It is critical that applicants follow the instructions in the Research Instructions for the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) 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.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. 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

This FOA supports applications to develop and implement phase II and beyond investigator-initiated single-site clinical trials. NHLBI seeks applications that propose to contribute to the evidence base for important health matters of relevance to the research mission of NHLBI and meet the NIH definition of a clinical trial (see NOT-OD-15-015). For additional information about the mission, strategic vision, and research priorities of the NHLBI, applicants are encouraged to consult the NHLBI website: http://www.nhlbi.nih.gov. In addition to scientific relevance and excellence, these clinical trials are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible.

This FOA is applicable to single site clinical trials that are phase II and above. For the purposes of this FOA, the definition of a single site clinical trial is one in which the protocol is implemented by one investigational site that conducts and coordinates the protocol. While a single site clinical trial may enroll participants from multiple locations/clinics within a geographic area, those participants will receive an intervention or undergo outcome assessments under the direction and oversight of one research team at one investigational site.

Proposed clinical trials may utilize a design anywhere along the continuum between explanatory and pragmatic. For this FOA, pragmatic trials are considered those that test an intervention under the usual clinical conditions in which it will be applied, while explanatory trials do so under more idealized circumstances. The trial design should be appropriate for the study question.

This FOA is intended to support Phase II or above single site clinical trials. This FOA will utilize a bi-phasic, milestone-driven R61/R33 mechanism consisting of a start-up phase (R61) and a full enrollment and clinical trial execution phase (R33). Applicants must address objectives for both a R61 and a R33 phase and are strongly encouraged to use project management principles as appropriate.

Phases of Award

The R61 phase will 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; establishment of a Data and Safety Monitoring Board and 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 R61 phase. Enrollment into the clinical trial will begin in the R61 phase to allow for an evaluation by the end of the R61 phase of early enrollment and the probability of successfully completing the trial on time and on budget. An administrative review of the extent to which peer-reviewed milestones (including enrollment milestones) are met in the R61 phase will determine whether the R33 phase award will be issued, subject to NHLBI funding availability.

Milestones

Delineation of milestones by the applicant for the R61 and R33 phases is a key characteristic of this FOA. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. This FOA will support applications that propose a series of milestones including expected enrollment goals in the R61 and R33 phases and for accomplishing the completion of the clinical trial on-time and on-budget. Applications that address contingency plans to proactively confront potential delays or disturbances in meeting the milestones are strongly encouraged. Satisfactory completion of R61 milestones will be assessed administratively by NHLBI to determine eligibility to transition to the R33 phase.

NHLBI policies regarding milestones and relevant clinical research/studies policies are described in NHLBI Accrual of Human Subjects (Milestones) Policy, NHLBI Policy for Inclusion of Women and Minorities in Clinical Research, and NHLBI Policy for Data and Safety Monitoring of Extramural Clinical Studies.

Clinical Trials Not Supported by this FOA

The following types of clinical trials are not intended to be supported by this FOA:

• Phase I (first-in-human) trials
• Observational studies that do not meet the NIH definition of a clinical trial
• Multi-site trials
• Drug or device safety trials

Specific Areas of Research Interest

Prior to submitting applications to this FOA, applicants are strongly encouraged to consult with the Scientific/Research contacts for the area of science for which they are planning to develop 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.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

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

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• 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

Other

• 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
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are 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

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) 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. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) 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.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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 DUNS number and 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.

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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH 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 SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

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. 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 NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the instructions in the Research Instructions for the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)
Telephone: 301-435-0270
Fax: 301-480-0730
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Facilities and Other Resources: Describe how the available infrastructure and performance site will be leveraged to facilitate the efficient operation of the proposed single-site clinical trial.

Other Attachments: Attachments listed below must be provided or the application will be deemed incomplete and will not be peer reviewed, with the exception of the "FDA or Other Applicable Regulatory Agency Strategy and Communications Plan", which must only be provided if applicable.

