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Grant Analysis

Purpose & Target

The core objective of this grant is to support the early-stage testing of pharmacologic or neuromodulatory device-based interventions for mental disorders. This involves using an 'experimental medicine approach' to rigorously validate molecular or circuit-based targets and evaluate their association with neurophysiological, behavioral, or clinical benefits. The grant is designed for research institutions, non-profits, for-profit organizations (including small businesses), and government entities capable of conducting complex clinical trials. It is a SECTOR-SPECIFIC grant, targeting the healthcare, mental health, pharmaceutical, and neuromodulation sectors. Geographically, it is open to organizations located in the United States and non-U.S. entities (foreign organizations). Key filtering criteria for initial screening: - Project must be an NIH-defined 'clinical trial'. - Focus on 'early-stage' intervention testing. - Must include 'objective measurement of molecular/circuit-based target engagement'. - Requires 'strong preliminary data' demonstrating target modulation. - Grant is a recurring opportunity with multiple submission deadlines, part of the R33 Exploratory/Developmental Phase II program.

Financial Structure

The National Institute of Mental Health (NIMH) intends to commit a total of $27,000,000 for FY 2026 to fund this NOFO and its companion NOFOs. This is a program budget, not a specific grant amount for PAR-25-183 alone.
Application budgets are not limited but must accurately reflect the actual needs of the proposed project.
The specific minimum grant amount per application is None.
The specific maximum grant amount per application is None.
The grant currency is USD (implied from the U.S. government funding source).
There are no matching fund requirements or co-financing obligations explicitly stated; cost sharing is not required.
Eligible costs include budgeting for the costs of data submission to the National Institute of Mental Health Data Archive (NDA).
Pre-award costs are allowable as described in the NIH Grants Policy Statement.
Financial reporting requires annual submission of the Research Performance Progress Report (RPPR), a final RPPR, an invention statement, and expenditure data for closeout.

Eligibility Requirements

Organizational Type and Status

Eligible organizations include a broad range of entity types:
- Higher Education Institutions (Public/State Controlled, Private)
- Nonprofits (with or without 501(c)(3) IRS status)
- For-Profit Organizations (Small Businesses, Other For-Profits)
- Local Governments (State, County, City or Township, Special District, Indian/Native American Tribal - Federally Recognized and Other)
- 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, Faith-based or Community-based Organizations, Regional Organizations)
- Non-domestic (non-U.S.) Entities (Foreign Organizations) are explicitly eligible to apply.
All applicant organizations must complete and maintain active registrations in the System for Award Management (SAM), obtain a Unique Entity Identifier (UEI), register with eRA Commons (ensuring at least one Signing Official and one Program Director/Principal Investigator account), and register with Grants.gov.
Foreign organizations (non-U.S. entities) must obtain a NATO Commercial and Government Entity (NCAGE) Code for SAM registration.

Project Type and Focus

The proposed project must be an NIH-defined 'clinical trial' and must focus on 'early-stage testing' of interventions.
The scope of work must include the 'objective measurement of molecular/circuit-based target engagement', with the choice of target supported by empirical evidence of its relationship to functional domains/symptoms and potential to address unmet therapeutic needs.
Interventions must be pharmacologic (with novel mechanisms of action) or neuromodulatory device-based.

Preliminary Data

The application must include preliminary data that demonstrates 'positive results' of the molecular/circuit-based target's modulation by varying dose or stimulation exposure in clinical studies.
Preliminary data must include 'reliable, objective, and valid measures of target engagement', including evidence of dose and/or stimulus optimization.
Evidence must be provided that a tolerable and safe dose range has been investigated, adequately testing the mechanism.
For neuromodulatory devices, preliminary data must include 'realistic head modeling' demonstrating stimulation capabilities.
For pharmacological interventions, preliminary data must include evaluation of safety and determination of an optimal dose/stimulus range by assessing dose-response relationships with respect to pharmacokinetics (PK) and a functional CNS pharmacodynamic (PD) readout of target engagement.

Regulatory Status

Applications must clearly list the FDA regulatory oversight status (e.g., Investigational New Drug (IND)/Investigational Device Exemption (IDE) status) or Non-significant risk (NSR) determination status.
If an FDA IND or IDE application/request has not yet been submitted, the grant application must describe the plan and timeline for submitting and obtaining this regulatory status.
If the drug/device is exempt from IND/IDE, the grant application must include justification and documentation for this exemption (e.g., documentation of NSR determination from an Institutional Review Board (IRB) and/or the FDA).

Exclusion Criteria

Applications will be considered non-responsive and will not be reviewed if they:
- Lack the objective measurement of molecular/circuit-based target engagement.
- Do not list the FDA regulatory oversight status.
- Propose non-human animal studies.
- Lack preliminary data on the proposed measure of target engagement.
- Propose to test pharmacological or device-based interventions where studies are already underway with the same target and population (applicants should check ClinicalTrials.gov).
- Are pharmacologic studies lacking inclusion of a functional CNS PD readout and evaluation of plasma drug levels.
- Are neuromodulatory device studies lacking thorough description of device settings, individualized modeling, specific contextual information, clear sham/control conditions, or neuronavigation procedures.

