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Grant Analysis

Purpose & Target

This grant, known as the 'Exploratory Clinical Neuroscience Research on Substance Use Disorders (R61/R33 Basic Experimental Studies with Humans (BESH) Required),' aims to fund exploratory and developmental clinical research that investigates the neurobiological mechanisms underlying Substance Use Disorders (SUDs). This includes fundamental brain circuitry and behavior related to substance use. It specifically targets basic science experimental studies involving human participants that fit the NIH definition of both a clinical trial and basic research. This funding opportunity is SECTOR-SPECIFIC, focusing on neuroscience, particularly within the context of addiction and substance use disorders. It is open to a broad range of organizational types, including research institutions, non-profits, and even for-profit entities, in the U.S. and internationally. It is a recurring grant opportunity with multiple application cycles through March 2026.

Financial Structure

This grant operates as a phased award (R61/R33) with specific budget considerations for each phase:

R61 Phase (Initial Exploratory/Developmental):
- The combined direct costs for up to two years in this phase cannot exceed $500,000.
R33 Phase (Expansion):
- Budgets for the R33 phase are not limited; they should reflect the actual needs of the proposed project.
- Important: If your application requests $500,000 or more in direct costs (excluding consortium Facilities & Administrative costs) in any single year of the R33 phase, you MUST contact a Scientific/Research Contact at least six weeks before submitting your application. This is a critical pre-submission requirement.
Total Project Period: The combined R61 and R33 phases have a maximum duration of five years (up to 2 years for R61, up to 3 years for R33).
Cost Sharing/Matching Funds: This grant DOES NOT require cost sharing or matching funds.
Eligible/Ineligible Costs: While not exhaustively detailed, all expenses must adhere to the general NIH Grants Policy Statement. Pre-award costs are allowable only as described in this policy.
Financial Reporting Requirements:
- Award recipients are required to submit a Research Performance Progress Report (RPPR) annually.
- Financial statements are also required as per the NIH Grants Policy Statement.
- For award closeout, a final RPPR, an invention statement, and the expenditure data portion of the Federal Financial Report are necessary.
- Recipients of applicable NIH grants must report all subawards over $25,000 to the Federal Subaward Reporting System (FSRS).
Financial Guarantees: No explicit financial guarantees are mentioned beyond adherence to federal regulations and standard grant terms.

Eligibility Requirements

This grant is open to a very wide range of organizations, both domestic (U.S.) and international, that are involved in research:

Eligible Organization Types:
- Higher Education Institutions: Public/State Controlled and Private Institutions of Higher Education.
- Nonprofits: Both those with and without 501(c)(3) IRS Status.
- For-Profit Organizations: Small Businesses and other For-Profit Organizations.
- Government Entities: Local (County, City or Township, Special District Governments), State, Federal (Eligible Agencies), and Indian/Native American Tribal Governments (Federally Recognized and Other).
- Other: Independent School Districts, Public Housing Authorities/Indian Housing Authorities, Native American Tribal Organizations, Faith-based or Community-based Organizations, Regional Organizations, and Non-domestic (non-U.S.) Entities (Foreign Institutions).
Geographic Location: Organizations from the U.S. and non-U.S. (Foreign Institutions) are eligible to apply.
Registration Requirements (Mandatory): All applicant organizations must complete and maintain active registrations with the following systems prior to application submission (this can take 6+ weeks, so plan ahead):
- System for Award Management (SAM) (requires annual renewal).
- Unique Entity Identifier (UEI) (issued as part of SAM.gov registration).
- NATO Commercial and Government Entity (NCAGE) Code (required for foreign organizations in lieu of a CAGE code for SAM registration).
- eRA Commons: Organizations must register and identify at least one 'Signing Official' (SO) and one 'Program Director/Principal Investigator' (PD/PI) account.
- Grants.gov: Requires an active SAM registration.
Principal Investigator (PD/PI) Eligibility: Any individual with the necessary skills, knowledge, and resources to lead the research project is invited to apply through their organization. PD/PIs must have an eRA Commons account affiliated with their organization.
Project Specifics:
- The proposed research MUST involve 'basic science experimental studies with humans.' This means studies that prospectively assign human participants to conditions and assess outcomes to understand fundamental phenomena, without specific applications towards processes or products in mind.
- The study MUST fall within the NIH's definition of a clinical trial AND meet the definition of basic research.
- Preliminary data is NOT required but can be included if available to demonstrate study feasibility.
- Applications MUST include clear, quantitative milestones and a defined path for transition from the initial R61 phase to the R33 phase. Failure to do so will result in the application being considered non-responsive and it will not be reviewed.
Exclusion Criteria:
- Studies with 'specific applications towards processes or products in mind' (e.g., mechanistic clinical trials, FDA Phase 0 or 1 studies, safety and efficacy studies) are NOT eligible for this grant; they should be submitted under the companion NOFO (PAR-23-157) or other appropriate announcements.
- Observational studies involving humans are also NOT eligible for this grant; they should be submitted under 'Clinical Trials Not Allowed' NOFOs.
- Duplicate or highly overlapping applications currently under review at NIH are NOT accepted.

