appropriate, NIMH strongly encourages intervention research that includes assessment of suicidal behavior using strategies that can facilitate data sharing (see NOT-MH-15-009 and https://www.phenxtoolkit.org/  for example constructs and corresponding assessment strategies) in order to advance understanding of how effective prevention and treatment of mental disorders might impact suicide relevant outcomes.

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 and Conducting Research with Participants at Elevated Risk for Suicide: Considerations for Researchers). 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. Applicants with data collection plans that involve multiple respondent groups (e.g., clients/patients, therapists/providers, supervisors, administrators) should address provisions for human subject protections and consenting procedures for all participant groups, accordingly. 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
• 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)

Non-domestic (non-U.S.) Entities (Foreign Organizations) 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 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.

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.

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.

As appropriate, Senior/Key Personnel descriptions demonstrate their expertise and track record in pharmacologic or device-based clinical trials, including expertise in industry-funded trials, recruitment and retention of trial subjects and methodological and statistical expertise. Also include recent collaborative clinical research efforts among members of the proposed team, if any. Provide the expertise within the research team in the measurement methods proposed (e.g., PET, fMRI, MRS, task based measures). 

Provide evidence that the PD(s)/PI(s) successfully carried out studies of similar structure and complexity as in the current application in the specified setting.

R&R 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:

Applications must include all the following items:

Specific Aims: State the specific objectives of the research effort of this project. Provide a  description of the experimental medicine-designed clinical study(ies) as well as how the proposed intervention could fill an important unmet need for those living with mental disorders.

Research Strategy: Include the following sections as part of the Research Strategy. Applications should not duplicate information provided in the attachment described in the PHS Human Subjects Clinical Trial Information form but may reference it to provide context as needed.

Factor 1. Importance of the Research

Significance:

• Describe the unmet therapeutic need that will be addressed by the intervention.
• Describe the rationale for selecting the intervention and CNS target and the empirical evidence about how the mechanism may be involved in producing an improvement in symptoms or function in patients with serious mental illness.

Innovation:

• Propose compelling rationale that the intervention selected is highly innovative (not already approved for a psychiatric indication, not ones used in standard practice such as SSRIs and ECT) and addresses an unmet therapeutic need, or otherwise has the potential for substantially improving outcomes for people with mental disorders. The novelty of the proposed molecular/CNS target should also be described.

Factor 2. Rigor and Feasibility

Approach:

• Provide a compelling scientific rationale for the protocol chosen. Present a clearly specified molecular/circuit-based target and describe how target engagement relates to biomarkers/measures of brain function and domain of function as well as symptoms/function. Present a clear conceptual framework that includes relevant empirical support for the intervention, its mechanism of action, and how the mechanism of action should lead to functional improvement.
• Provide a clear rationale for the choice of clinical domain or measure of function in a clinical population (it may be a population that is selected or enriched on the basis of a measure of function or biomarker.)
• Describe 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).

Rigor and Feasibility:

The preliminary data will inform the R33 proposed project including the approach to determine dose/stimulus response relationships, PK (for drugs), realistic head modeling (for devices) and target engagement to determine a narrower dose range that adequately engages the target. Describe both the preliminary data and the proposed project:

• Address whether a tolerable and safe dose range has been investigated that adequately tested the mechanism, with sufficient target exposure. Provide information on the specificity, safety, PK/PD, and brain penetration to support the study, to provide evidence that this is the right intervention to test the hypothesis. Note: Drugs must be sufficiently potent and selective for critical evaluation of target engagement and brain exposure. Studies of multi-target drugs (e.g., triple re-uptake inhibitors) will only be considered if the study design can provide non-ambiguous results about the CNS targets of interest, where each molecular target is measured for engagement, not just one. Devices must be appropriately designed to selectively reach the anatomical target. For deep penetrating devices, it must be demonstrated that deep targets are effectively and selectively reached, with a clinically acceptable target-to-non target ratio. Claims of deep targeting using noninvasive devices must be accompanied by rigorous pre-clinical and modeling data supporting the claims.
• A rigorous test of target engagement with clear, concrete milestones (Go/No-Go Criteria of success) must be accomplished before submitting an R33 grant application. As such, the preliminary data section must include the results of that initial study, including a clear explanation of the criteria and data used to support the decision to directly apply for an R33 instead of an R61/R33 award. In the results, include reliable, objective, and valid measures of target engagement, including dose and/or stimulus optimization to definitively and unambiguously support the intervention's ability to modulate the target. Additionally, safety and side effects need to be provided. Criteria of success in target engagement must be defined in terms of outcomes achieved (e.g., specific measures of target engagement) rather than as tasks completed, and quantitative threshold values should be specified for the measures used.
• In the proposed project, provide further validation for the dose or stimulus range needed for target engagement based on the results obtained in the preliminary data, and collect additional data using reliable outcome measures that quantify changes in the disorder, functional domain, or symptom(s) within the context of a trial.
• Describe how the properly controlled, Good Clinical Practice (GCP) standard, validation study will be conducted, not limited to these examples of methodologies: placebo controlled, PK, plasma levels of drugs, safety, and tolerability. Additionally, describe: a) how the stimulation/dose exposure range will be narrowed in the R33 proposed project based on the initial target engagement findings obtained in the preliminary data and how replication and extension will be conducted and b) how this project will evaluate associations between target engagement and subsequent symptom or functional change. Describe how sufficient data will be collected in the R33 proposed project in order to determine molecular/CNS target validation, based on relationships between target engagement, measures of brain function, and clinical or functional effects.
• Describe the feasibility of the approach in terms of having in place all the necessary elements to carry out recruitment, data acquisition and analysis in a timely manner. This information is critical because of the shorter timelines required for these studies.

