Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Heart, Lung, and Blood Institute (NHLBI)
Funding Opportunity Title	Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics: Clinical Centers (CC) (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	None
Funding Opportunity Announcement (FOA) Number	RFA-HL-14-027
Companion Funding Opportunity	RFA-HL-14-030, U01 Research Project Cooperative Agreements
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.838
Funding Opportunity Purpose	The purpose of this funding opportunity announcement (FOA) is to invite applications to participate in a new NHLBI Pulmonary Vascular Disease Phenomics Program (hereafter referred to as "PVDOMICS"). Teams of investigators will perform comprehensive, deep phenotyping across the current World Health Organization (WHO)-classified pulmonary hypertension (PH) clinical Groups 1 through 5 (http://www.nhlbi.nih.gov/health/health-topics/topics/pah/types.html). This program will consist of up to five clinical centers (CCs) and one data coordinating center (DCC). This FOA solicits applications for CCs and runs in parallel with a separate FOA that solicits applications for the DCC (see RFA-HL-14-030). CCs will participate in a study-wide protocol by enrolling patients and performing phenotyping, which will lead to novel subclassifications of patients with pulmonary vascular-right ventricular disease, based on molecular and radiographic as well as clinical characteristics, which can be associated with specific molecular mechanisms of pathogenesis. This research is intended to lead to identification of both endophenotypes of lung vascular disease and biomarkers of disease that may be useful for early diagnosis or for assessment of interventions to prevent or treat this condition. The common phenotyping protocol will be aimed at: (1) identifying subsets of PH patients that are similar with regard to the molecular basis of pulmonary vascular disease regardless of WHO clinical classification; (2) defining novel, clinically-relevant indices of therapeutic responsiveness to be useful as intermediate outcomes in clinical trials; (3) identifying biomarkers of disease risk and progression that can be used for early detection or as outcome measures in prevention trials. PVDOMICS will create a program-wide cohort of approximately 1,500 PH subjects and controls. A Steering Committee will be organized by the DCC to develop the study-wide protocol and monitor study operations

Posted Date	November 25, 2013
Open Date (Earliest Submission Date)	December 29, 2013
Letter of Intent Due Date(s)	December 29, 2013
Application Due Date(s)	January 29, 2014, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	June-July 2014
Advisory Council Review	August 2014
Earliest Start Date	September 2014
Expiration Date	January 30, 2014
Due Dates for E.O. 12372	Not Applicable

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

The purpose of this funding opportunity announcement (FOA) is to invite applications to participate as Clinical Centers (CCs) in a new NHLBI Pulmonary Vascular Disease Phenomics Program (PVDOMICS). This initiative is designed to advance our understanding of the genetic, pathobiologic, hemodynamic, and clinical commonalities across each clinical classification of pulmonary hypertension (PH) through phenotyping, which calls for measuring and integrating genomics, transcriptomics, proteomics, metabolomics, cell biology and tissue functioning, imaging, and other traits deemed necessary to fully describe the pulmonary vascular disease phenotype. A multidisciplinary team of investigators will be assembled to design and conduct the state-of-the-art phenomics protocol.

PVDOMICS will enroll and phenotype PH subjects as well as collect biospecimens for biomarker analyses. Up to five CCs will be supported; each led by investigator(s) with expertise in PH, pulmonary medicine, and/or cardiology. A Steering Committee (SC) of the Project Director(s)/Principal Investigator(s) (PD(s)/PI(s)) involved with the project will be organized to develop the necessary protocols and monitor study operations. This is a one-time funding opportunity to support PVDOMICS for a five-year project period.

This FOA runs in parallel with a separate FOA that solicits applications for a PVDOMICS Data Coordinating Center (RFA-HL-14-030).

Current classification of PH is based on a relatively simple combination of patient characteristics and hemodynamics, as follows:

Group 1 Pulmonary arterial hypertension (PAH)

Group 2 PH with left heart disease

Group 3 PH associated with lung diseases and/or hypoxemia

Group 4 PH attributed to chronic thrombotic and/or embolic disease (CTEPH)

Group 5 Miscellaneous

However, this clinical classification scheme is based on clinical presentation only, dictated by available treatment options, and is not tied to any molecular or cellular pathobiological mechanism. Pulmonary Hypertension is a complex, vascular remodeling disease, targeting lung vascular and interstitial cells, and involving blood- and bone marrow-derived cells as well as right ventricular myocytes and microvasculature. Furthermore, recent studies have revealed: the involvement of underlying systemic metabolic derangements, such as insulin resistance; heterogeneity of disease across individuals even with the same genetic mutations; increased prevalence of lung vascular disease in left heart failure and chronic airways diseases; and an increased number of hospitalizations and deaths among women, African-Americans, and older adults.

