Required Application Instructions

It is critical that applicants follow the 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

There is an urgent need for development of new treatments and for testing of existing clinical management strategies in adult populations with chronic pulmonary diseases and obstructive sleep apnea. To facilitate efficient conduct of both inpatient and outpatient studies in "real world" settings, the NHLBI is establishing a novel structure: the Pulmonary Trials Cooperative (PTC). The PTC will carry out multiple clinical studies in a variety of chronic pulmonary conditions, including but not limited to interstitial lung disease (ILD), pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), sarcoidosis, and obstructive sleep apnea. Asthma, and acute lung injury and critical care, are specifically excluded to avoid overlap with current programs. By studying multiple chronic pulmonary conditions in a single large program, the PTC will enable studies across a wide range of pulmonary diseases; encourage studies of patients with comorbid or intermediate conditions; involve a wide range of institutions, from major medical centers to community-based providers, in the recruitment, retention and follow-up of research subjects; and increase the efficiency of subject recruitment at individual sites by strongly encouraging the use of local medical information systems for the identification of potential research subjects.

This funding opportunity announcement (FOA) solicits applications (U01) for Protocol Leadership Groups (PLGs) to develop protocols and support the Lead Investigators in the conduct and analyses of these trials. Multiple PLGs will cooperate with a single Network Management Core (NEMO), which will have primary responsibility for organizing and operating the PTC. A companion FOA (RFA-HL-15-016) requests applications for the NEMO.

Each awarded PLG will be expected to finalize the design of a single, simple, pragmatic clinical trial (Phase 2 or Phase 3); to provide a Lead Investigator for oversight of the study during implementation; and to perform all aspects of centralized protocol data management, including support for screening and randomization, electronic transfer and collection of individual data in a central database, error checking and data quality control, and study analysis. In addition to the Lead Investigator, PLGs teams must include an investigator with expertise in statistical design and analysis as required to produce a complete protocol and manage the data collected. To this end, multiple PD/PI applications are encouraged. The PLGs are expected to cooperate with the NEMO and a network of 20-40 Clinical Centers assembled by the NEMO. The NEMO will coordinate Clinical Center activities and disperse protocol funds to support trial operations. Other than focusing on adult chronic pulmonary diseases or obstructive sleep apnea, no constraints are imposed on PTC trials with regard to interventions, subject characteristics, or sample size, except those implicit in the 4-year project period and the budgetary restrictions. The exact number depending overall on the nature and extent of the investigations proposed and the availability of funds.

PLGs will have primary responsibility for developing study forms and implementing a data management system for the specific protocol they propose. PLGs will also process, tabulate and report, in accordance with NHLBI policies, adverse events (AEs), provide quality control for the trial they propose, and analyze study data and draft the main study manuscript. If biospecimen collection is proposed as part of the trial, this should be appropriately justified in the PLG application, but responsibility for maintaining a biospecimen repository will reside with NEMO.

The PI(s) of each PLG will serve on an operations committee (OC) with primary responsibility for implementation, oversight, continuing evaluation, and reporting of PTC studies. The OC will also include the PI(s) of NEMO, rotating representatives of the Clinical Centers, one program official from the NHLBI, and a Chair appointed by the NHLBI (see RFA-HL-15-016). The PI(s) of each PLG awarded will vote only on general issues and on matters regarding their own protocol. A DSMB will also be established in accordance with NHLBI policies (see http://www.nhlbi.nih.gov/funding/policies/dsmpolicy.htm) to act as an independent advisory group to the NHLBI Director on issues of human subject safety and privacy, study integrity, and study progress.

Complementary Roles of PLGs and NEMO

NEMO will recruit and manage a network to implement protocols of the PLGs. The following table summarizes and clarifies the complementary functions of PLGs and NEMO. For a more detailed description, see RFA-HL-15-016.

