The National Institutes of Health (NIH) is reissuing the Parent R01 Clinical Trial Required Notice of Funding Opportunity (NOFO), PA-25-305. The R01 Research Project Grant supports discrete, specific research projects in scientific areas that align with the missions of participating NIH Institutes and Centers (ICs). This NOFO requires that at least one clinical trial be proposed. Applicants must ensure their research aligns with the programmatic interests of at least one participating IC, as some ICs only accept mechanistic studies through this NOFO.

The goals of this funding opportunity are to foster fundamental discoveries, promote innovative research, and expand knowledge to improve health outcomes. This includes developing human and physical resources, enhancing understanding of diseases, and supporting the collection and dissemination of medical information. NIH defines a clinical trial as a research study in which human subjects are prospectively assigned to one or more interventions to evaluate their effects on biomedical or behavioral outcomes. Mechanistic studies that explore biological processes, disease pathophysiology, or mechanisms of action for interventions also qualify under this NOFO.

Applications will be accepted for new, renewal, resubmission, and revision projects. There is no budget cap; however, proposed budgets must reflect actual project needs. The maximum project period is five years. Applications will be evaluated based on scientific and technical merit, innovation, feasibility, and investigator expertise. Proposed studies must comply with NIH's policies for human subjects protections, data management and sharing, and, where applicable, requirements related to vertebrate animals and biohazards. Projects involving FDA-regulated products must adhere to relevant regulatory requirements.

Eligible applicants include higher education institutions, nonprofits, for-profits, governments, tribal organizations, and international entities. Foreign organizations and foreign components of U.S. entities are eligible to apply. Applicants must complete required registrations, including obtaining a Unique Entity Identifier (UEI) and registering in the System for Award Management (SAM.gov), eRA Commons, and Grants.gov.

Applications must follow the NIH instructions outlined in the "How to Apply" Application Guide. Submissions must be made electronically via ASSIST, Grants.gov Workspace, or institutional system-to-system platforms. Errors must be corrected, and changed applications resubmitted before the deadline. Standard application due dates apply, with deadlines in February, June, and October of each year. Late submissions will not be accepted unless due to approved system issues.

Review criteria include the significance of the proposed research, its rigor and feasibility, and the expertise of the investigator(s) and research environment. Additional considerations include protections for human subjects, plans for inclusivity, data sharing plans, and the justification of budgets. Applications will undergo NIH peer review, followed by Advisory Council or Board review, with funding decisions based on scientific merit, program relevance, and availability of funds.

Successful applicants will receive a Notice of Award (NoA), which formalizes the funding agreement. All NIH-funded clinical trials must comply with ClinicalTrials.gov registration and reporting requirements. Recipients are also required to submit annual Research Performance Progress Reports (RPPR), invention statements, and final reports at the end of the project. For additional details, applicants are encouraged to contact the scientific or grants management staff of the relevant IC before submission.