Rapid advances in the mechanistic understanding of the disease, improved imaging techniques, "omics" technologies, and methods for biomarker discovery now provide an opportunity to re-define PH on the basis of these measures. A modern classification of PH should integrate clinical and molecular features to stratify the condition by pathobiology, rather than clinical presentation. The systemic features of the disease, the basis for disease susceptibility, and the therapeutically amenable features of the disease should also be incorporated into the phenotypes.

Many benefits may acrue from a better understanding of PH phenotypes. First, more sensitive measures of disease may be found, allowing earlier diagnosis of disease and enabling trials of interventions intended to prevent or forestall early disease. These may also suggest disease risk. Second, endophenotypes may be identified, allowing clinical trial enrollment of cohorts that respond more uniformly to mechanism-based therapies. Third, measures of disease severity that include biomarkers as well as clinical characteristics may prove useful as surrogate outcome measures in clinical trials. In particular, outcome measures that are more sensitive and specific than the 6-minute walk distance are urgently needed to improve the efficiency and fidelity of clinical trials. Overall, a more precise classification of lung vascular disease will foster novel biological concepts and catalyze innovative research for preventing lung vascular disease development and lead to developing more efficacious, precision approaches to individual therapy.

This initiative will support collaborative, protocol driven, comprehensive phenotyping across the currently classified Groups 1 5 PH patient populations in order to define and then refine novel pulmonary vascular disease phenotypes. To accomplish the scientific objectives, the NHLBI will support a multi-center, multidisciplinary, research consortium. The consortium will consist of up to five CCs, one Data Coordinating Center (DCC), a Steering Committee (SC), and an NHLBI Project Scientist (PS). Under the SC guidance and coordination through the DCC, PVDOMICS will develop a common protocol which will be used to define novel pulmonary vascular disease phenotypes. Comprehensive analysis of lung tissue, systemic vascular biomarkers, blood and marrow cells, right ventricular indices, and molecular traits in PH patients will be attained and integrated with robust clinical measures and imaging to derive the pulmonary vascular disease phenotypes.

Individual CCs must demonstrate the capability to recruit at least the following numbers of subjects over the duration of this program: Pulmonary Hypertension (PH) patients: Group 1 PH=80; Group 2 PH=80; Group 3 PH=80; Group 4 PH=10; Group 5 PH=as available; and controls (n=50). It is expected that multidisciplinary collaboration by lung vascular researchers, imaging specialists, bioengineers, geneticists, metabolomics and proteomics experts, pulmonologists and/or cardiologists will be assembled to accomplish the research goals of developing the protocol and analyzing the data. CCs are encouraged to partner with outside organizations such as the Pulmonary Hypertension Association, the American Heart Association, the American Thoracic Society, etc. to help facilitate subject enrollment and leverage costs as feasible.

The CCs will be expected to work closely with the DCC to participate intellectually in all aspects of the consortium, including developing consortium procedures and subcommittees, writing protocols and sample informed consent, protocol cost development, and recruitment. CC Project Director(s)/Principal Investigator(s) (PD(s)/PI(s)) will be expected to develop regular communication within their CC staff, including investigators and clinical coordinators to discuss enrollment, screening, adherence to protocols, and other consortium issues.

In addition to the funds awarded directly to the CCs, funds to conduct the phenotyping protocol will be part of the DCC’s (RFA-HL-14-030) grant award and will be distributed by the DCC to the CCs in accordance with protocol budgets as capitation.

Clinical centers will be responsible for the planning and collection of high-quality biospecimens that will permit the longitudinal molecular analysis of disease pathogenesis and response to therapy. Samples will be analyzed and stored at a central laboratory repository at the DCC, at a facility subcontracted to the DCC, or transferred to NHLBI BioLINCC (https://biolincc.nhlbi.nih.gov/home/). Samples are expected to be available to the wider scientific community for mechanistic work conducted under other funding mechanisms. The DCC is required to retain samples for as long as the PVDOMICS is funded. The DCC's budget will account for sample shipping costs from the CCs to the DCC as well as for storage costs.

