Participating Organization(s)
National Institutes of Health (NIH)
Components of Participating Organizations

National Heart, Lung, and Blood Institute (NHLBI)

Funding Opportunity Title
Rare Disease Cohorts in Heart, Lung, Blood and Sleep Disorders (UG3/UH3 Clinical Trial Not Allowed)
Activity Code
UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement
Announcement Type
New
Related Notices
None
Funding Opportunity Announcement (FOA) Number
RFA-HL-20-014
Companion Funding Opportunity
UG3/UH3 Exploratory/Developmental Phased Award - Cooperative Agreement
Catalog of Federal Domestic Assistance (CFDA) Number(s)
93.837, 93.838, 93.839, 93.840, 93.233
Funding Opportunity Purpose

The purpose of this FOA is to fund research centers that will establish longitudinal cohorts in rare HLBS diseases to investigate unaddressed research questions using epidemiologic study designs and methods that are appropriate for conditions affecting fewer than 200,000 persons in the US. These observational cohort studies should be designed to provide an evidence base for future interventional studies, including clinical trials; for developing better diagnostics than those that are currently available; for answering early translational questions; or for broader implementation of guidelines for managing these diseases.

This program will provide opportunities to advance rare disease research using genetics and deep phenotyping to characterize the disease and to identify disease sub-types; to use data science methods that integrate clinical and patient-reported outcomes with laboratory, imaging, environmental and -omics data to understand the natural history of disease; to generate data that differentiate patients with the same morphological phenotype but different genetic mutations and severity of outcomes; to elucidate genotype-phenotype interactions and multisystem phenotyping to develop reliable and valid predictive tools to determine who will respond to which treatments and when to intervene; and to encourage innovative methods such as telemedicine to include participants with rare diseases located in remote locations.

This initiative will allow applicants to study rare or related rare diseases, disorders, conditions or syndromes together based on pathogenesis, affected biochemical, cellular or physiological features or organ system involvement. Studying related rare diseases within the same cohort could help understand the nuances, and knowledge gained from one disease could accelerate the advances in related diseases. For example, investigators may propose to study hemoglobin disorders rather than only sickle cell anemia or thalassemia.
Posted Date

April 4, 2019

Open Date (Earliest Submission Date)
May 18, 2019
Letter of Intent Due Date(s)

30 days prior to the application due date

Application Due Date(s)
June 18, 2019, June 17, 2020 by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

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

October 2019, October 2020 

Advisory Council Review
January 2020, January 2021
Earliest Start Date

April 2020, April 2021

Expiration Date
June 18, 2020
Due Dates for E.O. 12372
Not Applicable
Required Application Instructions
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from 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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.
  4. Table of Contents

Background

The National Institutes of Health (NIH) and Food and Drug Administration (FDA) define rare diseases as those that affect fewer than 200,000 people in the US. Despite advances and opportunities for research in heart, lung, blood and sleep (HLBS) disorders, difficulties remain in managing rare HLBS diseases. The major challenges are lack of natural history studies that enable well-defined phenotypes and diagnostic criteria, and lack of longitudinal data on patients that enable predictive modeling and precision medicine.

While each rare disease affects fewer than 200,000 individuals in the US, the burden of disease is large. There are almost 7,000 rare diseases affecting more than 25 million Americans and their families. Approximately 80% of rare diseases are genetic; 50% of those affected are children and 30% of them will not live to their 5th birthday. Only five percent of rare diseases have an FDA-approved treatment. Many of these 7,000 rare diseases are HLBS disorders and within the NHLBI’s research mission.

Further, rare diseases pose challenges to identify and coordinate resources and expertise for small populations dispersed over wide geographic areas. Rare disease research requires multidisciplinary collaboration among scientists sharing resources and patient populations. Rigorous characterization and longitudinal assessment are needed to understand rare HLBS disease natural histories; to facilitate biomarker validation for diagnosis, disease progression, and responses to therapy; to identify molecular pathways and therapeutic targets; and to develop the mechanistic rationale for new treatments.

Rare diseases do not easily lend themselves to large epidemiologic studies; however, epidemiological methods and designs can be applied to rare diseases, such as observing the natural history of disease progression, characterizing genotype-phenotype interactions, and determining patient outcomes across the lifespan and during key developmental stages. Rare disease research can potentially generate large volumes of data ("Big Data") that are amenable to innovative data science methods and informatics and that can enable common data models, computational analyses of molecular, -omics, clinical, psychosocial and environmental data to identify mechanisms, predictive models and patient-level outcomes.

Investigation of rare diseases can also lead to advances for patients with common diseases. For example, research on familial hypercholesterolemia led to the discovery of statins and PCSK9 inhibitors. Cystic fibrosis research on CFTR (cystic fibrosis transmembrane conductance regulator) led to an increased understanding of pathological changes in chronic obstructive pulmonary disease (COPD). Mechanistic studies of immune thrombocytopenic purpura (ITP) can be generalized to better understand platelet biology.

The NHLBI expects that investigators funded through this Funding Opportunity Announcement (FOA) will provide an evidence-base for future interventions or diagnostics, demonstrate proof of principle for drug development, and/or answer early translational research questions. Cohorts designed to answer questions relevant to implementation outcomes are also encouraged such as previous study populations that could benefit from adoption of guidelines in remote locations and/or among underserved populations with rare HLBS diseases. These could include newborn screened populations that are insufficiently followed after diagnosis with an HLBS disease in the US Department of Health and Human Services Recommended Uniform Screening Panel.