Table: Summary of Functions

Protocol Leadership Groups (PLGs)

Network Management Core (NEMO)

Develop a protocol, serve as Lead Investigator for that protocol, and manage and analyze study data Obtain Food and Drug Administration (FDA) regulatory approval for the trial, including Investigational New Drug/ Investigational Device Exemption (IND/IDE) or exemption as needed Develop and maintain a secure web-based data entry system and associated case report forms. To the extent possible, common data elements and re-usable forms that are applicable in trials of different interventions and in a variety of pulmonary diseases should be employed. Make forms available to NEMO for use in other trials Randomize subjects to different study arms Maintain updated status reports of the trial on ClinicalTrials.gov Procure drugs and placebos, test and label, as needed Manage protocol data; provide data quality assessment and quality control; perform data cleaning and statistical analyses of data; using a data system that protects patient confidentiality at all steps in the submission and analysis of clinical trials data and ensure the technical integrity and security of the dataset Analyze biospecimens (if part of the protocol) Prepare manuscripts and publish results Prepare datasets for submission to an NHLBI data repository Process, tabulate and report AEs in accordance with NHLBI policies Identify study outcomes or unanticipated problems that might compromise subject safety and necessitate changes or termination of the studies Generate periodic reports to the NHLBI and the DSMB

Organize a network of Clinical Centers capable of conducting the breadth of PTC trials. With approval from NHLBI, distribute funds to activate efficient processes for identifying and contacting potential research participants Train and certify Clinical Centers staff Verify IRB approvals Create and maintain a 508 compliant web-site Maintain official study documents, inclusive of manuals of Standard Operating Procedures (SOPs) Schedule, organize, and accommodate all PTC committees and board meetings and teleconferences Distribute protocol-specific funds to the Clinical Centers on a per-patient basis via master trial agreements Monitor clinical center activities with site visits as needed Distribute drugs/placebos Store biospecimens Generate periodic reports to the NHLBI and the DSMB Monitor participant retention, protocol adherence, research subject safety and protection according to NHLBI and other government and regulatory policies Report the demographic characteristics of enrolled populations and implement remediation plans imposed by NHLBI to ensure nationally representative participation of women and minorities in PTC studies Identify study outcomes or unanticipated problems that might compromise subject safety and necessitate changes or termination of the studies

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) 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 PDs/PIs for the PLGs should have expertise in successfully designing, managing data for, and analyzing multi-center clinical trials in adults with chronic pulmonary diseases or sleep disordered breathing. Multiple PI leadership is encouraged.

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).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

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

The letter of intent should be sent to:

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (express mail ZIP: 20817)
Telephone: 301-435-0270
Email: nhlbichiefreviewbranch@nhlbi.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. The application should list the following sections:

a) Overall

b) Trial design

c) Data Management and Adverse Events Monitoring

d) Biospecimen justification

e) Plans for cooperation with NEMO

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

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

Other Attachment: Applicants are expected to provide a detailed draft protocol document as Other Attachment. This document should:

1) Summarize critical knowledge or information pertinent to the lung disease and intervention;

2) Demonstrate feasibility of the intervention;

3) Estimate intervention parameters;

4) Include statistical design parameters for the conduct and analysis of the trial;

5) Estimate the short and long term impacts of the intervention on the patient population specifically affected by the disease targeted;

6) Address recruitment and retention issues related to study population, intervention, and outcome;

7) Address whether adequate adherence to the treatment can be monitored and is achievable;

8) Identify standardized and validated survey instruments to be employed and, if using a population that differs culturally from the population for which the instruments were originally designed, demonstrate validity in that new population;

9) Describe training that will be required for Clinical Center staff to carry out the protocol. The protocol will be peer reviewed, but may be cooperatively refined, after grant award, with input from the various PTC components, namely the NEMO, DSMB, and OC.

