It is critical that applicants follow the Research (R) Instructions in 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

Research Objectives

This FOA is intended to support the implementation of Phase I investigator-initiated single or multisite clinical trials for therapeutic and/or diagnostic interventions 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). 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 and with streamlined administrative procedures wherever possible.

This FOA is applicable to single or multisite clinical trials that are Phase I including bridging studies. For the purposes of this FOA, 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).

Structure

This FOA will utilize a milestone-driven R33 mechanism. Applicants are strongly encouraged to use project management principles to help facilitate achievement of performance milestones as appropriate.

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.

Applicants applying for funding under this FOA should be ready to initiate the clinical trial within the first quarter of the project period. Discussion, submission, and attainment of applicable regulatory (FDA, DSMB, IRB) approvals, and establishment of drug (and placebo, if applicable) supplies, and any necessary third-party agreements should be established by the time of award. If time and support for these and other pre-clinical and/or trial readiness activities are desired, applicants should consider the companion FOA which utilizes an R61/R33 phased approach.

Milestones

Delineation of milestones by the applicant 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. 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.

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. Continued funding will be contingent on meeting agreed-upon milestones in the Notice of Award, and on achieving satisfactory progress. 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.

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.

Clinical Trials Not Supported by this FOA

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

• Phase II or III trials (See PAR-18-406, PAR-18-407, or PAR-18-410)
• Observational studies that do not meet the NIH definition of a clinical trial
• Trials designed to address hypotheses related to the biology and pathobiology of health and/or disease

Specific Areas of Research Interest

Investigators are strongly encouraged to consult with the Scientific/Research Contacts 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.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from 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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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) 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

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 Research (R) Instructions in the SF424 (R&R) Application Guide, 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
ethesda, MD 20892-7924 (Express Mail ZIP: 20817
Telephone: 301-435-0270
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.

Cover Page: A copy of the NHLBI approval letter to submit a grant application with direct costs over $500,000 in any year must be attached.

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: If the proposed trial is multisite, describe the facilities and resources available for the coordination of a multisite clinical trial. Describe how the infrastructure and performance sites will facilitate the efficient operation of the proposed multisite clinical trial.

All instructions in the SF424 (R&R) 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 SF424 (R&R) 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 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, with the following additional instructions:

Research Strategy:

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 section should include 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.
• A detailed description of the regulatory status including dates of IND approval.
• 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 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.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Use only for applications with due dates on or after January 25, 2018. When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) 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 SF424 (R&R) Application Guide must be followed with the following additional instructions:

Section 2 - Study Population Characteristics

2.2 Eligibility Criteria

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) participant retention and adherence strategies; 7) the safeguards for vulnerable populations as appropriate (e.g., children, pregnant women); 8) possible competition from other trials for study participants; 9) 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.

2.7 Study Timeline

Applicants must include both a description and a table or graph of the overall study timeline and key milestones.

Overall Study Timeline. Include estimated time of 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 clinical trial 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.

The milestone plan should describe the milestones that need to be reached 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 interest 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

Section 3 - Protection and Monitoring Plans

3.1 Protection of Human Subjects

1. Risks to Human Subjects

a. Human Subjects Involvement, Characteristics, and Design

Provide a detailed rationale explaining why the proposed study population is the most appropriate group to answer the research question(s).

b. Study Procedures, Materials, and Potential Risks

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). Describe participant follow-up procedures

3.3 Data and Safety Monitoring Plan

Specify criteria for adverse events reporting, intervention discontinuation and stopping guidelines.

3.5 Overall Structure of the Study Team

Include a description of the following:

• The role of the Executive Committee and Steering Committee as well as any internal or external advisory committees
• The oversight, responsibilities, and coordination of any sites or cores proposed
• The role of any sub-contractors or providers of services, personnel, or facilities
• The coordination among the separate components including NHLBI
• Key channels used to reach and inform each stakeholder group and receive feedback
• How disputes will be resolved between or among all stakeholders

Section 4 - Protocol Synopsis

4.1 Brief Summary

Include protocol title. Summary must represent the protocol that will be implemented at the sites.

4.2.a Narrative Study Description

Describe the intervention to be tested, and the protocol to be followed in each arm of the trial. Describe the proposed experimental design including a discussion of the clinical trial design and the rationale for the particular design chosen.

4.2.c Interventions - Description

Provide a detailed description of the therapeutic or diagnostic to be tested and how it will be administered. Describe the rationale for the choice of the intervention including such specific information as dose, period of administration, choice of formulation, device specifications, and key characteristics of other forms of proposed approaches such as diagnostic test and behavioral interventions. Specify criteria for intervention discontinuation and stopping guidelines.

4.6 Will the study use an FDA-regulated intervention?

4.6.a If yes, describe the availability of Investigational Product (IP) and the Investigational New Drug (IND)/Investigational Device Exemption (IDE) status

Provide evidence of prior communications (letters/emails) and/or the outcomes of the pre-IND or pre-IDE meeting with the FDA. If the protocol is exempt from an IND/IDE, if available, provide a copy of the exemption letter from the FDA.

If communication has not yet been established, describe the process that will be used for attaining all FDA or other applicable regulatory agency approvals necessary for the conduct of the trial and associated timeline. If the protocol is conducted under a non-US regulatory agency, a plan for attaining applicable regulatory approvals should be provided.

See additional requirements regarding IND/IDE submission in Section VI.

4.7 Dissemination Plan

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.

Section 5 - Other Clinical Trial Related

5.1 Other Clinical Trial-related Attachments

Attachments listed below must be provided or the application will not be peer 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 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 pro-actively 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.

Delayed Onset Study

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

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

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 the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Specific to this FOA: How likely are the results to contribute to the movement of the proposed therapeutic or diagnostic to phase II clinical trials?

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?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Specific to this FOA:

How well-defined are the roles and responsibilities of the PD/PI(s), collaborators, and other researchers? What evidence is provided to demonstrate the experience in product development and conduct of early phase clinical trials? 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? What evidence is there of statistical support appropriate for the proposed trial?

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?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

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?

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?

Does the application adequately address the following, if applicable?

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to this FOA:

What are the strengths and weaknesses of the study design? How strong is the evidence for equipoise? How well does the Protocol Synopsis describe the necessary elements of the clinical trial and how likely is it that the protocol can be efficiently implemented? Are the endpoints clearly defined and how appropriately is the intervention characterized? 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 attachment identify and describe risks to implementation and how well are contingency plans described? How strong is the discussion of event rates and are these realistic? Does the application propose to use existing available resources, as applicable? Does the application adequately address Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and good Manufacturing Practices (GMP) compliance if applicable?

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?

In addition, for applications proposing clinical trials:

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or 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?

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.

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Specific to this FOA:

Milestones: 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?

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.

Not Applicable

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 to this FOA. Following initial peer review, recommended applications will receive a second level of review by the NHLBI Advisory Council. 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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain "applicable clinical trials" on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

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.

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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.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 https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/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 https://www.hhs.gov/ocr/about-us/contact-us/index.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.

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.

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 RPPR, 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: http://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

Traci Heath Mondoro, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0050
Email: [email protected]

Patricia Noel, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0222
Email: [email protected]

Emily A. Tinsley, Ph.D., M.S.
Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0519
Email: [email protected]

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0287
Email: [email protected]

Anthony Agresti
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8014
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.