1. Clinical Protocol Synopsis

The filename "Clinical Protocol Synopsis.pdf" should be used and the file attached.

The synopsis will provide a concise snapshot of the overall trial. It will be considered by reviewers, in addition to the components of the regular application. The synopsis is meant to supplement the information provided in the Research Strategy and may not exceed 12 pages. The Clinical Protocol Synopsis should represent the protocol that would be implemented at the single site. It is meant to summarize the necessary elements of the clinical trial.

The Clinical Protocol Synopsis is expected to include the following information:

• Brief and/or Official Protocol Title
• Focus of the Study
• Objectives: A brief description of objectives, including the primary objective and secondary objectives (in a few sentences).
• Study Design: A brief description of the study design (e.g., randomized, double-blind and the Phase)
• Intervention to Be Tested: A description of the intervention to be tested, and a brief description of the protocol to be followed in each arm of the trial and the adherence assessment. Specify concomitant interventions, if applicable.
• Primary and Important Secondary Endpoints: Specify the endpoints for the primary and, if applicable, important secondary endpoints.
• Schedule of clinical and laboratory evaluations.
• Study Population: A brief description of the study population, including the sample size, gender, age, demographic group, required health status, and geographic location.
• Statistical Design and Power: Specify the number of subjects to be enrolled, the expected effect size, event rate, power and the statistical methods (per protocol, intent-to-treat) to compare groups with respect to the primary outcome measure. Specify criteria for intervention discontinuation and stopping guidelines.
• Group Assignment: Methods of assignment of participants to study groups and of randomization
• Subject Participation Duration: Time it will take for each individual participant to complete all subject visits.
• Study Duration: Estimated time (in months) from when the study opens to enrollment until: (1) completion of data collection; and (b) final data analyses.

2. Study Organization Plan

A Study Organization Plan must be provided as an attachment called "Study Organization Plan.pdf" and may not exceed 6 pages. The Study Organization plan should describe the study organization and administration, and include a communication plan. The Study Organization plan can include, but is not necessarily limited to: a description of committee structures needed to manage the complexity of the trial; the role of any internal or external advisory committees; the oversight, responsibilities, and coordination of the site proposed; and the role of any sub-contractors or providers of services, personnel, or facilities. The communication plan should include a description of the coordination between the major participants including NHLBI and identify the key channels used to reach and inform each stakeholder group and receive feedback. The organization plan should also describe how disputes will be resolved between all stakeholders.

3. Clinical Trial Experience

Applicants must provide a detailed listing of trials that demonstrate experience in trial coordination in the last 5 years. The table must be provided as an attachment called "Clinical Trial Experience.pdf" and may not exceed 3 pages.

The table columns should include:

Column A: clinical trial title

Column B: applicant's role in the trial

Column C: a brief description of the trial design

Column D: planned enrollment

Column E: actual enrollment

Column F: whether the trial(s) were completed on schedule or not

Column G: publication reference(s)

4. FDA or Other Applicable Regulatory Agency Strategy and Communications Plan

If applicable, a Regulatory Communication Plan must be provided as an attachment called Regulatory Communication Plan.pdf" and may not exceed 2 pages. This Regulatory Communication plan should reflect the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary for the conduct of the trial and associated timeline. For trials using an FDA-regulated product that require an Investigational New Drug (IND) or Investigational Device Exemption (IDE) application, the grant application must include evidence regarding the outcome of a pre-IND or pre-IDE meeting, or other evidence of communication with the FDA. If the protocol is conducted under a non-US regulatory agency, a plan for attaining applicable regulatory approvals should be provided. If the protocol is exempt from an IND/IDE, a copy of the exemption letter from the FDA should be provided. See additional requirements regarding IND/IDE submission in Part 2. Section VI.