All instructions in the SF424 (R&R) Application Guide must be followed. Applicants must identify professional staff and their qualifications needed to carry out all functions of the PLG, especially with regard to trial management, biostatistical analysis, and safety monitoring of the trial proposed. Applicants are strongly encouraged to name an experienced research team that will support the project management and implementation of the trial, and to list additional clinical research expertise they could draw upon on an as-needed basis, as well as any research resources they have established at their institution. Personnel must provide expertise in clinical trial design, biostatistics/statistical analysis, pulmonary medical expertise required for clinical and safety monitoring, as well as personnel with specialized knowledge related to the intervention or the population to be enrolled (e.g., chronic pulmonary or sleep disorders clinical trials and/or statistical and data coordination). Describe how key personnel are well-suited for their designated tasks, such as coordination, clinical data management (including establishing procedures and a study database, performing quality control, creating a website, and study-specific training), and statistical/analytical support. Describe experience in and/or a track record of carrying-out key tasks in a timely manner, including but not limited to successfully designing, implementing, and completing single- or multi-center clinical trials as well as working in a collaborative manner.

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

A detailed budget for the PLG trial management activities should be presented and must include activities related to implementing the protocol; close-out phase activities; participation in investigator meetings, OC and other leadership committee functions; site AE monitoring, communication, documentation, and reporting; support of study drug management. The budget should also include travel costs for one trip each year for two team members to attend OC meetings in Bethesda, MD, and other travel related to network operations. Budget requests to support trial management activities may not exceed $225,000 direct costs in any year (excluding consortium F&A).

The application budget should include costs to support one protocol over the project period. A detailed budget for the proposed trial should be entered in Section F. Other Direct Costs:

Line 8 should be identified as Protocol Costs and the corresponding protocol costs should be entered under Funds Requested ($) in this line. Costs for trial participant enrollment, treatment and follow-up (capitation costs), inclusive of drug procurement costs, when appropriate, should be estimated. Budgets need to reflect the actual needs of the proposed project.

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: The specific aims of the trial as well as the analysis of the results must be clearly and concisely presented. These should include a clear specification of the primary and major secondary endpoints (if any) to be measured, with discussion of the significance of various endpoints.

Research Strategy: The Research Strategy should be organized in a manner that will facilitate peer review. The Research Strategy must present an overview of the state of the science, current status and relevance of the trial, a discussion of the specific protocol, and the plan for data collection and analysis.

Significance: The significance of the proposed simple, pragmatic clinical trial must be clearly stated. It is particularly important that there be a discussion of how the trial will test the proposed hypotheses. The application should make clear the need for the study with emphasis on how the results will advance clinical practice. 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. If a Phase III clinical trial is proposed, indicate how the trial could potentially change clinical practice or practice guidelines.

Approach: The studies that led to the proposed clinical trial should be presented. Data from pilot studies which show the need for and the feasibility of the trial should also be presented. Additional supporting data from other research should be included so that the approach chosen is clearly justified. The protocol presented must allow for an overall assessment of the likelihood of the successful completion of the trial.

Experimental Approach: The proposed experimental approach should include a randomized, prospective design and the rationale for a pragmatic, simple trial that can be implemented in a variety of healthcare settings. The study of patient populations with co-morbid conditions or not well characterized phenotypically is encouraged.

Provide a clear description of the study population, including the characteristics of this population such as subject eligibility and inclusion/exclusion criteria; and why it is an appropriate group to answer the question. Document that the subjects can be recruited.

Provide a description and discussion of the specific protocol and the approach to data collection and analysis; recruitment and enrollment plans; methods of randomization; primary and secondary and outcome measures; treatment and any follow-up procedures. Statistical methods should be proposed that could be appropriately matched to the study design and include proposals for sample size and power calculations, plans for analyses, and data management and quality control procedures.

Provide recruitment and enrollment plans, including a discussion of where to find subjects for the proposed study. Discuss how an enrollment center could recruit and retain the proposed number of subjects (e.g., include a plan to monitor accrual, including women and minority subjects). Provide data supporting recruitment and retention estimates. For cluster-randomized trials, attention to recruitment of the groups as well as the subjects within the groups is needed.

