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Grant Analysis

Purpose & Target

To support early-stage clinical trials testing novel pharmacologic or neuromodulatory device-based interventions for mental disorders.
The core objective is to objectively measure and validate the intervention's molecular/circuit-based mechanism of action in humans.
Target recipient types: Open to diverse organization types including higher education, nonprofits, for-profits (small businesses and others), and governments.
Organizational size: Open to organizations of various sizes, without explicit employee count limitations beyond the capacity to conduct clinical trials.
SECTOR-SPECIFIC: Mental Health, Clinical Neuroscience, Pharmacology, Neuromodulation, Device Development, Public Health.
Geographic scope: Global eligibility, including non-U.S. entities.
Key filtering criteria: Must involve a clinical trial, focus on early-stage testing of novel pharmacologic or neuromodulatory device interventions for mental disorders, and include objective target engagement measurement with Go/No-Go milestones.
Grant frequency: Recurring opportunity with multiple deadlines annually until October 2027; reissued from a previous PAR, indicating an ongoing program within NIMH's clinical trial pipeline.

Financial Structure

Total program funding for FY 2026 for this NOFO and its companion NOFOs is $27,000,000.
Application budgets are not limited but must reflect the actual needs of the proposed project.
The R61 and R33 phases cannot be funded within the same fiscal year.
No cost sharing is required for this grant.
Costs for collecting and submitting Common Data Elements (CDE) data to the NIMH Data Archive (NDA) should be included in the requested budget.

Eligibility Requirements

Eligible Organization Types

Higher Education Institutions (Public/State Controlled, Private)
Nonprofits (with/without 501(c)(3) IRS Status)
For-Profit Organizations (Small Businesses, Other than Small Businesses)
Local Governments (State, County, City/Township, Special District, Indian/Native American Tribal Governments - Federally Recognized or Other)
Federal Governments (Eligible Agencies, 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).

Required Registrations and Certifications

Applicant organizations must complete and maintain active registrations with the System for Award Management (SAM), Unique Entity Identifier (UEI), eRA Commons, and Grants.gov. Registration can take 6 weeks or more.
Foreign organizations must obtain a NATO Commercial and Government Entity (NCAGE) Code for SAM registration.
All Program Director(s)/Principal Investigator(s) (PD/PIs) must have an eRA Commons account (can take up to 2 weeks).
Must list the FDA regulatory oversight status (e.g., Investigational New Drug (IND)/Investigational Device Exemption (IDE) status or Nonsignificant risk (NSR) determination) at the time of application submission, or describe plan/timeline for obtaining it.
Drugs/devices to be tested must have passed Phase I/EFS safety studies (in healthy or patient populations).
Responsive pediatric drug applications must be testing drugs already approved for use in pediatric patients in non-psychiatric indications, now being repositioned.

Experience and Capacity

Senior/Key Personnel must demonstrate expertise and track record in pharmacologic or device-based clinical trials, including experience in industry-funded trials.
Demonstrated expertise in subject recruitment and retention for trials.
Proven methodological and statistical expertise relevant to clinical trials.
Evidence of successfully carrying out studies of similar structure and complexity.

Scope of Work Exclusions

Applications that do not include objective measurement of molecular/circuit-based target engagement.
Non-human animal studies are not responsive.
Applications proposing to test pharmacological or neuromodulatory device-based interventions where studies are already underway to test them in that population and with the same target (applicants should check ClinicalTrials.gov for novelty).
Applications without a clearly defined measure of CNS target engagement in the R61 phase (and replication in R33) or a clearly defined and falsifiable Go/No-Go milestone.
Pharmacologic studies lacking a functional CNS pharmacodynamic (PD) readout or plasma drug levels measure, or a test of target engagement in a dose-dependent manner.
Neuromodulatory device studies lacking thorough description of device settings and algorithms, individualized modeling of received dose, specific contextual information regarding brain state when dose is delivered, clear sham/control conditions, or neuronavigation procedures.
Applications proposing only the R61 phase or only the R33 phase; combined R61/R33 phases are required for this NOFO.
Applications for 'First in Human' testing of new chemical entities or novel 'first-in-children' pharmacological agents/devices for psychiatric disorders (these should apply to PAR-25-180).
Applications for clinical trials to establish effectiveness where efficacy has already been demonstrated (refer to PAR-25-177, PAR-25-178).
Applications for large scale/pivotal trials of non-pharmacological interventions (refer to PAR-25-179).
Applications primarily focused on mechanistic clinical trials (refer to NIH Parent R01/R21 Clinical Trial Required or Basic Experimental Studies with Humans NOFOs).

Application Process

Application Process Timeline

Posted Date: November 27, 2024
Open Date (Earliest Submission Date): January 14, 2025
Letter of Intent Due Dates: 30 days before each application due date (optional, but encouraged).
Application Due Dates (by 5:00 PM local time of applicant organization):
- 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)
Expiration Date (of Funding Opportunity): October 16, 2027.
Applicants are encouraged to submit applications early to allow time for corrections. If a due date falls on a weekend or Federal holiday, the deadline is automatically extended to the next business day.