Application Process

Applying for this grant involves a structured electronic submission process with multiple deadlines:

Application Due Dates: There are several application due dates, occurring roughly three times a year. The latest application due date mentioned in the document is March 13, 2026, by 5:00 PM local time of the applicant organization. It's highly recommended to submit early to allow time for corrections if errors are found.
Letter of Intent (Encouraged): While not mandatory or binding, submitting a 'Letter of Intent' (LOI) about 30 days prior to the application due date is encouraged. It helps NIH staff estimate workload. The LOI should include the descriptive title, PD(s)/PI(s) contact information, key personnel, participating institutions, and the funding opportunity number.
Application Submission Methods: Applications must be submitted electronically through one of the following platforms:
- NIH ASSIST system
- An institutional system-to-system (S2S) solution (check with your institution)
- Grants.gov Workspace
Required Documentation and Materials: All applications must follow the detailed instructions in the 'Research (R) Instructions in the SF424 (R&R) Application Guide,' along with specific instructions in this funding opportunity. Key components include:
- Specific Aims: Clearly demarcate aims for both the R61 and R33 phases on a single attachment.
- Research Strategy: Separate, clearly labeled sections for both R61 and R33 phases. The R61 phase should focus on critical experiments, while the R33 phase should outline the plan to develop and expand the concept based on anticipated R61 results.
- Milestones: MANDATORY. Include as the last element of the Research Strategy section. These must be well-defined, quantitative, scientifically justified, and distinct from specific aims. They will be evaluated for scientific and technical merit.
- Data Management and Sharing Plan: Required for all research generating scientific data (effective for due dates on or after January 25, 2023).
- PHS Human Subjects and Clinical Trials Information form: Required if human subjects are involved. You MUST answer 'yes' to all four questions on the 'Clinical Trial Questionnaire' for this NOFO.
- Resource Sharing Plan: Required.
- Limited Appendix Materials: Only blank questionnaires or surveys are allowed in the Appendix.
Project Implementation Timeline: The maximum project period is 5 years (up to 2 years for the R61 phase and up to 3 years for the R33 phase). The scope of your proposed project should dictate the requested timeline.
Transition from R61 to R33: Transition is not automatic or guaranteed. It requires submitting a 'transition package' (progress report, R33 research plan) no less than two months before the R61 phase completion. NIH Program staff will evaluate this, and funding for the R33 phase depends on successful completion of R61 milestones, program priorities, and funding availability. Approximately 50% of R61 grants are expected to transition to R33.
Application Assistance:
- eRA Service Desk: For issues with ASSIST, eRA Commons, application errors, and post-submission issues.
- NIH General Grants Information: For instructions, processes, and NIH grant resources.
- Grants.gov Customer Support: For Grants.gov registration and Workspace issues.
- Scientific/Research Contact(s): For inquiries about the funding opportunity's scientific scope and potential projects (Vani Pariyadath, Ph.D., and John Fedota, Ph.D. from NIDA are listed contacts). Contact them at least 6 weeks prior to submission if requesting $500,000+ direct costs in any R33 year.

Evaluation Criteria

Applications are evaluated for 'scientific and technical merit' through a peer review process, leading to an 'Overall Impact' score. This score reflects the project's likelihood of significantly influencing the research field, considering the following criteria:

Overall Impact: Assesses the potential for the project to exert a sustained and powerful influence on the research field.
Scored Review Criteria (each receives a separate score):
- Significance: Does the project address an important problem or barrier in the field? Is the supporting prior research rigorous? How will successful completion improve scientific knowledge, technical capability, or clinical practice, and change current concepts, methods, or technologies?
- Investigator(s): Are the PD(s)/PI(s) and other researchers well-suited with appropriate experience, training, and a record of accomplishments? For multi-investigator projects, is the expertise complementary, and is the leadership and organizational structure appropriate? Expertise in study coordination, data management, and statistics is also assessed.
- Innovation: Does the application propose novel theoretical concepts, approaches, methodologies, instrumentation, or interventions that challenge and shift current paradigms? Are the innovative elements in the design/research plan appropriate and enhancing?
- Approach: Are the overall strategy, methodology, and analyses sound and appropriate for the aims? Are weaknesses in prior research addressed? Are strategies to ensure a robust and unbiased approach presented? Are potential problems, alternative strategies, and benchmarks for success outlined? For human subjects, are plans for protection and inclusion (sex, race, ethnicity, age) justified? This section specifically evaluates:
  - Study Design: Is it justified and appropriate for the outcomes? Is the rationale well-supported? Is it adequately powered for the research questions and efficient? Are study populations, intervention arms, and duration justified? Are ethical issues, informed consent, recruitment, retention, and handling of dropouts adequately addressed? Are quality control plans appropriate?
  - Data Management and Statistical Analysis: Are plans appropriate for the study design? Are procedures for data management and quality control adequate?
  - Specific to this NOFO: How well-defined, quantitative, and clinically meaningful are the proposed milestones for the R61 Phase? How clearly will the R33 Phase develop and expand based on the R61 completion?
- Environment: Will the scientific environment (institutional support, equipment, physical resources) contribute to success? Does the project benefit from unique features or collaborative arrangements? For multi-site studies, is the capability to conduct the trial at proposed sites adequate?
Additional Review Criteria (not scored separately but contribute to overall impact):
- Study Timeline: Is it detailed, feasible, and justified? Does it incorporate efficiencies?
- Protections for Human Subjects: Evaluation of risks, protections, benefits, and importance of knowledge gained, and data and safety monitoring.
- Inclusion of Women, Racial and Ethnic Minorities, and Individuals Across the Lifespan: Evaluation of plans for inclusion (or justification for exclusion) based on scientific goals.
- Vertebrate Animals: Assessment of proposed procedures, justifications for use, and interventions to minimize discomfort.
- Biohazards: Assessment of potential hazards and proposed protections.
- Resubmissions: Evaluation of responses to previous review comments and changes made.
- Foreign Organizations: Assessment of special opportunities offered by foreign talent, resources, populations, or environmental conditions.
- Select Agent Research: Assessment of information regarding select agents, registration status, monitoring, biosafety, and security.
- Resource Sharing Plans: Comments on the reasonableness of sharing plans or rationale for not sharing.
- Authentication of Key Biological and/or Chemical Resources: Comments on plans for identifying and ensuring the validity of resources.
- Budget and Period of Support: Consideration of whether the budget and requested period are justified and reasonable.

Compliance & Special Requirements

This grant comes with several compliance obligations and unique features:

Regulatory Compliance:
- All awards are subject to the NIH Grants Policy Statement and federal regulations (42 CFR Part 52, 45 CFR Part 75, and 2 CFR Part 200).
- Human Subjects Protection: Strict adherence to guidelines for protecting human subjects from research risks is required. Institutions must ensure all protocols are reviewed by their Institutional Review Board (IRB) or Independent Ethics Committee (IEC).
- Data and Safety Monitoring: For all NIH-funded clinical trials, robust data and safety monitoring plans are mandatory to ensure participant safety and data integrity.
- Inclusion Policies: Plans for the inclusion (or justified exclusion) of individuals based on sex, race, ethnicity, and age (including children and older adults) must be detailed and justified.
- Vertebrate Animals: If applicable, proposals must adhere to guidelines for the ethical use and care of vertebrate animals.
- Biohazards: Assessment and adequate protection plans are required for any potentially hazardous materials or procedures.
- Data Management and Sharing (DMS) Policy: Effective January 25, 2023, a Data Management and Sharing Plan is required for all research generating scientific data. Recipients must implement the approved plan.
Ethical and Non-Discrimination Standards:
- Recipients must comply with federal civil rights laws prohibiting discrimination based on race, color, national origin, age, sex, and disability.
- Meaningful access must be provided for individuals with limited English proficiency and effective communication for persons with disabilities.
- A safe and respectful work environment free of sexual harassment is expected.
Financial Integrity and Performance:
- Awards are subject to the Federal Awardee Performance and Integrity Information System (FAPIIS), which involves reviewing an applicant's integrity, business ethics, and performance record.
- Recipients with cumulative federal awards over $10,000,000 must report civil, criminal, and administrative proceedings in SAM and FAPIIS.
Unique Aspects and Challenges:
- Phased Award (R61/R33): This structure supports highly exploratory and developmental research in the initial (R61) phase, with the potential to expand into a larger (R33) project. The R61 phase is acknowledged to be 'risky,' with an expected 50% transition rate to the R33 phase. Successful transition is contingent on meeting well-defined, quantitative milestones.
- Dual Definition Requirement: A key distinguishing feature is the requirement that the proposed studies MUST simultaneously meet the NIH definition of a clinical trial AND the definition of basic research. This specifically excludes studies with immediate product/process applications or purely observational studies.
- Focus on Basic Research: This grant is for understanding fundamental aspects of phenomena without specific applications towards processes or products in mind. This differentiates it from applied or translational research.
Strategic Opportunities: This grant offers a unique opportunity for high-risk, high-reward research that could lead to significant breakthroughs in understanding the neurobiological underpinnings of substance use disorders. It is particularly suited for novel areas of investigation or innovative uses of existing methodologies.

Grant Details