Provide a detailed description of the intervention to be tested (clinical or behavioral).

Provide a description and justification for all clinical, laboratory, physiological, and/or behavioral tests needed to answer the research questions. If biospecimen collection is proposed as part of the trial, this should be appropriately justified.

Discuss any potential biases or challenges in implementing the research protocol and how they will be addressed.

Applicants should describe the SOPs they have in place and the processes they use when coordinating multi-center projects.

Applicants should document their experience in project and data management of recent trials and describe the collaborative leadership structure used.

Data Management and Quality Control: Discuss any special issues related to blinding of study results, data confidentiality, and subject privacy.

Statistical Methods: The application should discuss options for the randomization scheme, power analysis, and sample size justification. Sample size and power calculations should link to the primary and secondary endpoints. The effect size used in power calculations should be specified and justified.

Protection of Human Subjects:

ClinicalTrials.gov Registration

The human subjects section should describe plans for registering the clinical trial in the ClinicalTrials.gov registry.

Letters of Support: Provide letters of support as needed to document commitments of institution and other parties involved (e.g., institutional commitment of study importance/feasibility).

Institutions should document commitment to the PD/PI by providing departmental and institutional support letters and are encouraged to demonstrate appropriate commitment such as protected time, departmental research leadership position, facilities, space, or resources for the PD/PI).

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) 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: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

A copy of the clinical protocol and a copy of the consent form template must be provided in the Appendix.

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

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

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 by the Center for Scientific Review and responsiveness by the National Heart, Lung, and Blood Institute (NHLBI), NIH.

Applications that are incomplete and/or nonresponsive will not be reviewed. Applications proposing trials in asthma, acute lung injury, or critical care, and in pediatric populations or studies that cannot be completed within the 4-year grant period are non-responsive to this FOA.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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.

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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? If the primary outcomes of the trial are achieved, how critical will the information be to overcoming or addressing key challenges in the field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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? Are the responsibilities of key staff members well-suited to their expertise? Will the application(s) involve the appropriate personnel to ensure appropriate coordination, clinical data management (including establishing the database and performing quality control), and statistical/analytical support? Does the PD(s)/PI(s) provide evidence of experience in and/or a track record of working collaboratively? Does the PD(s)/PI(s) have a track record of carrying-out key tasks in a timely manner, including but not limited to successfully designing, implementing, and completing single- or multi-center clinical trials? Does the PD(s)/PI(s) have a successful track record in chronic pulmonary or sleep disorders clinical trials and/or statistical and data coordination? Are the investigators prepared to carry-out the key tasks in a timely manner, including, but not limited to establishing procedures, the web site, and specific training?

Innovation

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? For Phase III clinical trials, how will the proposed clinical trial potentially change clinical practice or practice guidelines?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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? Is the study designed to address outcomes that will be informative and reportable? Is the study planning to appropriately power the answer to the research question, test the proposed hypothesis/hypotheses, and collect the necessary data? Is the trial designed to conduct the research in an efficient way?

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? Is the planned recruitment sound? Is the plan to monitor accrual adequate? Are the proposed data management and quality control procedures adequate? Are the proposed analyses appropriate?

Environment

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? Does the institution provide departmental and institutional letters that demonstrate appropriate commitment for the PD/PI(s) such as protected time, departmental research leadership position, facilities, space, or resources?

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.

• Are interactions/communications between the PLG and NEMO clearly described and creatively optimized?

Protections for Human Subjects

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.

Inclusion of Women, Minorities, and Children

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.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

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.

Capitation Costs

Are the estimated capitation costs commensurate with the research to be performed?

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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).

Resource Sharing Plans

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) Genome Wide Association Studies (GWAS).

Budget and Period of Support

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.

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 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.