Required Documentation and Submission Materials

Application forms package must be accessed through NIH ASSIST, Grants.gov Workspace, or an institutional system-to-system solution.
Standard Forms (SF424(R&R) series): Cover, Project/Performance Site Locations, Other Project Information, Senior/Key Person Profile.
Budget Forms: R&R Budget and R&R Subaward Budget.
PHS 398 Cover Page Supplement.
PHS 398 Research Plan: Must include the following attachments:
- Specific Aims: Concise R61 and R33 specific objectives, description of experimental medicine study(ies), potential unmet need, and the Go/No-Go milestone criteria.
- Research Strategy: Sections on Significance, Innovation, Rigor and Feasibility, and Expertise and Resources. This includes detailed descriptions of R61 and R33 phases, technical approach for target engagement, proposed dose range, and feasibility.
- Milestones (Go/No-Go Criteria) section: A clear, objective, quantifiable, and scientifically justified metric for target engagement that dictates progression from R61 to R33.
- Resource Sharing Plan.
- Data Management and Sharing Plan: Mandatory. Must comply with the 2023 NIH Policy and detail data submission to the NIMH Data Archive (NDA), including budget for CDE data submission.
PHS Human Subjects and Clinical Trials Information form: Required for human subjects research. Includes Study Record(s) or Delayed Onset Study record.
- Recruitment and Retention Plan: Detailed sources, monitoring procedures, strategies for diversity, potential challenges, and evidence of feasibility.
- Study Timeline: Benchmarks for study procedures, training, enrollment, data collection, analysis, and data sharing.
- FDA Regulatory Status: Description of Investigational Product (IP) availability and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status (or plan/timeline for obtaining it).
- Other Clinical Trial-Related Attachments: (e.g., Intervention Manual/Materials, screenshots of mobile interventions, technological specifications). Videos are not allowed.
PHS Assignment Request Form.
Appendix: Only blank questionnaires or blank surveys are allowed. No publications or other material.

Support Offered

Financial assistance is provided via a 'Grant' mechanism.
Applicants are strongly encouraged to consult with NIMH staff prior to developing their application to clarify policies and discuss project consistency with program priorities.

Project Implementation and Reporting Obligations

The maximum project period is 5 years, with up to 2 years for the R61 phase and up to 3 years for the R33 phase.
Funding for the R33 phase is contingent on successfully meeting the Go/No-Go milestones in the R61 phase.
Recipients must submit the Research Performance Progress Report (RPPR) annually and financial statements as required by NIH policy.
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; all other data is due at publication or prior to the end of the grant.
Timely registration and results reporting for applicable clinical trials on ClinicalTrials.gov is mandatory.
Timely submission of reportable events and annual review determinations from the clinical trial's data and safety monitoring entity.

Post-Award Requirements

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of the award.
Adherence to the approved Data Management and Sharing Plan is required.

Evaluation Criteria

Overall Impact

Reviewers will provide an overall impact score reflecting the likelihood of the project exerting a sustained, powerful influence on the research field(s) involved.

Scored Review Criteria

Factor 1. Importance of the Research (Significance and Innovation):
- Clear demonstration of addressing an unmet therapeutic need.
- Potential of the intervention to validate or reject the chosen CNS target.
- Strong rationale for selecting the intervention and CNS target, supported by empirical evidence of the mechanism's role in improving symptoms or function.
- Proposed intervention must be highly innovative (e.g., not already approved for a psychiatric indication, not standard practice).
- Novelty of the proposed molecular/CNS target is essential.
Factor 2. Rigor and Feasibility (Approach):
- Clearly specified molecular/circuit-based target and its relationship to biomarkers/measures of brain function, domains of function, and symptoms.
- A clear conceptual framework with strong empirical support for the intervention, its mechanism of action, and expected functional improvement.
- Rationale for the choice of clinical domain or measure of function in the target population.
- Adequate assessment and justification for participant co-enrollment (if applicable), including ethical implications, risks, benefits, and mitigation strategies.
- For the R61 phase: Study design must include an approach to determine dose/stimulus response relationships, pharmacokinetics (PK) for drugs, realistic head modeling for devices, and target engagement to identify a narrower, effective dose range for the R33 phase. A tolerable and safe dose range, adequate for testing the mechanism, must be proposed.
- For the R33 phase: The plan must further validate the dose or stimulus range based on R61 results and collect data with reliable outcome measures quantifying changes in the disorder/function. 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 regarding recruitment, data acquisition, and analysis within specified timelines.
Factor 3. Expertise and Resources (Investigator(s) and Environment):
- Combined expertise of the research team in clinical trials (pharmacologic/device-based), including successful track record in early clinical trials (e.g., recruitment/retention rates, ClinicalTrials.gov reporting, publications, industry-funded trial experience).
- Methodological and statistical expertise, and experience with all proposed measurement methods (e.g., PET, fMRI, MRS).
- Demonstrated governance for conducting the study as proposed and within specified timelines.
- Effective utilization of existing infrastructure (e.g., CTSAs, practice-based research networks) or a strong justification if such efficiencies are not incorporated.

