NINDS Efficacy and Exploratory Clinical Trials (UG3/UH3 - Clinical Trial Required)

The National Institute of Neurological Disorders and Stroke, a component of the National Institutes of Health within the U.S. Department of Health and Human Services, is offering the NINDS Efficacy and Exploratory Clinical Trials (UG3/UH3 - Clinical Trial Required) funding opportunity under PAR-27-065. The program supports investigator-initiated clinical trials addressing the mission and research interests of NINDS and intended to develop interventions that prevent neurological disorders or improve outcomes. Supported interventions may include small molecules, drugs, biologics, medical devices, surgical interventions, behavioral interventions, diet-based approaches, rehabilitation strategies, and other preventive or therapeutic interventions. The opportunity encompasses early and middle phase exploratory trials, confirmatory or pivotal clinical trials, comparative effectiveness trials, pragmatic trials, and appropriate adaptive designs. Studies addressing neurological diseases and care across the lifespan are encouraged. The program uses a milestone-driven UG3/UH3 phased cooperative agreement. The UG3 phase primarily supports planning, trial start-up, and establishment of feasibility and generally lasts one year, although it may extend for up to two years when necessary. Permitted UG3 activities include development of data management systems and quality management tools, recruitment and retention planning, finalization of study procedures and statistical analysis plans, regulatory and IRB approvals, acquisition of necessary drugs or devices, site contracting and training, site activation, and initiation of enrollment. Enrollment is expected to begin by the end of the UG3 phase or sooner. Projects demonstrating satisfactory progress against negotiated UG3 milestones may transition to the UH3 phase for full trial implementation. The UH3 phase may be planned for up to six years, while the combined UG3 and UH3 project period cannot exceed seven years. Projects exceeding five total years require exceptional justification. Application budgets are not limited but must reflect the actual needs of the proposed project. The source does not specify an award minimum, maximum, total program funding amount, or anticipated fixed number of awards; the number of awards depends on NIH appropriations and the number of sufficiently meritorious applications received. Cost sharing is not required. Pre-award costs are allowable only under applicable NIH Grants Policy Statement provisions. Applications involving preclinical research and development, synthetic route selection and drug product development, ancillary studies, clinical experiments not directly intended to develop a preventive or therapeutic intervention, disease pathogenesis or therapeutic-target discovery studies, primary biomarker discovery or validation, Basic Experimental Studies Involving Humans, and other activities identified as nonresponsive will not be considered for funding. Eligible applicants include public and private institutions of higher education, nonprofit organizations with or without 501(c)(3) status, small businesses, other for-profit organizations, state governments, county governments, city or township governments, special district governments, federally recognized and other tribal governments, eligible federal agencies, U.S. territories or possessions, independent school districts, public and Indian housing authorities, Native American tribal organizations, faith-based and community-based organizations, regional organizations, and non-U.S. organizations. Foreign organizations and foreign components are permitted, but applications involving foreign subawards or subcontracts are noncompliant under the stated NIH policy. Applicant organizations must maintain required SAM, UEI, eRA Commons, and Grants.gov registrations, while all PDs and PIs must have eRA Commons accounts and valid ORCID registrations linked to their profiles. Organizations may submit multiple applications if each is scientifically distinct, subject to NIH restrictions concerning duplicate or highly overlapping applications. Applications must follow the Research instructions in the NIH How to Apply Application Guide together with all program-specific requirements in the NOFO. Applications may be prepared and submitted through NIH ASSIST, an institutional system-to-system solution, or Grants.gov Workspace, with application status tracked through eRA Commons. Required content includes the applicable SF424 forms, budget materials, PHS 398 Research Plan, Human Subjects and Clinical Trials information, and other applicable forms and attachments. The Research Plan must clearly address specific aims, significance and biological relevance, supporting evidence and rationale, study approach, trial design, study population, interventions, outcomes, potential biases, milestones, and relevant next-step or go/no-go criteria. A Data Management and Sharing Plan is required when the proposed NIH-funded research will generate scientific data. Clinical trial applications must also address study timelines, participant enrollment milestones, safety monitoring, site monitoring, statistical design and power, and regulatory requirements. Where an FDA-regulated drug or device is involved, readiness for the applicable IND or IDE process must be demonstrated, and required regulatory approval must be obtained before transition to the UH3 phase. Applications are evaluated through NIH peer review for overall impact, including the importance of the research, significance and innovation, rigor and feasibility of the approach, investigator expertise, and adequacy of institutional resources. Reviewers also consider applicable human-subject protections, vertebrate animals, biohazards, authentication of key resources, and whether the proposed budget and period of support are reasonable. For exploratory trials, reviewers specifically examine the proposed next steps in therapeutic development and the adequacy of go/no-go criteria. Funding decisions additionally consider scientific and technical merit, availability of funds, and relevance to program priorities. Continued funding is milestone dependent, and NINDS may reduce, curtail, or terminate support when milestones, recruitment, protocol implementation, safety, data quality, or other material requirements are not satisfactorily met. The opportunity was posted August 31, 2026, and opens for applications September 9, 2026. The first listed application deadline is November 9, 2026, with additional submission cycles extending through March 9, 2029 for new applications and March 10, 2029 for allowed renewal, resubmission, or revision submissions. Applications are due by 5:00 PM local time of the applicant organization, and deadlines falling on weekends or federal holidays are automatically extended to the next business day. The NOFO expires March 10, 2029. For the first cycle, scientific merit review is anticipated in March 2027, Advisory Council review in May 2027, and the earliest start date is July 2027. Scientific or research questions may be directed to Exploratory_Efficacy_Trials@ninds.nih.gov. Financial and grants management questions may be directed to ChiefGrantsManagementOfficer@ninds.nih.gov. Applicants are encouraged to consult NINDS program staff during application development, particularly regarding trial planning, milestones, recruitment, devices, and use of existing NINDS clinical trial networks.

Demonstrate a compelling scientific rationale and important unmet need; design the trial for rigor, reproducibility, and feasibility; justify the study population, intervention, outcomes, sample size, and analysis; establish measurable and time-bound UG3 and UH3 milestones; provide realistic recruitment and retention plans; clearly define applicable go/no-go criteria and next development steps; demonstrate regulatory readiness for FDA-regulated interventions; consult NINDS program staff early, particularly for device studies and trials potentially suited to existing NINDS clinical trial networks; ensure the application complies with both the NIH Application Guide and NOFO-specific instructions.