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

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

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

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

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

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

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 primary 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:

• All aspects of their study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators. The awardee agrees to accept close coordination, cooperation, and participation of NIH staff in those aspects of scientific and technical management of the study including those outlined under "NIH Responsibilities".
• Awardees will participate in regular meetings and teleconferences and will support any committees, task forces, and advisory panels as needed.
• Support or other involvement of industry or any other third party in the study--e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIH support; or special access to project results, data, findings, or resources--may be advantageous and appropriate.
• Award recipients will own the rights in any tangible work products created under the terms of the cooperative agreement. Work products may include such things as research reports, papers, research, findings, training curricula, data sets, books, patient tools, and other materials. All such products shall be made accessible to the public and are subject to Government rights of access, as appropriate, in accordance with NIH’s legal directives and authorities.

NIH staff has substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The NHLBI Project Scientist will have access to the data and work with the PD(s)/PI(s) to ensure the objectives of the program are being met. The primary responsibility for the program resides with the awardee, although specific tasks and activities will be shared among the awardee and the NIH Project Scientist.
• The NHLBI reserves the right to phase out or curtail the award (or an individual component of the award) in the event of inadequate progress.
• The NHLBI Project Scientist will act as a resource and facilitator for activities of the awardee with other NIH, DHHS, or other federally-sponsored research networks that may be relevant to this effort.
• The NHLBI Project Scientist will serve as a resource to provide scientific/programmatic support during the accomplishment of the clinical trial by participating in the design of the activities, advising in the selection of sources or resources, advising in management and technical performance, or participating in the preparation of publications.
• The NHLBI Project Scientist will participate in the monitoring of recruitment, retention and follow-up of study participants, and monitoring of data integrity and quality control through consideration of annual reports, site visits, patient logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting patient enrollment targets, adherence to uniform data collection procedures, gender and minority representation and the timeliness and quality of data reporting.
• The NHLBI Project Scientist will assist in the development and modification of study protocols, meeting regulatory requirements, and monitoring patient safety.
• The NHLBI Project Scientist will interact with the PD(s)/PI(s) on a regular basis to monitor progress. Monitoring may include: regular communication with the PD(s)/PI(S) and her/his staff, periodic site visits, fiscal reviews, and other relevant stewardship matters.
• NHLBI will establish a Data and Safety Monitoring Board (DSMB) in accordance with NHLBI policies to provide expert advice to the institute regarding study performance and human subject protection. Members of the DSMB will be independent of the study and free of conflict of interest. The NHLBI Project Director will operate as the executive secretary for all DSMB meeting attending both open and closed sessions.
• Additionally, an NHLBI Program Official will be responsible for the normal scientific and programmatic stewardship of the award, and will be named in the award notice.

Areas of Joint Responsibility include:

• The PD(s)/PI(s) provide, in concert with the NHLBI Project Director, support necessary to ensure that sites and investigators, and NHLBI and other research partners fully comply with federal regulatory requirements, including but not limited to those relating to human subjects protections, informed consent, and reporting of adverse events.
• Awardees and NHLBI will jointly develop appropriate confidentiality procedures for data collection, processing, storage and analysis to ensure the confidentiality of data on individual health care provider organization patients, health care providers and other institutions.
• All awardees and NHLBI will cooperate to ensure the timely and broad dissemination of lessons learned, to inform researchers and health care systems engaged in research in health care settings.
• An Operations Committee (OC) composed of three Clinical Center PIs on a rotating basis (as described in the Network Structure management section), the NEMO PD/PI(s), the PLG PDs/PIs who originated the trial idea, and the NHLBI Project Scientist will be the main governing body of the network. The NHLBI will appoint an OC Chair who may or may not be independent of the Clinical Centers and NEMO, to preside over OC meetings and serve as the OC representative to DSMB.

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 investigator chosen without NIH staff voting from among the PI of the FOA, one

NIH designee and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. 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 annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

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

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

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: GrantsInfo@nih.gov

Antonello Punturieri, M.D., Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0230
Email: punturieria@nhlbi.nih.gov

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

Catherine Sanchez
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-402-3839
Email: sanchezc@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 Parts 74 and 92.