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

Purpose

The purpose of this UG3/UH3 Funding Opportunity Announcement (FOA) is to retrospectively identify and then prospectively compare the best practices being used by primary care providers (PCP) in the United States (US) to manage asthma. The Managing Asthma in Primary Care (MAP) Program will consist of three functional units, including a Primary Care Network (PCN), a Data Management Team (DMT), and a Clinical Consultant Team (CCT). In the UH3 phase, these units will collaborate to collect data from existing electronic health records (EHRs) using common data elements (CDEs) to capture the characteristics of patients with asthma managed in primary care, their care providers and practice settings, the current management practices (CMPs) or treatment plans used, and the patient outcomes. By the conclusion of the UG3 phase, prospective clinical trials comparing the CMPs that appear most effective in specific patient groups based on the retrospective EHR analysis will be ready to begin. Subsequently in the UH3 phase, the three units will conduct the clinical trials to assess those CMPs that were determined to be most effective in specific populations of patients with asthma who are managed in primary care.

A Bioinformatics Group (BIG) will be funded separately and will have primary responsibility for data analysis. The BIG is described in more detail in the companion FOA, RFA-HL-19-006.

Background

The usual translational research process, which relies on replicated, randomized controlled trials (RCTs) for each particular therapeutic intervention in specific patient groups, is limited in its ability to inform all of the potential questions that may arise in clinical practice and to assess all of the potential management plans that care providers might prescribe. This is especially problematic for conditions such as asthma, a heterogeneous disease that affects a diverse population of patients, for which numerous therapeutics can be used, and for which many nonpharmacological resources are available to provide or facilitate patient care. The results of RCTs may have limited generalizability given the small proportion of the 24 million affected by asthma in the US who participate in RCTs, the limited involvement of primary care providers (PCPs) and their patients in these trials, and the diverse demographics of individuals with asthma in the US.

With the widespread availability of the EHR and by developing disease-specific common data elements (CDEs; standardized terms for the exchange of data among EHRs), investigators now have the potential to overcome some of the limitations of the traditional translational process and augment the knowledge gained through RCTs using data that exists in the primary care environment. Specifically, data from a diverse patient population that is representative of all asthma patients in the US (not only those who might participate in a randomized controlled trial) who receive their care in a variety of primary care settings can be studied both retrospectively as well as prospectively. In addition, all of the CMPs that PCPS actually use in specific circumstances, including not only medications but also other resources that can be used by patients or care providers, can be defined using CDEs.

Structure

To complete the objectives of the MAP program, three distinct units will collaborate to collect retrospective data and design clinical trials in the UG3 phase, then conduct prospective clinical trials in the UG3 phase.

Phases of Award

The UG3 phase will support the development of asthma CDEs to be collected from the EHRs, a prioritized list of asthma outcomes to be measured, any requisite regulatory approvals [such as Institutional Review Board(IRB)/Data and Safety Monitoring Board (DSMB) approval] prior to the initiation of both the retrospective and prospective clinical trials, retrospective data collection from the EHRs using CDEs, transfer of data to the BIG, and then design of the prospective clinical trials based on the results of the retrospective analysis. Applicants are strongly encouraged to address a comprehensive project management plan that includes consideration of the feasibility of completion of on-time and on-budget performance milestones. All necessary activities needed to allow the prospective clinical trials to be successfully launched with adequate resources at the onset of the UH3 award should completed during the UG3 phase. Enrollment into the prospective clinical trials is expected to begin at the onset of the UH3 award. Subject to NIH funding availability and scientific priorities, UH3 awards will be made after administrative review with particular attention to the extent to which the milestones established for the UG3 phase have been met. If the UH3 is funded, an additional administrative review will be scheduled within the first two years of the UH3 to assess progress toward UH3 milestones, including enrollment milestones and data collection (completeness).