Application Process

Application Deadlines

New, Renewal, Resubmission, and Revision applications are due by 5:00 PM local time of the applicant organization on the following dates:
- February 14, 2025
- June 17, 2025
- October 15, 2025
- February 13, 2026
- June 15, 2026
- October 15, 2026
- February 17, 2027
- June 15, 2027
- October 15, 2027 (latest deadline)
A Letter of Intent (LOI) is encouraged 30 days prior to the application due date, though it is not required nor binding and does not affect the review process.

Submission Process

Applications must be submitted electronically through either the NIH ASSIST system, Grants.gov Workspace, or an institutional system-to-system (S2S) solution.
Applicants must adhere to the instructions in the 'Research (R) Instructions' within the 'How to Apply - Application Guide', as well as any specific instructions outlined in this funding opportunity. Deviations may lead to delays or rejection.
Strict page limitations apply and must be followed.

Required Documentation

Standard Forms (SF424(R&R)): Includes Cover, Project/Performance Site Locations, Other Project Information, and Senior/Key Person Profile. Ensure key personnel demonstrate expertise and track record in clinical trials.
PHS 398 Cover Page Supplement.
PHS 398 Research Plan: This is a critical component and must include:
- Specific Aims: Clear objectives of the research, description of the experimental medicine-designed clinical study, and how the intervention addresses an unmet need.
- Research Strategy: Detailed sections covering Significance, Innovation, Approach, Rigor and Feasibility, and Expertise and Resources.
- Preliminary Data: A mandatory section detailing results of initial studies, especially positive outcomes related to target modulation, and 'Go/No-Go Criteria of success'.
- Resource Sharing Plan.
- Data Management and Sharing Plan: Required for all applications, outlining how scientific data will be managed and shared, including submission to the NIMH Data Archive (NDA).
PHS Human Subjects and Clinical Trials Information Form: Required when human subjects are involved, including a Study Record or Delayed Onset Study record. This section must detail:
- Recruitment and Retention Plan: Description of sources, monitoring procedures, strategies for a diverse sample, and plans for potential shortfalls.
- Study Timeline: Benchmarks for finalizing procedures, training, intervention manuals, data collection, analysis, and data sharing activities.
- FDA Regulatory Oversight Status: Documentation or a plan to obtain Investigational New Drug (IND)/Investigational Device Exemption (IDE) status or Nonsignificant risk (NSR) determination.
Intervention Manual/Materials: If applicable, these materials (e.g., screenshots of mobile interventions, training manuals) must be uploaded as a separate file.
PHS Assignment Request Form.

Project Implementation and Reporting

Projects have a maximum duration of 3 years.
A detailed timeline for establishing agreements, timely subject recruitment, and ensuring all necessary regulatory clearances and permissions are in place before funding is required.
Award recipients are required to submit the Research Performance Progress Report (RPPR) annually, with a final RPPR at closeout.
Data submission to the National Institute of Mental Health Data Archive (NDA) is required semi-annually (January 15 and July 15 for descriptive/raw data) and at the time of publication or grant end for all other data.
ClinicalTrials.gov registration and results reporting are expected for all trials.

Application Support

Applicants are strongly encouraged to consult with NIMH staff early in the application development process. Agency contacts for scientific/research inquiries (by study population and intervention type), peer review, financial/grants management, and application submission are provided.

Evaluation Criteria

Overall Impact

Reviewers will assess the likelihood of the project to exert a sustained, powerful influence on the research field involved, considering the scored review criteria below.

Scored Review Criteria

Factor 1. Importance of the Research (Significance and Innovation):
- Significance: Description of the unmet therapeutic need and strong rationale for selecting the intervention and CNS target, supported by empirical evidence of its mechanism's involvement in improving symptoms or function in patients with mental illness.
- Innovation: Proposal of a compelling rationale that the intervention is highly innovative (e.g., not already approved for psychiatric indication, not standard practice like SSRIs/ECT) and addresses an unmet therapeutic need, or has potential for substantially improving outcomes. Novelty of the proposed molecular/CNS target is also considered.
Factor 2. Rigor and Feasibility (Approach):
- A compelling scientific rationale for the chosen protocol, including a clearly specified molecular/circuit-based target and its relationship to biomarkers/brain function/symptoms.
- A clear conceptual framework with empirical support for the intervention and its mechanism of action leading to functional improvement.
- Justification for the choice of clinical domain or measure of function in the patient population.
- Assessment of planned co-enrollment for participants, addressing ethical implications, risks, burdens, benefits, and scientific validity.
- Thorough description of preliminary data and its role in informing the proposed project, especially for dose/stimulus response relationships and target engagement.
- Demonstration of a 'rigorous test of target engagement' with clear, concrete milestones (Go/No-Go Criteria of success) defined by quantitative threshold values.
- Description of how the properly controlled, Good Clinical Practice (GCP) standard, validation study will be conducted (e.g., placebo-controlled, PK, safety, tolerability).
- Evidence of sufficient data collection to determine molecular/CNS target validation based on relationships between target engagement, brain function measures, and clinical/functional effects.
- Feasibility of the approach in terms of recruitment, data acquisition, and analysis within timely manner given shorter study timelines.
Factor 3. Expertise and Resources (Investigator(s) and Environment):
- Combined expertise of the research team in clinical trials (pharmacologic/device-based), including experience with industry-funded trials, subject recruitment and retention, methodological and statistical expertise, and proficiency in all proposed measurement methods.
- Evidence of a strong track record in successfully conducting early clinical trials (e.g., reporting in ClinicalTrials.gov, publications).
- Description of the governance structure for conducting the study as proposed and within specified timelines.

