The NIDDK High Risk Multi-Center Clinical Study Cooperative Agreement (U01 Clinical Trial Not Allowed) aims to support high-risk, multi-center observational studies addressing diseases within the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). These studies must be hypothesis-driven and focus on advancing understanding, diagnosis, prevention, or treatment of diseases such as diabetes, digestive disorders, kidney diseases, and related conditions. The program is specifically for studies classified as “high-risk” due to invasive measures, complex interventions, operational challenges, or studies in vulnerable populations. The research must have significant clinical impact, and applications proposing low-risk observational studies, interventional clinical trials, or animal/in-vitro studies are not eligible.

The program employs a two-phase funding process: an initial U34 Implementation Planning Phase (PAR-25-090) for preparatory activities and this U01 Multi-Center Clinical Study Cooperative Agreement for conducting the actual research. Applicants who have not completed the planning phase via U34 must demonstrate readiness to begin recruitment and study activities immediately upon award. The program emphasizes meaningful engagement with patients, community members, and healthcare providers in developing and executing the study. This engagement should go beyond basic outreach, fostering bidirectional communication and ensuring the study addresses community needs effectively.

Eligible applicants include public and private higher education institutions, nonprofits, for-profit organizations, small businesses, state and local governments, tribal governments, and regional organizations. Foreign entities cannot apply directly, but foreign components contributing specialized data analyses or laboratory assays are permissible. Applicants must be registered in SAM.gov, eRA Commons, and Grants.gov and must include a Plan for Enhancing Diverse Perspectives (PEDP) with actionable strategies to ensure inclusivity in the study team, participants, and broader project design.

The application must contain a detailed study protocol, statistical analysis plan, milestone plan, and a summary of all completed planning activities. Clear timelines for participant recruitment, data collection, analysis, and dissemination of findings must be included. The proposal should demonstrate robust statistical planning, participant recruitment feasibility, and strategies for addressing biases and operational challenges. Engagement with affected communities and integration of diverse perspectives are also key components of the application.

Applications will be evaluated based on three primary factors: importance of the research, rigor and feasibility of the approach, and expertise and resources available to the research team. Additional considerations include the Plan for Enhancing Diverse Perspectives, participant protection, data safety monitoring plans, and compliance with NIH policies. Reviewers will assess whether the study addresses a significant evidence gap, employs rigorous and reproducible methodologies, and can be completed successfully within the proposed timeline and budget.

The application deadlines follow NIH standard due dates, with the final expiration date on November 6, 2026. Applicants are strongly encouraged to consult with NIDDK program staff at least 12 weeks before submitting their applications. Awards will be based on scientific merit, program priorities, and availability of funds. Post-award, recipients must adhere to NIH and NIDDK reporting requirements, including the timely submission of progress reports, adherence to data sharing plans, and compliance with all regulatory and ethical standards.