5. 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 evidence-based strategy that will be used throughout the project to ensure that the unique goals of 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 planning team and identify control points and processes that are key to scientific and fiscal performance. This will include a description of the organizational strategy that defines internal control points and business roles. A description of the key methodology, standards, and processes governing resource management, study deployment, operations/execution, and study closure should be included. The management plan should also describe how the team will resolve fiscal and logistical issues in a timely manner, i.e., by pro-actively evaluating and prioritizing issues that jeopardize study goals and necessitate corrective responses. Describe processes required for orderly project closure including how data and specimens will be handled. In summary, the project management plan should 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.

The Plan should address how enrollment data will be shared on a regular basis with NHLBI, including any proposed use of electronic enrollment data reports directly to NHLBI's clinical trial data management system.

6. Data Management Plan

A Data Management Plan must be provided as an attachment called "Data Management Plan.pdf" and may not exceed 3 pages. The Data Management Plan should include a description of the approach to data management, including data management systems, methods of data entry, case report forms, and methods for monitoring the quality and consistency of the intervention(s) and data collection; policies and methods for ensuring blinding of study results; data confidentiality and subject privacy.

The dataset 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.

7. Statistical Analysis Plan

A Statistical Analysis Plan must be provided as an attachment called "Statistical Analysis Plan.pdf" and may not exceed 3 pages. The Statistical Analysis Plan should include:

• A description of study outcome measures, including estimates of treatment effect, power, and sample size. The plan should justify the proposed sample size based on appropriate study assumptions and power calculations. The calculations must be linked to the study endpoints and to the hypothesis(es) being tested. Include a description of the methods to be used in the analysis of the primary outcome data, plans for interim and final analyses; methods of bias control; and methods for handling missing data (as applicable). The description should be detailed enough to allow replication of the analysis by an independent statistician.
• For Phase III clinical trials, include plans for evaluation of the primary outcome(s) by race/ethnicity and gender, and include all relevant data to assess whether or not the trial includes adequate numbers of subgroups of participants to allow for separate and adequately powered analyses. Adaptive designs should include a pre-specified adaptation plan that allows for clear go/no-go decisions and pre-specified analysis boundaries.

8. Single Site Justification Plan

A Single Site Justification Plan must be provided as an attachment called "Single Site Justification Plan.pdf" and may not exceed 2 pages. This plan should describe how all participants for the trial will be enrolled at a single institution and in the allotted timeline.

All instructions in the SF424 (R&R) Application Guide must be followed. All Key Personnel who are major contributors to the study must provide an NIH Biosketch whether or not they are budgeted. Describe the experience of key personnel in the conduct of clinical trial coordination and management, including success in meeting milestones and timelines, expertise in the content area of the proposed clinical trial, and expertise in biostatistics and clinical trial design. 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 respective 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.) are proposed to facilitate the implementation of all aspects of the clinical trial, including recruitment of subjects, design/implementation of the clinical protocol, and coordination of roles/responsibilities.

All instructions in the SF424 (R&R) Application Guide must be followed.

The application must provide detailed, annual budgets that will enable the trial to meet its milestones. In the budget justification, provide the detailed budget needs (per year and total) and an implementation and cost management plan (e.g., capitation).

If partial funding is 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 Term and Condition of Award. If the Third Party support ceases and the trial is no longer tenable without the Third Party support, a close-out plan may be requested.

Include budget support, if needed, for any personnel to attend steering committee/executive committee meetings.

If applicable, budgets should include all costs associated with DSMB activities, including preparing reports for the DSMB, meeting reimbursement for DSMB members, and support for at least one DSMB meeting per year. Applicants should assess the need for liability insurance for DSMB members and provide a plan commensurate with the risk of the trial. The budget should include provision for executing the plan proposed. Include a plan for assessing DSMB member conflict of interest, and put associated costs in the budget.

All instructions in the SF424 (R&R) Application Guide must be followed.

