NHLBI Early Phase Clinical Trials for Therapeutics and/or Diagnostics for HLBS Disorders (R33 CT Required)

NHLBI Early Phase Clinical Trials for Therapeutics and/or Diagnostics for HLBS Disorders (R33 CT Required) is sponsored by National Institutes of Health (NIH). Supports early-phase clinical trials for therapeutics and diagnostics, focusing on transparency and integrity.

PAR-25-026: NHLBI Early Phase Clinical Trials for Therapeutics and/or Diagnostics for HLBS Disorders (R61/R33 Clinical Trial Required) This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Heart, Lung, and Blood Institute ( NHLBI ) Funding Opportunity Title NHLBI Early Phase Clinical Trials for Therapeutics and/or Diagnostics for HLBS Disorders (R61/R33 Clinical Trial Required) R61 / R33 Exploratory/Developmental Phased Award January 28, 2026 - NIH Removing AIDS Application Due Dates from NOFOs.

See Notice NOT-OD-26-029 . March 31, 2025 - This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission.

April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 . August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023.

See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189 .

Funding Opportunity Number (FON) Companion Funding Opportunity Exploratory/Developmental Grants Phase II See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s) 93. 838, 93. 837, 93.

840, 93. 839, 93. 233 Funding Opportunity Purpose The objective of this Notice of Funding Opportunity (NOFO) is to support investigator-initiated, Phase I clinical trials for diagnostic and therapeutic interventions for heart, lung, blood, and sleep (HLBS) disorders in adults and children.

In addition to supporting clinical trial start-up and implementation activities, this NOFO will provide support for final stage preclinical activities needed for the implementation of the proposed trial. All the activities proposed in the R61 phase must be directly related to the therapeutic/diagnostic in preparation for the clinical trial. The proposed trial can be single or multi-site.

This NOFO will utilize a bi-phasic, milestone-driven mechanism of award where the first phase can be used to finalize required pre-trial activities such as stability, shipping studies, and site training. Open Date (Earliest Submission Date) The following table includes NIH standard due dates marked with an asterisk.

Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Workspace to prepare and submit your application and eRA Commons to track your application. Part 1.

Overview Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Section II.

Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V.

Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII.

Other Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description The objective of this funding opportunity will be to support investigator-initiated, Phase 0 and I clinical trials (including bridging studies) for diagnosis and therapeutic interventions (e.g., drugs, devices, and biologics, including cells and cell products) for heart, lung, blood, and sleep (HLBS) disorders in adults and children.

NHLBI seeks applications that propose to contribute to the evidence base for important health matters of relevance to the research mission of NHLBI and which meet the NIH definition of a clinical trial (see NOT-OD-15-015 ).

In addition to supporting clinical trial start-up and implementation activities, this PAR will provide support for final stage, agent-associated preclinical activities needed for the implementation and conduct of the proposed trial. This NOFO is applicable to single or multi-site clinical trials that are Phase I, including bridging studies.

For the purposes of this NOFO, the definition of a bridging study is a study performed to provide clinical data that allows extrapolation of the existing data from the population approved to receive the therapeutic or diagnostic into a new population (e.g., from adult subjects into pediatric subjects).

NHLBI seeks to enable early translational research as a means of facilitating and accelerating the development of new clinical interventions. This includes identifying unmet medical needs and opportunities, knowledge and resource gaps, and developing programs that bridge the gaps between mechanistic, discovery, and early translational research.

For additional information about the mission, strategic vision, and research priorities of the NHLBI, applicants are encouraged to consult the NHLBI website . In addition to scientific relevance and excellence, these clinical trials are expected to be conducted with a high degree of efficiency and with streamlined administrative procedures wherever possible.

This NOFO will utilize a bi-phasic, milestone-driven R61/R33 mechanism consisting of a start-up phase (R61) and a clinical trial execution phase (R33). Applicants must address objectives for both the R61 and the R33 phase and are strongly encouraged to use project management principles as appropriate.

The R61 phase can be up to two years and will support late-stage product development activities required to allow the therapeutic or diagnostic to be administered to humans. Examples of activities that will be allowed include: stability studies, final formulation studies, establishment of shipping and receiving protocols, Investigational New Drug (IND) filing, and Phase 0 clinical trials.

