Single-Site Investigator-Initiated Clinical Trials (R61/R33 Clinical Trial Required)

The Single-Site Investigator-Initiated Clinical Trials funding opportunity, issued by the National Heart, Lung, and Blood Institute (NHLBI) under the National Institutes of Health (NIH), is designed to support the development and execution of single-site clinical trials across a broad spectrum of trial types. The focus includes Phase II or higher trials testing therapeutic, behavioral, preventive, and implementation science strategies. The mechanism of support is a phased award structure (R61/R33), where the R61 phase addresses preparatory activities and the R33 phase covers full trial execution. The goal is to foster efficient, milestone-driven clinical studies that align with NHLBI’s mission of improving public health through heart, lung, blood, and sleep-related research. The NHLBI prioritizes trial designs that are both rigorous and innovative, such as adaptive or Bayesian models, and emphasizes pragmatic implementation under typical clinical conditions. Applications must justify their proposed methodology and articulate the clinical need and evidence gaps being addressed. Trials are expected to contribute meaningfully to public health by addressing disparities and improving outcomes across diverse populations. The application must describe plans for participant recruitment and retention, risk management, and data dissemination, with a preference for multidisciplinary teams, including experts in biostatistics and trial design. Eligibility for this opportunity is broad, including domestic and foreign academic institutions, nonprofits, for-profit organizations, local and state governments, tribal entities, and others. However, foreign subawards or subcontracts are not allowed under this NOFO. Each application must be unique and scientifically distinct. Applications proposing multi-site trials, Phase I trials, observational studies, or those focusing solely on safety assessments are considered non-responsive. Applications must include several critical documents for consideration: a Single-site Justification Plan, a Trial Management Plan detailing team structure and risk mitigation strategies, a Clinical Research Experience document listing past relevant studies, and a Community Engagement Plan demonstrating collaboration with local partners. These documents must follow prescribed formats and page limits. Applicants are also required to register with federal systems such as SAM, eRA Commons, and Grants.gov. This funding opportunity accepts new, resubmission, and revision applications. It opens for submissions on May 2, 2026, with multiple due dates through 2028, operating on a recurring schedule. The earliest possible start date for awarded projects is April 2027. The total performance period can extend up to five years, with one year allocated to the R61 phase and up to four years for the R33 phase. Progress is rigorously monitored with required milestones for each phase. NHLBI retains the right to discontinue funding if performance metrics are not met. Applications will be evaluated through the NIH peer review process based on significance, innovation, rigor, feasibility, and the experience of the investigators. The review also considers diversity, participant recruitment, community engagement, and data sharing strategies. Contact emails are provided for each NHLBI division, enabling applicants to seek early guidance, which is strongly encouraged at least 12 weeks prior to submission. The NOFO expires on November 3, 2028.

Applicants should clearly articulate core milestones and contingency plans to secure continuation to the R33 phase. Community engagement and inclusive recruitment metrics are heavily emphasized. Poor milestone performance may result in early termination.