The field of phenomics pursues the systematic measurement and analysis of qualitative and quantitative traits (clinical, biochemical, imaging, etc.) for the refinement and characterization of phenotypes, some of which may be shared between different disease states. Research activities supported by this initiative may include, but are not limited to, the following general approaches:

1. Deep phenotyping - measuring and integrating genomics, transcriptomics, proteomics, metabolomics, cell biology and tissue functioning, and imaging and whole organism measurements to achieve a more complete description of the normal and pathophysiologic processes which are themselves traits of the organism, therefore comprising the phenotype. The goal for deep phenotyping is the identification of as many contributing individual factors or traits as possible which comprise the pulmonary vascular disease phenotype.

2. Dynamic phenotyping - incorporating multiple measurements over time and after provocation (e.g., after drug exposure in a clinical trial or after exercise), so that both variability over time and individual responses can be measured and catalogued. This approach can be used to get a complete picture of a patient with pulmonary vascular disease or, on a smaller scale, to get a complete description of a pulmonary artery endothelial cell from that patient.

3. Intermediate phenotypes (or endophenotypes) - clinical entities associated with the disease but closer to the biologic underpinnings of the disease. Endophenotypes may be more objectively defined than the disease diagnosis and may contribute to a wide spectrum of diseases, potentially linking conditions together. The ideal endophenotype is reliably-assessed and stable over time, is associated with the disease of interest, and is at least as heritable as the disease itself. For example, levels of oxidative stress, endothelial dysfunction, and mitochondrial dysfunction are potential endophenotypes.

The final research activities supported in PVDOMICS will be determined by input from all CCs selected to participate, and in collaboration with a DCC, assisted by input from the SC, such that the collective activities will involve:

• Developing a common phenotyping protocol for PVDOMICS that includes a summary of the study; the background and significance; the study design and methods including eligibility requirements, phenotypic measures, outcome assessments (as warranted) and statistical analyses; and writing a manual of operations that details the methods, procedures, and operations of PVDOMICS.
• Developing a vocabulary and definitions for key terms needed to describe novel cohorts and phenotypes.
• Identifying, screening, recruiting, and enrolling the target number of subjects.
• Phenotyping subjects at baseline and in accordance with the protocol, obtaining and processing biological specimens, performing laboratory tests, and shipping biospecimens to specified laboratories and repositories.
• Analyzing study data and disseminating study results.

The research proposed for PVDOMICS should clearly result in any or all of the following:

1. Definition of a precise lung vascular disease ontology to assist data integration across studies.

2. Identification of novel biomarkers derived from deep and/or dynamic phenotyping that may be useful as intermediate or primary outcomes in future clinical trials.

3. Identification of subpopulations of patients with lung vascular-right ventricular disease appropriate for targeted enrollment in clinical trials that:

a. Test novel, mechanistic-based therapeutics.

b. Test novel, phenotype-based management strategies.

4. Identification of endophenotypes which may reflect preclinical disease or predict prognoses.

Activities or outcomes NOT supported:

• The PVDOMICS consortium will not perform animal model studies.
• Phase III therapeutic trials of new pharmaceutics or interventions and cross-sectional studies without collection of longitudinal data are not allowed under this initiative.
• Development of a registry is not the goal of research conducted under this initiative.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NHLBI intends to commit $1,170,000 (total costs) for fiscal year 2014 to fund up to five clinical centers. NHLBI intends to commit an estimated $7,410,000 (total costs) over a 5-year period.
Award Budget	Clinical Center application budgets are limited to $150,000 (Direct Costs) in the first year and a maximum of $200,000 (Direct Costs) in each of the subsequent years (years 2-5). Budgets should reflect the actual needs of the proposed project.
Award Project Period	The scope of the proposed project should determine the project period. The maximum project period is five years.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for 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, 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
Fax: 301-480-0730
Email: [email protected]

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

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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. In addition, use the following instructions:

Facilities and Other Resources: Institution descriptions should include information about the clinics and medical facilities in which PH patients, Groups 1-5, are cared for, including a description of the numbers of patients that would be expected to be eligible for participating in the PVDOMICS observational study.

Other Attachments: Provide the following information as a single PDF file entitled (PD/PI name) PVDOMICS.pdf :

• One-page budget for the proposed phenotyping protocol (see section "R&R Budget" for suggested content and format);
• A table documenting participation in observational studies and/or clinical trials in PH patients (from any clinical Group 1-5) from the last 5 years by the PD(s)/PI(s): study title, intervention or observational objectives, dates, numbers of patients enrolled.