Any subcontracts to conduct consortium activities must provide a detailed budget.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy: The Research Strategy must present an overview of the state of the science and relevance of the trial, a detailed discussion of the specific protocol, and the approach to data collection, analysis, and dissemination.

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 hypotheses and why there is clinical equipoise. 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 section should include a description of the supporting data, the experimental approach, and a milestone plan.

Supporting Data: Describe the formative clinical studies (including any pilot studies) that provide the basis for the proposed clinical trial. Include other research as appropriate to demonstrate that the approach chosen is justified. If the clinical trial is Phase III, include relevant data used to determine that the proposed trial includes adequate numbers of subgroups of participants to allow for separate and adequately powered analyses. 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: The proposed experimental approach should include an appropriate design and the rationale for the particular design chosen. The experimental approach description should include:

• An overall project timeline (this can be provided as a table or graph).
• A detailed description of the study population and why it is the most appropriate group to answer the question.
• A detailed description and rationale for the research hypothesis(es), methods of randomization if applicable, primary and secondary outcome measures, intervention(s), and participant follow-up procedures.

A Recruitment and Retention Plan showing enrollment goals and number of potential participants available at the site. The plan should also 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/assent process; 6) participant retention and adherence strategies; 7) possible competition from other trials for study participants; 8) safeguards for vulnerable populations as appropriate (e.g., children, pregnant women); 9) strategies for outreach to minorities and women; and 10) engagement of the clinical community/ies that will play a critical role in the recruitment, retention and overall conduct of the clinical trial including the prioritization of this clinical trial in the context of other overlapping clinical research.

The experimental approach description should include:

• A detailed description of the intervention to be tested and how it will be administered. Describe plans for optimizing protocol adherence at the site.
• A detailed description and justification for all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. Use of patient reported outcomes as well as non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems) need to be described. 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 detailed description of the approach to obtain regulatory approvals.
• A discussion of potential challenges in implementing the research protocol and how they will be addressed.
• Contingency plans if the effect size or event rate is underestimated

Milestone Plan: As appropriate for the goals of the project, describe the key milestones that need to be met throughout the lifecycle of 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.

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. The plan should include anticipated challenges to meeting milestones and propose potential mitigation or corrective actions strategies. Milestones should address overall recruitment and retention goals. The milestones should 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 in the R61 application.

It is expected that enrollment into the clinical trial will begin in the R61 phase to allow for an evaluation by the end of the R61 phase of early enrollment and the probability of successfully completing the trial on time and on budget.

The milestone plan must also describe the milestones that need to 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.

Milestones of particular interest during the R61 phase may include but are not limited to:

• Complete finalized clinical protocol
• Final Informed consent(s) and, if applicable, assent form(s)
• Agreements in place for product supply (if applicable)
• Comprehensive laboratory plan
• Pharmacy/Laboratories Identification (as applicable)
• Contracts/Third Party Agreements (if applicable)
• Training of study staff
• Final Management/Communication Plan
• Final IRB-approved Data and Safety Monitoring Plan
• Site Performance Plan
• Data Completeness and Quality Monitoring Reporting Plan
• Completion of regulatory approvals
• Enrollment of the first subject
• Submission of data and reports to convey readiness for transition to R33 phase

The application should also include a series of milestones for the completion of the specific aims of the clinical trial (R33) phase and contingency plans. Milestones and timelines for the R33 phase may need to be revised and finalized at the time of the R61/R33 transition meeting. Milestones of particular interest during the R33 phase include but are not limited to:

• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study participants, including women, minorities and children (as appropriate)
• Assessment of site protocol implementation performance
• Collection of data related to primary and secondary endpoints and database lock
• Submission of primary manuscript to peer-reviewed scientific journal(s) and dissemination of results
• Submission of study results to ClinicalTrials.gov within 12 months of the primary completion date

Letters of Support: Letters of support from clinicians or clinical department chairs whose support are necessary to the successful conduct of the trial should be provided.