Milestones

Coordination of the efforts of multiple units (PCN, DMT, CCT and BIG) to achieve the program objectives in a timely manner will be monitored through the use of milestones. A milestone is defined as an accomplishment on a specified project timeline. Milestones signify the completion of a major project stage or activity. Progress from the UG3 phase to the second (UH3) phase of the program will be contingent on completion of the UG3 milestones. Satisfactory completion of UG3 milestones will be assessed administratively to determine eligibility to transition to the UH3 implementation phase. This FOA seeks applications that include a series of comprehensive milestones for completion of the clinical trials (in the UH3 phase) and provide contingency plans to proactively address potential delays in meeting the milestones. Applications will also include a PCN project management plan that will describe the plans and processes to ensure milestone completion based on the coordinated efforts of all units. In addition, NIH staff, in collaboration with the awardee, will closely monitor progress at all stages. If at any time the project fails to make satisfactory progress toward meeting milestones (e.g., recruitment falls significantly below the projected milestones for recruitment), NIH may consider ending support and negotiating a phase-out of the award. Continuation of the award is conditional upon satisfactory progress in meeting milestones and subject to the availability of funds.

Examples of Current Management Practices (CMPs) that could be compared in prospective clinical trials:

For illustrative purposes only, the following examples describe hypothetical groups of patients with asthma and potential treatment approaches that could be compared in clinical trials conducted by the PCN. The actual groups of patients and interventions to be tested (in the UH3 phase) will be based on analyses of retrospective data collected during the UG3 phase.

Practices intended to improve medication adherence could be tested in patients with asthma who had at least one emergency room or unscheduled visit to their PCP in the previous year despite receiving a prescription for at least one controller medication. For example, the following two CMPs could be compared: 1) a pharmacy service that automatically sends patients reminders for prescription refills and allows "one click" refills or 2) an online educational video demonstration of asthma self-management, including how to use a variety of devices that deliver inhaled medications. Effectiveness could be measured as absence of an emergency room or unscheduled PCP visit in the six months following randomization. The analysis could be stratified with respect to first language (primary English speaker or not primary English speaker) of the patient if the efficacy of specific CMPs appeared to vary by first language.

Asthma patients who have not had an emergency room visit or unscheduled visit to their PCP within the past year could be divided into 6 sub-groups based on their currently prescribed asthma regimen (rescue medication only, as-needed controller, and scheduled controller) and the primary care practice location (rural or urban). A separate trial could be conducted in each group. For example, those on a scheduled controller in urban settings could be randomized to either a) reduce the controller dose with office visits before dose changes to ensure control is maintained, or b) reduce the controller dose with calls from a nurse to assess asthma control before dose changes are made. Those on a scheduled controller in rural settings could be randomized to either a) reduce the controller dose with telemedicine visits before dose changes to ensure control is maintained, or b) reduce the controller dose based on scheduled text messages to provide a self-assessment tool to measure asthma control and determine dose changes. Effectiveness in both the rural and urban settings could be measured as the intervention that results in the lowest possible dose of controller medication needed without loss of asthma control (need for an emergency room visit or unscheduled PCP visit or contact).

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 not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not 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.

The PD/PI (or contact PD/PI for MPI applications) for the UG3/UH3 application is expected to be a member(s) of the PCN, noting that the role of the PD/PI(s) in the PCN is not specified (i.e., the PD/PI may be an investigator at a PCN site or have another role in the infrastructure of the PCN.

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

Bethesda, MD 20892-7924 (Express Mail zip code 20817)

Telephone: 301-435-0270

Email: NHLBIChiefReviewBranch@mail.nih.gov

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. Attachments listed below must be provided or the application will not be peer reviewed.