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

All instructions in the SF424 (R&R) Application Guide must be followed. In addition, use the following instructions:

CC applicants must submit a detailed budget for costs related to the study site operation (including investigator salaries). This budget should include travel costs to attend Steering Committee (SC) meetings as well as other travel related to PVDOMICS operations. These costs must not exceed $150,000 Direct Costs in the first year and $200,000 Direct Costs each year thereafter.

Suggested travel commitments for planning purposes:

Year 1:

• PD/PI (or PDs/PIs if a multi-PD/PI plan is used) attending two (2) SC meetings to be held in Bethesda, MD, or another convenient/central location(s).
• PD/PI (or PDs/PIs, if a multi-PD/PI plan is used) attending one (1) Observational and Safety Monitoring Board (OSMB) meeting in Bethesda, MD.
• PD/PI (or PDs/PIs, if a multi-PD/PI plan is used) attending two (2) External Advisory Committee (EAC) meetings in Bethesda, MD.

Years 2-5:

• Two SC meetings each year
• One OSMB meeting in Bethesda, MD, each year
• One EAC meeting per year in Bethesda, MD

In addition, a cost estimate for the subject phenotyping protocol and biospecimen collection and shipping for the study-wide protocol should be presented, using a budget table or spreadsheet rather than the SF 424 R&R budget forms. Phenotyping/biospecimen costs should not be included in the SF 424 R&R budget page forms or totals. For application purposes, it may be assumed that the final study cohort will be composed of approximately 1,500 PH patients and controls.

Protocol funds to perform the study-wide phenotyping protocol will be awarded to the DCC and be distributed by the DCC to the CCs on a capitation basis in accordance with budgets approved by the Steering Committee and NHLBI. For planning purposes, it is estimated that $2,000,000 for each of years 2-5 (total costs) will be available for the study-wide protocol.

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

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

Research Strategy: CC applicants should provide a detailed protocol that describes background information about pulmonary vascular disease and how PH subjects' selection and enrollment, characterization and phenotyping, and biospecimen collection and handling will be performed. CC applicants will describe phenotypic characterization protocols for pulmonary vascular disease and a plan for integrating the data obtained to use for answering research questions in future clinical trials development.

In lieu of a traditional research strategy, with the usual headings, applicants should use the following content guidelines in preparing their applications:

1. CC Organization and Recruitment Plan (recommend 4 pages).

Applicants should describe the organizational plan of the CC including:

a. A description of the key personnel and their interactions to accomplish recruitment and retention in the study-wide protocol, as well as a plan for the methods and frequency for communication within the CC for review of screening and recruitment. Previous collaborations and interactions should be described.

b. A discussion of the challenges and solutions for identification of appropriate patients across the PH clinical classification scheme (Groups 1-5). The application should describe plans to recruit patients from multiple, pertinent departments and/or clinics and/or satellite sites.

c. A narrative to prove the ability to enroll at least 88 subjects per year (years 2-4) and 36 subjects in year 5, including appropriate controls, in accordance with the following distribution for PH: Group 1 PH n=80, Group 2 PH n=80, Group 3 PH n=80, and Group 4 PH n=10. Experience in clinical trials or other large-scale observational studies, clinical catchment capacity and staffing may be part of this narrative. Applicants that do not have prior experience enrolling PH patients at the projected rate should describe plans to meet the target enrollment goals. This could include documenting volume of PH patients seen annually and the distribution of patients across the Groups 1-5 clinical classification. Institutions that are tertiary referral centers should discuss the challenges and solutions regarding identifying and recruiting eligible patients already undergoing treatment by community physicians.

2. Phenotyping Proposal (recommend 8 pages):

Applicants should describe the phenotyping activities that would contribute to a study-wide program:

a. Introduction/background: description of the importance of the study-wide protocol in the context of the current understanding of PH and pulmonary vascular disease.

b. The hypotheses or questions to be addressed by the phenotyping activities, preliminary data, rationale, and significance of the anticipated results. In preparing this part of the application, applicants should expect their proposed research strategies to be evaluated in the context of the following anticipated PVDOMICS outcomes:

(1) Definition of a precise, lung vascular disease ontology to assist data integration across studies.

(2) Identification of novel biomarkers derived from deep and/or dynamic phenotyping that may be useful as intermediate or primary outcomes in future clinical trials.