Factor 3. Expertise and Resources

Investigators:

• Describe the combined expertise of the research team as a whole in terms of its ability to promote synergy and cover the critical elements of clinical trials expertise, track record in successfully conducting early clinical trials (e.g., subject recruitment and retention rates, reporting in clinicaltrials.gov, publications, experience in industry-funded trials), methodological and statistical expertise, and experience in all measures to be included in the study (e.g., handling repeated measures designs, missing data, effect size).
• Describe the governance for conducting the study as proposed and within specified timelines.

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

Applications must provide a clear description of:

1. Recruitment and Referral sources, including detailed descriptions of the census/rate of new cases and anticipated yield of eligible participants from each source;

2. Procedures that will be used to monitor enrollment and track/retain participants for follow-up assessments;

3. Strategies that will be used to ensure a diverse, representative sample;

4. Potential recruitment/enrollment challenges and strategies that can be implemented in the event of enrollment shortfalls (e.g., additional outreach procedures, alternate/back-up referral sources);

5. Evidence to support the feasibility of enrollment, including descriptions of prior experiences and yield from research efforts employing similar referral sources and/or strategies.

2.7 Study Timeline

Applications must provide a timeline for reaching important study benchmarks such as: (1) finalizing the study procedures and training participating clinical site staff; (2) finalizing the intervention manual and assessment protocols, including fidelity measures/procedures, where applicable; (3) enrollment benchmarks; (4) completing all subject assessments and data collection activities, including data quality checks; (5) analyzing and interpreting results; and (6) preparing de-identified data and relevant documentation to facilitate data sharing, as appropriate.

Timeline: Present a timeline for establishing necessary agreements with all partners (e.g., compound or device supplier for the studies). Provide information on how timely subject recruitment will occur. Provide evidence that all necessary regulatory clearances and permissions (e.g., IND for compound, permissions for rating scales) have been obtained or will be in place before funding.

Section 4 - Protocol Synopsis

4.5 Will the study use an FDA-regulated intervention?  (yes/no)

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

For studies of pharmacologic compounds and devices, at the time of the application's submission, there must be either an open Investigational New Drug application (IND) or Investigational Device Exemption (IDE) in place, or a documented FDA-submitted application/request for an IND or IDE. The grant application must describe the status of any such pending regulatory submissions. If an FDA IND or IDE application/request has not yet been submitted by the time of the grant application submission due date, the grant application must describe the plan and timeline for submitting the request for and obtaining the IND/IDE. If the drug/device is exempt from the IND/IDE, the grant application must include the justification and documentation for why the drug/device would be exempt (e.g., documentation of NSR determination from an IRB and/or the FDA).

Section 5 - Other Clinical Trial-Related Attachments

5.1 Other Clinical Trial-related Attachments:

Applications may include materials related to intervention delivery or training of providers in this section.  As appropriate, this may include screenshots of mobile interventions, technological specifications, training manuals or treatment algorithms. Videos are not allowable. Applicants must upload the attachments for Intervention Manual/Materials as a separate file, as applicable. Applicants should combine these into one file and must use the "Intervention Manual/Materials" to name this other attachments file. 

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.

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply- Application Guide.

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.

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

Applicants Requesting $500,000 or more for direct costs (less consortium F&A) in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) do not need to contact a Scientific/Research Contact to follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

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. 

Not Applicable

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]

For All Pediatric Studies

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

For Adult Studies (Pharmacologic Interventions)

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

For Adult Studies (Device-based Interventions)

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

For Adult Studies (Multimodal/Combination Interventions)

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

For All Geriatric Studies

Jovier Evans, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-6328
Email: [email protected]

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

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2508
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.