1. Summary of PCN membership: To summarize the information regarding PCN performance sites, a one page table must be provided as an attachment called "Summary of PCN membership.pdf". The table should include the following rows:

• Row 1: Number of primary care practices
• Row 2: Number of primary care providers
• Row 3: Range, mean, and median number of primary care providers per practice
• Row 4: Number of states in which practices are located
• Row 5: Number of counties in which practices are located
• Row 6: Proportion of practices in "mostly urban" counties (based on US census 2010 county rurality level https://www.census.gov/geo/reference/urban-rural.html (County classification look up table)
• Row 7: Proportion of practices owned or located in a hospital or university
• Row 8: Proportion of primary care providers who are physicians (with an M.D. or D.O. degree from an institution in the United States)
• Row 9: Demographic summary of sex, race, and ethnicity of primary care providers
• Row 10: Summary of primary care provider age (range, mean, median), years as primary care provider (range, mean, median), and years in current primary care practice
• Row 11: Number of patients with asthma who receive care in practices (total)
• Row 12: Summary of race and ethnicity of patients with asthma by age (less than 5 yo, 5-11 yo, 12-18 yo, 19-30 yo, 31-70 yo, and >70 yo)
• Row 13: Range, mean, median of duration of EHR data collection that will be available for transfer to the DMT
• Row 14: Range, mean, and median duration of follow up of patients with asthma with the same PCP

2. PCN Project Management Plan: A PCN Project Management Plan (PMP) must be provided as an attachment called "MAP PCN Project Management Plan.pdf" and may not exceed 3 pages. The PCN PMP should describe the strategy that will be used throughout the project to ensure that the milestones are accomplished within the specified schedule. The PCN PMP should describe:

• The role(s) of the any project leaders or managers;
• The proposed governance/leadership of the PCN and procedures that will be used to monitor and ensure progress and quality of the research;
• Processes and plans to facilitate collaboration and communication among the PCN, DMT, and CCT as well as the BIG;
• The contingency plans in the event that there is inadequate progress toward achieving the UG3 and/or UH3 milestones;
• The project's critical path (including timelines) to meet scientific objectives within budgetary limits;
• Business roles, executive decision-making, and accountability standards;
• Plans to ensure regulatory/oversight (DSMB and IRBs) review in a timely manner;
• Key methodology and standard operating procedures governing resource management, study conduct, operations/execution, and study closure;
• How the project management team will proactively identify any emerging barriers to meeting the scientific objectives of the program.

3. DMT membership: To demonstrate that the DMT has the complementary skills to complete the data management activities that are critical to complete the scientific objectives of this program, a summary of the collective expertise and clinical trial experience of the individuals must be provided as an attachment called "DMT summary.pdf" and may not exceed 3 pages. Applications should describe each of the members of the DMT, their expected role on the project, the number of clinical trials they have completed working in a similar role, number of clinical trials completed using CDEs and EHRs, number of clinical trials completed on time, and experience working with other members of the DMT and any of the sites in the PCN.

4. CCT membership: To demonstrate that the CCT has the complementary skills to complete clinical consultant activities that are critical to complete the scientific objectives of this program, a summary of the collective expertise and clinical trial experience of the individuals must be provided as an attachment called "CCT summary.pdf" and may not exceed 3 pages. Applications should describe each of the members of the CCT, their training and experience managing patients with asthma, as well as their experience with the following activities:

• Working with primary care providers;
• Developing CDEs, (describe the disease area or content);
• Writing clinical trial protocols (including the proportion of predominantly "pragmatic clinical trials");
• Working with bioinformatics experts;
• Writing clinical trial analysis plans.

All instructions in the SF424 (R&R) Application Guide must be followed. Applications must include personnel and corresponding biographical sketches for the PCN, DMT, and CCT members who are expected to be major contributors to the completion of the scientific objectives of the program. Key personnel must provide an NIH Biosketch whether or not they will receive budget support.

Document the relevant experience of each PD/PI and all Key Personnel and clearly define their roles and responsibilities in this program. In the Other Project Role Category field, specify if the person is a member of the PCN, DMT, or CCT. Please note that the PD/PI or MPIs for the application are expected to be members of the PCN, whether at a performance site or fulfilling an administrative or other role.

Ensure that a multidisciplinary team of appropriate personnel will contribute to the coordinated completion of the milestones and, therefore, scientific objectives of the program.