Submissions containing animal studies are not permitted for this NOFO. If the project needs additional animal studies or any other activities that are not covered under this NOFO to be ready for the early phase clinical trial, applicants are encouraged to apply for Catalyze grants or Catalyze preclinical services. Information about the Catalyze program can be found here: Catalyze - About (nhlbicatalyze.

org) The R61 phase will also support finalization of the protocol and the informed consent/assent document; the development of the manual of operations, case report forms and other resources necessary to the performance of the protocol; further development of study partnerships; review of the protocol; and Institutional Review Board approval of the trial.

All necessary regulatory approvals, as well as source(s) of the necessary drugs, devices or other resources as needed, should be obtained to allow for the successful launch of the proposed clinical trial in the R33 phase. An administrative review of the extent to which peer-reviewed milestones are met in the R61 phase will determine whether the R33 phase award will be issued, subject to NHLBI funding availability.

In addition to the primary aim of assessing the safety of the therapeutic/diagnostic product, secondary aims in the R33 phase may include: 1) further testing of the intervention's feasibility, safety, and acceptability; 2) determining the optimal dose for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout of the biological signature in response to multiple doses of the product; 3) determining the pharmacokinetics of the dose and formulation of the product to be used in future trials to justify the frequency of dosing; and 4) developing functional biological signature measures and clinical outcome measures feasible for use in larger efficacy and effectiveness trials.

The specific activities appropriate for the R33 phase will depend on the product under study and available preliminary data on the product. Delineation of milestones by the applicant for the R61 and R33 phases is a key characteristic of this NOFO. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity.

This NOFO will support applications that propose a series of milestones including manufacturing and product development goals in the R61 phase and trial conduct in the R33 phase. Applicants are expected to complete the trial on time and on budget. Applications that address contingency plans to proactively confront potential delays in meeting the milestones are strongly encouraged.

Milestones must address timing of overall recruitment/enrollment and retention goals, including accrual goals for women, minorities, and individuals of all ages including children and older adults. It is expected that performance of core milestones, such as planned enrollment goals, will be shared on a regular basis through eConnect , an NHLBI platform that facilitates transfer of electronic information to NHLBI.

After review, NHLBI will determine eligibility to transition to the R33 phase; this includes completion and analysis of any Phase 0 clinical trials. With the entirety of the Phase I clinical trial in the R33 phase, there will be additional administrative review of accrual milestones within this phase.

It is expected that the performance of critical milestones such as expected enrollment goals will be shared on a regular basis through an NHLBI clinical dashboard database.

Milestones and metrics may include IND or IDE filing, IRB protocol approval, successful transition to R33 phase, timely startup of clinical trial protocol and completion of trial and trial-specific milestones, publication of trial results, and/or specific plan for transition to next appropriate clinical study or returning to basic research studies to refine and improve the approach.

Additional NHLBI policies relevant to clinical research are the NHLBI Policy for Inclusion of Women and Minorities in Clinical Research , and the NHLBI Policy for Data and Safety Monitoring of Extramural Clinical Studies .

Applications Not Responsive to this NOFO The following types of clinical trials are considered outside the scope of this NOFO, and applications proposing such activities will be considered non-responsive to this NOFO and will be withdrawn without review: Phase II or III trials (see PAR-22-189 , PAR-22-192 , or PAR-22-193 or their reissuances for NHLBI NOFOs that support Phase II or III trials) Observational studies that do not meet the NIH definition of a clinical trial (see NOT-OD-15-015 ) Trials designed to address hypotheses related to the biology and pathobiology of health and/or diseases.

Mechanistic or Basic Experimental Studies in Humans (BESH) ( NOT-HL-19-690 ) Specific Areas of Research Interest Investigators are strongly encouraged to consult with the Scientific/Research Contacts listed in Section VII for the area of science for which they are planning to develop an application prior to submitting an application. Early contact (at least 12 weeks prior to submission) is encouraged.

This period of time provides an opportunity for NHLBI staff to discuss the scope and goals, and to provide information and guidance to the applicants. See Section VIII. Other Information for award authorities and regulations.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs. Section II. Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO. Required: Only accepting applications that propose clinical trial(s).

Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Application budgets in the R61 phase are limited to $250,000 in direct costs per year.

Application budgets in the R33 phase should not exceed $1,515,000 in direct costs per year. The maximum period of the combined R61 and R33 phases is 5 years, with up to 2 years for the R61 phase and up to 3 years for the R33 phase. The scope of the proposed project should determine the requested project period.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO. Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement , are allowed. Applicant organizations must complete and maintain the following registrations as described in the How to Apply- Application Guide to be eligible to apply for or receive an award.