(3) Identification of subpopulations of patients with lung vascular-right ventricular disease appropriate for targeted enrollment in clinical trials (within a 5 year timeframe of PVDOMICS) that:

a. Test novel, mechanistic-based therapeutics.

b. Test novel, phenotype-based management strategies.

(4) Identification of endophenotypes which may reflect preclinical disease or predict prognoses.

c. Proposed methods for phenotyping: Include all specific tests and methods as appropriate. Include the rationale for choosing specific phenotype characteristics for integration with genetic, molecular and/or biospecimen data. Provide a description of any biospecimen collection and samples processing; applicants should propose and justify the collection of specific biospecimens (e.g., blood and bone marrow cells, right ventricular tissues, lung explants).

Applicants are encouraged to describe any special expertise or unique strengths they can offer to the collaborative effort (e.g., innovative study design, genetics/genomics/proteomics, bioinformatics, team leadership and training, patient recruitment strategies, dissemination activities, access to already characterized cohorts of patients).

d. Proposed methods of data analysis: It is expected that the phenotyping activities performed will lead to development of novel research cohorts for which interventional studies could be designed and new clinical classifications of disease proposed. Applicants should describe how the phenotyping data obtained can be analyzed and used for:

(1) identifying subsets of PH patients that are likely to be similar with regard to the molecular basis of pulmonary vascular disease regardless of WHO clinical classification;

(2) defining novel, clinically-relevant indices of therapeutic responsiveness to be useful as intermediate or primary outcomes in clinical trials;

(3) identifying biomarkers of disease risk and progression to be useful as measures for lung vascular diseases detection and prevention research.

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 modifications:

Applicants should state their general support of collaborative research and their willingness to participate in a collaborative and interactive manner with other CCs, the DCC, and the NHLBI in all aspects of the PVDOMICS program.

The DCC will be responsible for coordinating the dissemination of PVDOMICS research findings and relevant protocol materials. Applicants to this FOA for PVDOMICSCCs should indicate here their willingness to collaborate with the DCC and other SC members in dissemination efforts.

It is expected that PVDOMICS research resources, such as the Manual of Operations, study manuals, case-report forms, and phenotype ascertainment instruments will be made available to the public immediately after approval by the PVDOMICS SC and implementation into the study. The DCC applications are expected to include a plan for sharing these resources in response to RFA-HL-14-030 .

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.

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.

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

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 NHLBI, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Activities NOT supported by PVDOMICS (and therefore constituting non-responsive applications):

• The PVDOMICS consortium will not perform animal model studies.
• Phase III therapeutic trials of new pharmaceutics or interventions and cross-sectional studies without collection of longitudinal data are not allowed under this initiative.
• Development of a registry is not the goal of research conducted under this initiative.

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?

Will the phenotyping activities proposed lead to identification of novel, clinically-relevant indices of therapeutic responsiveness, to be useful as intermediate or primary outcomes in clinical trials?

Will the phenotyping activities proposed lead to identification of novel, clinically-relevant indices of disease risk and progression to be useful as measures for chronic lung vascular diseases detection and prevention research?

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?

Do the PD(s)/PI(s) have experience conducting observational and/or clinical trials in pulmonary vascular disease and Groups 1-5 PH patients?

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?

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? 

Are the phenotyping activities proposed feasible from ethical, organizational, and budgetary perspectives?

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 plan for recruiting patients into the phenotyping protocol feasible and are effective approaches for overcoming obstacles to recruitment presented?

If a center is a tertiary center, have barriers and solutions to recruitment been described?

Do the applicants demonstrate a high likelihood of achieving recruitment goals for Groups 1-5 PH patients?

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?

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.

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.

Applications from Foreign Organizations

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

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 the 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 on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the 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 the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants 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 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 following primary responsibilities:

• The Clinical Center (CC) PD(s)/PI(s) will be responsible for the overall function of all Pulmonary Vascular Disease Phenomics Program (PVDOMICS) research activities. The PD(s)/PI(s) will be responsible for oversight of protocol development, "omics" activities performance and/or coordination of performance with subconsortia, data collection, data safety and confidentiality, quality assurance, data analysis, coordination of data distribution, and implementation of all data sharing plans. The DCC PD(s)/PI(s) will be responsible for the distribution of protocol funds to the Clinical Centers. The DCC PD(s)/PI(s) will be responsible for coordination of manuscript preparation, activities of the Steering Committee (SC), External Advisory Committee (EAC), and Observational and Safety Monitoring Board (OSMB).
• Support or other involvement of industry or any other third party in the PVDOMICS studies 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. Awardees must follow NHLBI policy concerning third party agreements.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