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

This application must include the PCN budget, and any subcontract budgets necessary for the PCN, in collaboration with the DMT and CCT, to meet its milestones. Separate itemized budgets must be prepared for each subcontract. The application must provide detailed annual budgets that will enable the PCN to meet the scientific objectives of the program. In the budget justification, provide the detailed budget needs (per year for each site and total) and an implementation and cost management plan (e.g., capitated payments for clinical trial participants).

Any subcontracts for the conduct of the retrospective study or the prospective clinical trials (e.g., for CCT) must be a subcontract to the PCN. Separate itemized budgets must be prepared for each subcontract and/or for each collaborating team.

If portions 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.

Budgets should also include the following:

• Support for key personnel to travel to a yearly in-person meeting with NHLBI program staff to be held in the Washington, D.C. area.
• Support for publication and dissemination of results.
• Support for the DSMB to review data twice annually via teleconference/webinar in the UH3 phase.
• Support for central IRB review if anticipated to be applicable.

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:

Specific Aims

Use the Specific Aims of the UG3 phase to describe how the investigators will achieve the objective of designing prospective clinical trials that include the entire spectrum of asthma patients managed by PCPs in the US, based on the evidence obtained the analysis of retrospective EHR data.

Use the Specific Aims of the UH3 phase to demonstrate how investigators will meet the objective of establishing the most effective management practices for all patients with asthma managed by PCPs in the US based on the results of the completed prospective clinical trials.

Research Strategy

Describe the planned approach to accomplish the ultimate objective of the program, to establish the most effective management practices for all patients with asthma managed by PCPs in the US. Throughout the research strategy, specify the roles and approaches that the PCN, the DMT, and CCT, will play in achieving the milestones. Explicitly specify the milestones that will be used to monitor progress and the timeline for milestone completion. Clearly delineate the strategy that investigators will use to have IRB- and DSMB-approved prospective clinical trial protocols by the conclusion of the UG3 phase and to complete the clinical trials, including data analysis, by the conclusion of the UH3 phase.

At a minimum, define the approach to be taken by the PCN, the DMT, and the CCT to complete the following milestones:

UG3 Phase Milestones

• Define a comprehensive set of asthma CDEs: The CDEs must encompass all of the potentially relevant factors that may affect (directly or indirectly) the asthma outcomes of patients managed in primary care as well as measure the outcomes. Relevant patient characteristics (including classification of their asthma), provider characteristics, clinical practice settings, CMPs (any intervention intended to affect a patient's asthma, including but not limited to pharmacological treatment, education, monitoring, and environmental assessments or modifications), and clinically relevant asthma outcomes must be captured by the CDEs. The data set provided to the BIG for analysis in the retrospective study will be strictly limited to the CDEs (though the same CDE may be collected at multiple different time points for the same individual). Subsequently, the CDEs will also be used for data collection in the prospective clinical trials. Describe in sufficient detail the approach that the CCT members will use to develop the asthma CDEs, including how they will ensure the CDEs will capture innovative interventions that PCPs may be using in practice.
• Prioritize the asthma outcome measures: Propose an approach, utilizing the expert opinions of CCT, for prioritizing the most clinically meaningful asthma outcomes that will be captured by the CDEs in the retrospective study and prospective clinical trials. The results of the trials based on these measures should provide evidence to impact the care of patients with asthma managed by a PCP. The approach to prioritization of the asthma outcomes must provide the BIG with sufficient information to select the most effective CMPs in the retrospective study (i.e., the outcomes to be measured may integrate multiple endpoints, but the approach to prioritizing or ranking CMPs must be clearly defined). Use the same outcomes in the prospective clinical trials. Propose different priorities (or goals for care) for specific patient populations. Describe the process for incorporating the perspectives of the PCN members in completing this milestone.
• Propose an approach for CMP development: The CMPs (which may be groups of interventions) will be defined by the BIG's analysis of the EHR data (without regard to the clinical appropriateness); however the CCT must propose an approach to facilitate the grouping individual interventions. When consulted by the BIG, the CCT will use this approach to achieve the (BIG's) desired number of CMPs. Explain and justify the rationale for how the CCT will group similar (though not identical) interventions. Describe the process for incorporating the perspectives of the PCN members in completing this milestone.
• Complete retrospective data collection: Describe the DMT's approach to converting EHR data into CDEs and assessing the integrity of the process. Provide a comprehensive plan (including but not limited to any resources or facilities that will be used as well as data security) for the approach to EHR data collection, from the individual PCN EHRs through the delivery of a complete dataset of asthma CDEs to the BIG. Describe where and how data will be transferred and stored.
• Write the protocols for the prospective clinical trials: Describe the CCT's process for developing new protocols for specific patient populations that will allow the relevant CMPs to be compared on the basis of the retrospective study results produced by the BIG. Summarize how the proposed PCN will provide a representative patient population for the entire US population of patients who receive asthma care from a PCP, describe the position of the potential trials along the pragmatic-explanatory continuum using the PRECIS indicators described in https://www.bmj.com/content/350/bmj.h2147 and https://www.precis-2.org, and the PCN's experience in conducting such a trial (including trials based on CDEs collected from EHR data).
• Obtain approvals of the protocols: Describe the approach to the protection of all human research subjects that will be involved in the retrospective study and prospective clinical trials, including the plan for obtaining consent, IRB approvals, and data safety monitoring oversight and approval.