All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information.

System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually . The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.

NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM. gov registration process.

The same UEI must be used for all registrations, as well as on the grant application. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registrations; all registrations must be in place by time of submission.

eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants. gov – Applicants must have an active SAM registration in order to complete the Grants.

gov registration. Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.

If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply-Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

This means that the NIH will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application. A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced.

Applications that are out of compliance with these instructions may be delayed or not accepted for review. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed. Cover Letter: A copy of the NHLBI approval letter to submit a grant application with direct costs over $500,000 in any year must be attached. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information All instructions in the How to Apply- Application Guide must be followed. Facilities and Other Resources : If the proposed trial is multi-site, describe the facilities and resources available for the coordination of a multi-site clinical trial. Describe how the infrastructure and performance sites will facilitate the efficient operation of the proposed multi-site clinical trial.

Other Attachments: The following attachments marked as "Required" must be provided, or the application will not be reviewed: 1. Clinical Trial Research Experience : Applicants must provide a detailed listing of projects that demonstrate experience of the proposed team in late translational research and early phase clinical trials in the last 5 years. The table must be provided as an attachment called "Product Development Experience.

pdf" and may not exceed 3 pages. The table columns should include: Column A: product development program title Column B: applicant's role in the development program Column C: a brief description of the development program Column D: a brief description of the early phase trial Column E: planned enrollment Column F: actual enrollment Column G: publication reference(s) 2.

Project Management Plan : A Project Management Plan must be provided as an attachment called "Project Management Plan. pdf" and may not exceed 3 pages. The Project Management Plan should describe the strategy that will be used throughout the project to ensure that the unique goals of the preparatory work and the clinical trial are met.

Project management planning should directly support the needs of scientific study leadership to identify barriers, make timely responses, and optimize the allocation of limited resources to meet pre-defined study objectives.

The project management plan should describe: The role of the project manager The project's critical path to meet scientific objectives within budgetary limits Business roles, executive decision-making, and accountability standards The contingency plans in the event that there is inadequate progress toward achieving the R61 and/or R33 milestones Key methodology and standard operating procedures governing resource management, study deployment, operations/execution, and study closure How the project management team will resolve fiscal and logistical issues in a timely manner including plans to proactively evaluate and prioritize study risks and issue corrective responses Processes required for orderly project closure including how data and specimens will be handled In summary, the project management plan must provide sufficient detail to demonstrate the ability to achieve the goals of the clinical trial on-budget and on-time and to successfully manage and mitigate risks.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. The PD(s)/PI(s) of the clinical trial must be experienced in the conduct of clinical trial coordination and management, including success in meeting milestones and timelines, and have expertise in the content area of the proposed clinical trial.

The experience of each PD/PI and all Key Personnel must be carefully documented and roles and responsibilities must be well defined. In addition, the responsibilities and authority of each PD/PI must be specified.

The application must ensure that a multidisciplinary team of appropriate personnel (clinician, statistician, data manager, study coordinator(s), etc.) is proposed to facilitate the implementation of all aspects of the clinical trial, including recruitment of subjects, and design/implementation of the clinical protocol. All instructions in the How to Apply- Application Guide must be followed.

If parts of the costs of the trial are to be provided by sources other than NHLBI, these contributions must be presented in detail in the budget justification. Third Party support of the proposed research activity (if approved) will be incorporated as a Special Award Condition.

Applicants are reminded that although Cost Share is not required, if these types of costs are included in the research application and peer reviewed, it is expected that these costs will not be covered by NHLBI. Include budget support for publication and dissemination of results. All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions: The Research Strategy must present an overview of the state of the science, current status and relevance of the trial, a detailed discussion of the specific protocol, and the approach to data collection.

Provide a brief description of study research objectives. The following criteria must be addressed: Significance: The significance of the proposed clinical trial and importance of the question must be clearly stated. It is particularly important that there be a discussion of how the trial will test the proposed hypothesis(es) and the unmet need or gap that is filled with the new therapeutic or diagnostic.

The application should make clear the need for and timeliness of the study with emphasis on how the results will address an evidence gap and therefore advance our knowledge of theory and practice in this area. Include a description of how results will impact clinical care to improve health. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance.