If partial funding is to be provided by sources other than NHLBI, provide Letter(s) of Support signed by an authorized representative.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Applications should address plans to make available within 3 years of the end of the NHLBI period of support for the project, data not previously released and other study materials or products not previously distributed to individuals who are not study investigators in accordance with the NHLBI Data Sharing Policy available at http://www.nhlbi.nih.gov/funding/datasharing.htm.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Applicants are required to follow our Post Submission Application Materials policy.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

Reviewers will consider the overall feasibility of the project and whether the clinical trial will answer a key scientific question and be completed on time and within the proposed budget.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA:

If the primary outcomes of the trial are achieved, how critical will the information be with regard to addressing the evidence gap and advancing knowledge of theory and practice? How likely is it that the trial results will contribute critical clinical knowledge? How likely are the results to contribute to the improvement of clinical care?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA:

How strong is the application in demonstrating that the PD(s)/PI(s) and Key Personnel have the experience and capability to conduct the proposed trial and meet the milestones and timelines? How well defined are their roles and responsibilities? What evidence is provided to ensure that the clinical site will employ the appropriate personnel to recruit subjects and design/implement the clinical protocol? How strong is the project management team at the contributing institution to facilitate the implementation of all aspects of the trial? How strong is the plan for coordination of roles/responsibilities of the leadership?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Specific to this FOA:

What strengths and weaknesses are there in the study design? How appropriately is the study designed to answer the research question, test the proposed hypothesis/hypotheses, and collect the necessary data? How efficient is the trial design? How strong is the evidence for equipoise? How well does the Clinical Protocol Synopsis attachment describe the necessary elements of the clinical trial and how likely is it that the protocol can be efficiently implemented at the single site? How strong are the formative clinical studies, including any pilot studies, underpinning the trial? How strong is the discussion of event rates and are these realistic? Are the endpoints clearly defined and how appropriately is the intervention characterized? What evidence is there that the study population has been appropriately defined? What evidence is there in the Recruitment and Retention Plan that the accrual goals can be reached within the proposed time frame? How appropriate is the plan to monitor accrual? Is the study timeline appropriate to complete the goals, meet the milestones, and address the scientific question(s)? Are adverse events appropriately captured and monitored? How effectively does the Project Management Plan identify and describe risks to implementation and how well are contingency plans described?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA:

What evidence is provided that the planned analyses are appropriate for the proposed study design? Is there evidence of the ability of the individual center to (1) enroll the proposed numbers, (2) adhere to the protocol, (3) collect and transmit data in an accurate and timely fashion, and (4) operate within the proposed organizational structure?

If the clinical trial is Phase III, does the application include all relevant data to assess whether or not the trial should include adequate numbers of subgroups of participants to allow for separate and adequately powered analyses?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Specific to this FOA:

What facilities and resources are available to adequately coordinate a clinical trial? Is there strong evidence that the institution has the available resources needed to conduct a trial at the performance site?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Milestones

How strongly do the milestones address the specific aims of each phase? Are the listed milestones appropriate for the goals of the project? To what extent are the milestones relevant, measurable, achievable, result-focused and time-bound? How strong are the proposed contingency plans in the event that there is inadequate progress towards achieving the R61 and/or R33 milestones?

Data and Safety Monitoring

Is the proposed Data and Safety Monitoring Plan appropriate for the proposed clinical trial? What is the quality of the DSM Plan to monitor the site and participating facilities (labs, pharmacies)?

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NHLBI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: https://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Division of Blood Diseases and Resources

Pablo Cure, MD, MPH
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0065
Email: [email protected]

Division of Cardiovascular Sciences

Yves Rosenberg, MD, MPH
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0550
Email: [email protected]

Division of Lung Diseases

Gail Weinmann, MD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0233
Email: [email protected]

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: [email protected]

Anthony Agresti
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0166
Email: [email protected]

Jennifer Cho
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0166
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.