UH3 Phase Milestones

• Conduct clinical trials: Describe the PCN's approach clinical trial conduct, monitoring, and oversight. The description should include but not be limited to how the EHR will be used to identify eligible subjects, make random assignments to treatment groups, identify protocol deviations and violations, and collect safety data. Include plans for data monitoring as well as monitoring the safety of subjects. Describe the anticipated burden of participation for MAP PCPs and patients with asthma. Propose approaches to minimize this burden and enhance participation of both patients and PCPs. Provide timelines for data collection, study monitoring including DSMB oversight, and data transfers to the BIG.
• Analyze and interpret clinical trial data: The CCT and PCN will interpret the results provided by the BIG and disseminate trial results.

Throughout the Research Strategy, highlight any aspects of the overall approach to the completion of the milestones that are innovative or novel.

Identify and address potential concerns related to the participation of human research subjects in both phases of the program.

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.
• For this application, explicit plans for making the asthma CDEs publicly available after the completion of the prospective clinical trials are expected to be included.

Appendix:

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

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.

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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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.

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 interventions 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 generalizable will the results from the proposed research be to the entire US population of asthmatic patients and the range of primary care settings in which they receive medical care?

How well does the CCT's plan for prioritizing asthma outcomes reflect clinically relevant measures that will impact the care of patients with asthma managed by a PCP?

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 does the proposed membership of the PCN, DMT, and CCT provide the broad range of expertise required to complete the scientific objectives of this program (including the generalizability to all patients with asthma managed by a PCP in the US, and the ability to conduct clinical research including designing and conducting prospective clinical trials using EHRs and CDEs)?

How robust is the PCN Project Management Plan? Is the approach described for coordinating the efforts of investigators likely to ensure timely completion of the UG3 and UH3 milestones?

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?

Specific to this FOA:

How likely is it that the CCT's plan for developing CDEs will capture innovative interventions that PCPs may be using in 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:

How robust are the approach and justification for grouping the interventions into CMPs?

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?

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?

Specific to this FOA:

How strong is the evidence that the PCN will be capable of conducting EHR-based clinical trials and to do so in a sufficiently large and diverse population of patients with asthma?

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)?

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.

Not Applicable

Not Applicable

Not Applicable

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 the National Heart, Lung, and Blood Institute, 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.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned 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 National Heart, Lung, and Blood 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.