Additional Review Criteria (Considered, not scored)

Protections for Human Subjects: Evaluation of justification for involvement, adequacy of protection against risks, potential benefits, importance of knowledge to be gained, and data and safety monitoring for clinical trials.
Vertebrate Animals and Biohazards (if applicable): Assessment of appropriate use and protection measures.
Resubmissions, Renewals, Revisions: Evaluation of previous progress or appropriateness of scope expansion.

Additional Review Considerations (Considered, not scored)

Authentication of Key Biological and/or Chemical Resources: Plans for identifying and ensuring validity.
Budget and Period of Support: Evaluation of justification and reasonableness in relation to the proposed research.

Compliance & Special Requirements

Regulatory and Ethical Compliance

Clinical Trial Requirement: This funding opportunity only accepts applications that propose NIH-defined clinical trial(s).
FDA Regulatory Oversight: Applications must demonstrate clear FDA regulatory oversight (e.g., Investigational New Drug (IND)/Investigational Device Exemption (IDE) status or Nonsignificant risk (NSR) determination) or provide a detailed plan and timeline for obtaining it before funding.
IRB/IEC Approval: All study protocols must be reviewed and approved by the applicant institution's Institutional Review Board (IRB) or Independent Ethics Committee (IEC).
Data and Safety Monitoring: A comprehensive 'Data and Safety Monitoring Plan' is required for all clinical trials to ensure participant safety and data integrity. This includes oversight by independent safety monitors or Data and Safety Monitoring Boards.
Human Subjects Protection: Detailed plans for the protection of research participants and consenting procedures for all participant groups are mandatory. Ethical implications and the risks, burdens, and benefits of co-enrollment (if applicable) must be addressed.
Nondiscrimination: Recipients must comply with all applicable nondiscrimination laws and submit an Assurance of Compliance (HHS-690).
Federal Regulations: All awards are subject to the terms and conditions outlined in the NIH Grants Policy Statement, 2 CFR Part 200 (Uniform Administrative Requirements), and relevant sections of the Public Health Service Act and Federal Regulations (42 CFR Part 52).

Data Management and Security

Data Management and Sharing Plan (DMSP): A DMSP is mandatory for all applications and must adhere to the 2023 NIH Policy for Data Management and Sharing. The plan must detail data types, formats, standards, access, preservation, and timelines.
National Institute of Mental Health Data Archive (NDA): Investigators funded under this NOFO are expected to share data via the NDA. This requires formulating an enrollment strategy to obtain information for generating a Global Unique Identifier (GUID) for each participant and a budget strategy to cover data submission costs. Data quality certification before submission is expected.
Cybersecurity: For recipients interacting with HHS systems or handling Personal Identifiable Information (PII)/Personal Health Information (PHI), plans and procedures modeled after the NIST Cybersecurity framework are required.
Common Data Elements (CDEs): Use of CDEs, especially for mental health human subjects research, is strongly encouraged to facilitate data sharing and standardization. Costs associated with CDE collection and submission to NDA should be included in the budget.

Project-Specific Requirements

Experimental Medicine Approach: Projects must focus on validating the presumed mechanism of action of the intervention through objective measures of target engagement rather than solely on clinical efficacy at this early stage.
Innovation Preference: The grant strongly encourages testing of interventions not previously approved/marketed for psychiatric disorders, including interventions in active development, repurposed agents/devices from non-CNS indications, or expanding uses of neuromodulatory devices to other indications/populations.
Multimodal Interventions: Accepted if the pharmacologic agent or neuromodulatory device is novel. Applications must provide a clear and careful description of the combination of therapies and how combination parameters (including dosage) will be assessed, aiming for positive synergy.
Pediatric Populations: For multimodal interventions in pediatric populations, a novel intervention should be paired with a previously established intervention (e.g., FDA approved/cleared). Repositioned drugs must already be approved for use in pediatric populations for non-psychiatric indications.
Specificity of Targets: NIMH is interested in novel molecular or circuit-based targets as they relate to functional domains or symptom(s) of mental disorders, rather than broad diagnostic categories.

Special Considerations

Suicide Outcomes: Where feasible and appropriate, intervention research is strongly encouraged to include assessment of suicidal behavior to advance understanding of how mental health interventions might impact suicide-relevant outcomes.
Staff Consultation: Applicants are strongly encouraged to consult with NIMH staff when developing their application to clarify policies, guidelines, and project consistency with program priorities.

Grant Details