• The PVDOMICS Project Scientist (PS) will participate in Steering Committee activities. Several procedures are in place to manage potential conflicts of interest by the PS administering the cooperative agreement. The PS adheres to stringent NIH ethics rules and financial disclosure; staff are prohibited from observing scientific review of competing applications from an investigator with whom they have published in the last three years; recruitment progress is reviewed by study-independent staff (quarterly within the Division; semi-annually or quarterly by the Observational and Safety Monitoring Board (OSMB) and supervisory staff, and annually by the NHLBI Director); the PS will generally be asked to leave the room during OSMB reviews of study results; recommendations made by the PS in annual progress reports are reviewed by a grant specialist in a separate Division (Office of Grants Management) and/or a separate NHLBI Program Official assigned to review annual progress reports and make recommendations; the PS will not seek lead authorship of primary publications and will obtain approval by supervisors to participate in secondary publications.
• The Project Scientist will work with awardees on issues coming before the Steering Committee and, as appropriate, other committees (e.g., recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, and preparation of publications). The Project Scientist will have the same access, privileges, and responsibilities regarding the collaborative data as the other members of the Steering Committee.
• The NHLBI reserves the right to phase out a study (or an individual award) in the event of (1) failure to develop or implement mutually agreeable collaborative protocol; (2) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control; (3) major breach of a protocol or substantive changes in the agreed-upon protocol with which NHLBI cannot concur; or (4) human subject ethical issues that may dictate an early phase out of the program.
• Annual continuation and level of funding for the CCs will be based on NHLBI review of actual recruitment and overall performance, determined as part of the NHLBI review of the annual non-competing continuation grant progress reports submitted by awardees.
• 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:

• Awardees agree to the governance of the study through a Steering Committee (SC). One investigator from each CC, two from the DCC, a Chairperson to be appointed by the NHLBI, and the NHLBI Project Scientist will comprise the SC. All major scientific decisions will be determined by majority vote of the SC. Each CC, the DCC, and the NHLBI Project Scientist will have one vote; the Chair will have one vote in case of a tie. Note that although the DCC is expected to have two representative participants (one with expertise in the core operations of the DCC as pertains to the common protocol activities and one with expertise in the high-throughput -omics activities being performed in PVDOMICS), in all SC meetings, the DCC has only one vote. It is anticipated that SC meetings will be held at least once a month by conference call and two times a year in person. The first year during consortium establishment and initial protocol selection may require more frequent contact.
• Interaction with an External Advisory Committee (EAC). The EAC will provide scientific advice to the SC and the NHLBI on issues of phenotyping, potential outcome measures, biospecimen processing and analysis, genetics, genomics, proteomics, data analysis, study feasibility, and the potential impact of PVDOMICS results on future clinical trials and for use in early disease detection and prevention research. EAC members will be appointed by the NHLBI. This Committee is expected to consist of approximately five voting members, three members will be from academic institutions not affiliated with PVDOMICS and two members from pharmaceutical or biotechnology companies that have made substantial contributions or commitments to lung vascular disease/PH trials and/or PVDOMICS (such as monetary contributions, subject data and specimens procured in separate studies that incorporate the PVDOMICS Protocol, or in kind contributions of high throughput specimen analyses). Additional scientific experts from these companies may attend meetings and participate in discussions of the EAC with the prior approval of the NHLBI. The EAC will meet twice during the first year and annually afterwards. The EAC members may be acknowledged as a group in publications of the PVDOMICS group, but it is expected that the members of the EAC will not participate directly in data analysis or serve as authors on PVDOMICS papers.
• An independent Observational and Safety Monitoring Board (OSMB) will be appointed by the Director, NHLBI to provide overall monitoring of study performance, interim data, and safety issues. An NHLBI scientist, other than the NHLBI Project Scientist, shall serve as Executive Secretary to the OSMB.

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 Steering Committee chosen without NIH staff voting, 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)

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TTY: 301-451-5939
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
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Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
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GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY: 301-451-5936
Email: [email protected]

Timothy M. Moore, MD, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0222
Email: [email protected]

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

Anthony Agresti
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0186
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.