Milestones (Go/No-Go Criteria)

A clear Go/No-Go milestone metric must be included between the R61 and R33 specific aims, highlighting the measure of target engagement and briefly listing the statistical test/threshold to be applied.
Adequate functional target engagement must be the key criterion for progression from R61 to R33.
Milestones must be pre-specified, objective, quantifiable, rigorously defined, feasible, and scientifically justified.
Criteria of success must be defined in terms of outcomes achieved (e.g., specific target engagement measures) with quantitative threshold values, rather than just tasks completed.
Criteria should demonstrate dose/stimulation-dependent effects at the proposed site of action and provide preliminary evidence of acceptable safety/tolerability at that dose.
Clear conditions must be spelled out under which the PD/PI would not proceed to the R33 phase.

Additional Review Criteria (Considered for Overall Impact, Not Scored Separately)

Protections for Human Subjects: Evaluation of justification, risks, protections, benefits, and data/safety monitoring for clinical trials.
Vertebrate Animals: (If applicable) Evaluation of procedures, justifications for use/species, interventions to minimize discomfort, and euthanasia methods.
Biohazards: (If applicable) Assessment of hazardous materials/procedures and proposed protections.
Resubmissions/Renewals/Revisions: Evaluation of progress, appropriateness of expansion, or full application as presented.

Additional Review Considerations (No Scores)

Authentication of Key Biological and/or Chemical Resources: Assessment of plans for 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

FDA Oversight: Applications must clearly state the FDA regulatory oversight status of the intervention (e.g., Investigational New Drug (IND)/Investigational Device Exemption (IDE) status or Nonsignificant risk (NSR) determination).
Human Subjects Protection: All research involving human subjects must adhere to NIH policies and guidance (e.g., NOT-MH-19-027). This includes rigorous data and safety monitoring plans and Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approval of all protocols.
Clinical Trial Registration: Applicable clinical trials must be registered and have results submitted on ClinicalTrials.gov. NIH expects all trials to comply.
Federal Regulations: Recipients must comply with 2 CFR Part 200 (Uniform Administrative Requirements), relevant sections of the Public Health Service Act, and the NIH Grants Policy Statement.
Non-discrimination: Compliance with applicable non-discrimination laws is required, affirmed via SAM.gov registration and submission of HHS-690 Assurance of Compliance.
Health IT Standards: If the award involves implementing or acquiring health IT, it must meet standards in 45 CFR part 170, Subpart B, and be certified under the ONC Health IT Certification Program if applicable to eligible clinicians/hospitals.

Data Management and Security

Data Sharing: Mandatory compliance with the 2023 NIH Policy for Data Management and Sharing. All generated scientific data must be made available.
NIMH Data Archive (NDA): Investigators are required to share data via NDA, using Global Unique Identifiers (GUIDs) and NDA's Data Dictionary. Data quality must be certified prior to submission.
Cybersecurity: Recipients who have ongoing access to HHS information systems or handle sensitive data (PII/PHI) obtained from HHS must develop plans and procedures modeled after the NIST Cybersecurity framework.

Specific Project Requirements

Intervention Novelty: Strong preference for testing interventions not previously approved/marketed for psychiatric disorders, or those repurposed from non-psychiatric indications or discontinued development.
Mechanism-Based Approach: A core requirement is the objective measurement of molecular/circuit-based target engagement, which is critical for assessing the intervention's presumed mechanism of action and for Go/No-Go decisions.
Phased Award (R61/R33): The application must propose both a R61 (exploratory/developmental) phase and a R33 (Phase II) phase. The R61 focuses on establishing target modulation and dose-response, while the R33 confirms engagement in a larger sample and links it to functional outcomes.
Go/No-Go Milestones: These must be pre-specified, objective, quantifiable, and based on outcomes (specifically, adequate functional target engagement) rather than just completion of tasks.
Suicide Assessment: Where feasible and appropriate, intervention research should include assessment of suicidal behavior using strategies that facilitate data sharing.
Multimodal Interventions: Acceptable if the pharmacologic agent or neuromodulatory device is novel, and the proposal clearly demonstrates synergistic effects and appropriate control conditions.
Pediatric Populations: For multimodal interventions in pediatric populations, a novel intervention should be paired with a previously established (FDA-approved/cleared) intervention.
Device-Specific Requirements: Neuromodulatory device studies must include thorough descriptions of device settings, individualized modeling of the received dose (spatial and temporal), specific contextual information (e.g., brain state during delivery), clear sham/control conditions, and neuronavigation procedures.
Pharmacology-Specific Requirements: Pharmacological intervention studies must include a functional CNS pharmacodynamic (PD) readout and plasma drug levels measure to assess target engagement.
Recruitment Diversity: Strategies to ensure a diverse, representative sample are required within the recruitment plan.

Grant Details