The Department of Health and Human Services (HHS) and the National Institutes of Health (NIH) have reissued a Notice of Funding Opportunity (NOFO) titled "Clinical Trial Readiness for Rare Diseases, Disorders, and Syndromes (R21 Clinical Trial Not Allowed)." This initiative, PAR-25-450, aims to support clinical projects that address critical needs for clinical trial readiness in rare diseases by facilitating the movement of candidate therapeutics or diagnostics toward clinical trials. The NOFO emphasizes developing and testing rigorous biomarkers and clinical outcome assessment measures, or defining the presentation and course of rare diseases to enable the design of upcoming clinical trials. The maximum project period is 2 years, with a budget of up to $275,000 direct costs. Applications must focus on rare diseases affecting fewer than 200,000 individuals in the U.S. and should not propose clinical trials. The NOFO encourages leveraging existing research resources and partnerships to optimize trial readiness.