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

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

Ensuring that the design and analysis of the retrospective study and prospective clinical trial(s) are completed in a timely and valid manner. To do so, PIs will define the PCN PMP in the application which will include the following plans:

• Proposed governance/leadership of the PCN
• Procedures that will be used to monitor and ensure progress and quality of the research
• Processes and plans to facilitate collaboration and communication among the PCN, DMT, and CCT as well as the BIG. This should include meeting frequency, including for the in person meetings of key personnel.
• The contingency plans in the event that there is inadequate progress toward achieving the UG3 and/or UH3 milestones;
• Business roles, executive decision-making, and accountability standards;
• Resource management, study conduct, operations/execution, and study closure

The application will also include a milestone driven timeline for which PIs will be held accountable.

NHLBI Staff Responsibilities:

One NHLBI Project Scientist will be substantially involved in this project above and beyond the normal stewardship of an NIH IC Program Official. NHLBI may elect to have a dual-role approach where a single individual may act as both the NHLBI Project Scientist and Project Officer. The NHLBI program scientist/official (PS/PO) will provide recommendations to finalize the following documents:

• PCN PMP
• Project milestones (including timelines)

In addition, the PO/PS will participate in the monitoring and meetings of the PCN, as well as the CCT and DMT when necessary based on critical activities. The PO/PS will specifically monitor trial enrollment, data completeness, DSMB activities, and ensure resource sharing.

The Division of Lung Diseases will conduct an administrative review to determine progress toward achievement of milestones near the conclusion of the UG3 phase, and another review of progress within the first two years of the CCC UH3 phase. If the milestones have not been satisfactorily met, subsequent funding years may not be approved.

The NHLBI reserves the right to phase-out or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable protocol, (b) substantial shortfall in subject recruitment milestones, core milestones mutually agreed-upon by the recipient organization and PD/PI and the NHLBI (c) substantive changes in the agreed-upon methodologies and tools with which NIH cannot concur, (d) human subject ethical issues that may dictate a premature termination, or (e) results that substantially diminish the scientific value of study continuation.

Areas of Joint Responsibility include:

Approval of the final PCN PMP and the project milestones (and timeline). The Authorized Organizational Representative (AOR) is responsible for communicating progress on achievement of each milestone for the collaborative project to the NHLBI Grants and Program Officers listed on the Notice of Award. Award continuation, even during the period recommended for support, is conditional upon satisfactory progress. If, at any time, milestones mutually agreed upon by the recipient organization and PD/PI and the NHLBI are not met, the NHLBI may consider ending support and negotiating an orderly phase-out of the award. NHLBI Grants Management and Program Officers will closely monitor progress at all trial stages including milestones, accrual, completeness of data, and safety.

Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. Support or other involvement of industry or any other third party in the study (e.g., participation by the third party; involvement of study resources or citing the name of the study or NHLBI support; or special access to study results, data, findings or resources) may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI.

NHLBI will partner with the PD/PI to ensure CDE dataset preparation and sharing in a public repository occurs.

Study investigators are strongly encouraged to publish and to release publicly and disseminate results, tools, resources and other products of the study, in accordance with the study protocols and governance. It is expected that all methods, analyses, software, and algorithms will be made available in a timely matter to the scientific community. A plan for dissemination of study results will be developed by the awardee PD/PI in collaboration with the NIH Project Scientist and incorporated as a Special Term and Condition in the NoA. Within 3 years of the end of the period of NHLBI support for the project, data not previously released and other study materials or products not previously distributed are expected to be made available 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.

Data and Safety Monitoring:

An independent Data and Safety Monitoring Board (DSMB) may be appointed by the Director, NHLBI to oversee patient confidentiality and participant safety in the clinical trials and to provide overall monitoring of interim data and safety issues, if warranted once the prospective clinical trials have been designed. Alternatively, with the approval of NHLBI, the PI(s) may be authorized to establish an institutional DSMB to provide independent oversight of the study. Meetings of the DSMB will ordinarily be held by teleconference.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the grantee, an NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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, application errors and warnings, documenting system problems that threaten on-time submission, and 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)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Michelle Freemer, MD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0202
Email: michelle.freemer@nih.gov

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
Telephone: 301-435-0270
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

Kim Stanton
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8054
Email: stantonk@nhlbi.nih.gov

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.