The **NHLBI Early Phase Clinical Trials for Therapeutics and/or Diagnostics for HLBS Disorders (R61/R33 Clinical Trial Required)** funding opportunity supports investigator-initiated Phase 0 and I clinical trials for diagnostic or therapeutic interventions targeting heart, lung, blood, and sleep (HLBS) disorders in adults and children. This funding opportunity, issued by the **National Heart, Lung, and Blood Institute (NHLBI)**, utilizes a bi-phasic, milestone-driven approach, where the **R61 phase** allows for final pre-trial activities, and the **R33 phase** supports the full clinical trial. Projects may focus on single-site or multi-site trials and must contribute to advancing clinical interventions that address unmet medical needs relevant to NHLBI's mission.

The **R61 phase**, which may last up to two years with a budget cap of **$250,000 in direct costs per year**, focuses on final-stage preclinical and trial-readiness activities. These include formulation studies, stability testing, shipping and handling protocols, IND or IDE filings, and development of clinical protocols, manuals of operations, and informed consent documents. Activities such as site training, obtaining Institutional Review Board (IRB) approvals, and establishing agreements for drug or diagnostic product supplies are also supported. Successful completion of peer-reviewed milestones in this phase determines eligibility for transition to the R33 phase, which is contingent on NHLBI administrative approval.

The **R33 phase**, lasting up to three years with a budget limit of **$1,515,000 in direct costs per year**, supports the execution of the proposed clinical trial. The primary aim in this phase is to assess the safety and feasibility of the intervention, while secondary aims may include testing dose-response relationships, pharmacokinetics, and pharmacodynamics, as well as developing biomarkers and outcome measures for future larger trials. Applicants must define clear milestones for both phases, including timelines for enrollment, data collection, and dissemination of findings. Key milestones include IND or IDE filing, IRB approvals, recruitment benchmarks, and completion of trial protocols.

Eligible applicants include **higher education institutions**, nonprofits, for-profit organizations, state and local governments, tribal organizations, and federal agencies. Non-U.S. institutions are not eligible, though foreign components of U.S.-based projects are allowed. Applications must comply with NIH registration requirements, including those for **SAM.gov**, **Grants.gov**, and **eRA Commons**, and are subject to NIH policies for clinical trial reporting and data sharing. Letters of intent are encouraged 30 days prior to submission deadlines, which follow the standard NIH schedule: **June 4, October 2, and February 3 annually**.

The application must include a detailed **Project Management Plan**, outlining strategies for meeting milestones, managing risks, and ensuring the project stays within budget and timeline constraints. A **Clinical Trial Research Experience** attachment must also document the team’s relevant expertise. Reviewers will evaluate applications based on their significance, innovation, study design, investigator qualifications, and feasibility. Applications must demonstrate a well-justified rationale, evidence for equipoise, and robust statistical analysis plans. A clear timeline for achieving recruitment and trial goals, along with contingency strategies for challenges, is essential.

Evaluation will include an administrative review at the R61/R33 transition point to assess milestone completion. NHLBI will monitor progress through regular reporting via an electronic clinical dashboard. Successful projects are expected to advance interventions to Phase II trials or provide meaningful data to inform future studies. Applicants are strongly encouraged to engage NHLBI program officials at least **12 weeks before submission** for guidance on aligning proposals with program priorities.