Innovation: Explain how the application challenges and seeks to shift current research or clinical practice paradigms. Approach : The research approach should include detailed descriptions of the supporting data and the experimental approach. Supporting Data.

Describe the preclinical studies that provide the basis for the proposed clinical trial. Include other research as appropriate to demonstrate that the approach chosen is justified. Conceptualization and planning must have progressed to a stage sufficient to allow for an overall assessment of the likelihood of the success of the trial.

Experimental Approach. Critical features of conducting the clinical trial that are not already submitted as part of the PHS Human Subjects and Clinical Trials Information form must include, but are not limited to, the following experimental approach items: A detailed description and rationale for the research hypothesis(es).

A description of the laboratory evaluations (as appropriate) and plans to implement and monitor Good Clinical Practices (GCP), Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP), as appropriate should be provided. A discussion of potential challenges in implementing the research protocol and how they will be addressed.

An overall summary of the product development plan and the go/no go milestones remaining that will be analyzed in the R61 phase of the application. A detailed description of the approach to obtain regulatory approvals. A discussion of event rates and contingency plans if the effect size or event rate is underestimated.

Resource Sharing Plan : Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions: All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan.

All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Datasets should be prepared in accordance with requirements for NHLBI data repository datasets and associated documentation for submission to the Biological Specimen and Data Repository Information Coordinating Center ( BioLINCC ) and the NHLBI Policy for Data Sharing from Clinical Trials and Epidemiological Studies , and in accordance with the Guidelines for NHLBI Data Set Preparation .

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide. No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions: If you answered “Yes” to the question “Are Human Subjects Involved?

” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record. Study Record: PHS Human Subjects and Clinical Trials Information All instructions in the How to Apply- Application Guide must be followed.

Section 2 - Study Population Characteristics If applicable, include the required health status of study participants. 2.

5 Recruitment and Retention Plan The Recruitment and Retention Plan should address: 1) the expertise of the individual(s) responsible for screening, approaching and consenting potential participants; 2) engagement of patient advocacy groups; 3) the process for identification and screening of study participants; 4) primary and back-up recruitment strategies (e.g., use of electronic health records); 5) implementation of the consent and/or assent process(es); 6) possible competition from other trials for study participants; 7) engagement of the clinical community(ies) that will play a critical role in the recruitment and retention.

Provide a table of the recruiting sites and site PD/PIs showing enrollment goals and number of potential participants available at each site. Applicants must include both a description and a table or graph of the overall study timeline and key milestones. Overall Study Timeline .

Include estimated study duration (in months) including but not limited to (a) when the study opens to enrollment; and (b) when data will be cleaned and ready for analysis.

The study timeline should include a description of key milestones that need to be met throughout the lifecycle of the preparatory phases and the clinical trial (R61 and R33 phases) to ensure its success, the processes that will be used to reach the milestones, and a timetable identifying when each of these key milestones will be met. Key Milestones .

A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, measurable, results-focused and time-bound. Milestones must address timing of overall recruitment/enrollment and retention goals.

The milestones must address accrual goals for women, minorities and children and any other identified requirements for completion of the approved research. Transition to the R33 phase is predicated on the successful completion of the milestones proposed and peer-reviewed for the R61 phase of the application.

The milestone plan should include key milestones that need to be met during the R61 phase to allow for successful launch of the trial in the R33 phase. The milestone plan also needs to describe the milestones that must be reached in the R33 phase to address the specific aims, and ensure the successful completion of the clinical trial and dissemination of its results.

Investigators and NHLBI will review and mutually agree upon a final revised milestone plan that will be included in the Terms and Conditions of the grant (if awarded). Milestones of particular interest during the R61 phase include but are not limited to: Completion of all product formulation studies Registration of the trial in ClinicalTrials.

gov Completion of GCP training Final shipping and distribution methods for the experimental therapeutic or diagnostic Completion of regulatory approvals IRB approval of finalized clinical protocol Completion of final Informed Consent(s) and, if applicable, assent form(s) Completion of agreements in place for product supply (if applicable) Development of a comprehensive laboratory plan Pharmacy/Laboratories Identification (as applicable) Establishment of contracts/third party agreements (if applicable) Development of final Management/Communication Plan Completion of IRB-approved Data and Safety Monitoring Plan Completion of Site Performance Plan Completion of Data Completeness and Quality Monitoring Reporting Plan The application should also include