Program Purpose and Objectives

The purpose of this FOA is to fund research centers that will establish longitudinal cohorts in rare HLBS diseases to investigate unaddressed research questions using epidemiologic study designs and methods that are appropriate for conditions affecting fewer than 200,000 persons in the US. These observational cohort studies should be designed to provide an evidence base for future interventional studies, including clinical trials; for developing better diagnostics than those that are currently available; for answering early translational questions; or for broader implementation of guidelines for managing these diseases.

This program will provide opportunities to advance rare disease research using genetics and deep phenotyping to characterize the disease and to identify disease sub-types; to use data science methods that integrate clinical and patient-reported outcomes with laboratory, imaging, environmental and -omics data to understand the natural history of disease; to generate data that differentiate patients with the same morphological phenotype but different genetic mutations and severity of outcomes; to elucidate genotype-phenotype interactions and multisystem phenotyping to develop reliable and valid predictive tools to determine who will respond to which treatments and when to intervene; and to encourage innovative methods such as telemedicine to include participants with rare diseases located in remote locations.

This initiative will allow applicants to study rare or related rare diseases, disorders, conditions or syndromes together based on pathogenesis, affected biochemical, cellular or physiological features or organ system involvement. Studying related rare diseases within the same cohort could help understand the nuances, and knowledge gained from one disease could accelerate the advances in related diseases. For example, investigators may propose to study hemoglobin disorders rather than only sickle cell anemia or thalassemia.

NHLBI expects investigator teams to be multidisciplinary including subject matter experts in the fields required to answer proposed research questions. Applicants will be encouraged to include junior investigators on their teams. Project teams will be expected to collaborate with patient advocacy organization(s), if one exists, to identify unaddressed research questions important to patients for the rare disease being studied and to help with recruitment and retention.

To address knowledge gaps and increase the evidence base for future research, this FOA will support natural history and epidemiological studies that advance insights into molecular, genomic, environmental and lifestyle determinants of rare HLBS diseases and their outcomes leading to diagnostic and therapeutic strategies that meet FDA requirements for drug development tools.

Each research center will have a study-specific Steering Committee that will be responsible for overseeing the development, conduct, data management, data analysis, and dissemination of findings for the proposed cohort. Each study Steering Committee will be chaired by the Program Director/Principal Investigator (PD/PI) for the specific cohort and will include NHLBI Program Official(s) as well as appropriate subject matter experts and patient advocacy group representation, as appropriate. Because the NHLBI is committed to advancing fields in data science, awardees should commit to collect data as findable, accessible, interoperable and reusable (FAIR Data Principles, Wilkinson et al., 2016) and to data sharing.

Specific Areas of Research Interest

Research supported by this FOA should fall within the NHLBI mission of heart, lung, blood and sleep (HLBS)-related disorders. Some examples of eligible rare HLBS diseases underrepresented in the current NHLBI portfolio include:

Rare Blood Diseases

Acquired aplastic anemia, antiphospholipid syndrome, Creutzfeldt-Jakob disease, Cooley’s Anemia, Fanconi Anemia, hemophagocytic lymphohistiocytosis, hemophilias, hereditary hemorrhagic telangiectasia, heparin-induced thrombocytopenia, paroxysmal nocturnal hemoglobinuria, rare bleeding disorders, rare nutritional anemias, rare thrombotic disorders, rare hemolytic anemias, thrombocytopenias of different etiologies, thrombotic thrombocytopenic purpura

Rare Lung Diseases

Alpha-1-antitrypsin deficiency, Birt-Hogg-Dubé Syndrome, Hermansky-Pudlak Syndrome, pediatric interstitial lung diseases, primary ciliary dyskinesia, pulmonary alveolar microlithiasis, pulmonary alveolar proteinosis, pulmonary arterial hypertension, pulmonary Langerhans cell histiocytosis, sarcoidosis

Rare Cardiovascular Diseases

Alagille Syndrome, Ehlers Danlos Syndrome, DiGeorge Syndrome, dysbetaliproproteinemia, familial hypercholesterolemia, hereditary hemorrhagic telangiectasia, Hutchinson-Gilford progeria syndrome, inherited channelopathies (Long-QT Syndrome, Brugada Syndrome), Kawasaki Disease, Klippel-Trenaunay-Weber Syndrome, Loeys Dietz Syndrome, Marfan Syndrome, Peripartum Cardiomyopathy, Pompe Disease, rare inherited cardiomyopathies (such as arrhythmogenic right ventricular dysplasia, Danon Disease, LEOPARD Syndrome, Noonan Syndrome), Tangier Disease, Turner Syndrome

Rare Sleep Disorders

Advanced sleep phase circadian disorder, narcolepsy, Klein-Levine syndrome, sleep-related eating disorder, fatal familial insomnia, exploding head syndrome (episodic cranial sensory shock), central hypoventilation syndrome

Research questions of interest include, but are not limited to the following:

  • Characterization of the rare disease cohort being studied, including genetic, phenotypic, imaging and laboratory data.
  • Natural history of progression of HLBS rare disease being studied and clinical outcomes
  • Generation of data (laboratory, clinical and imaging data) to improve diagnosis and to distinguish subtypes of the rare disease being studied
  • Development of algorithms to aid decision-making for clinical management of the rare disease being studied
  • Validation of biomarkers that meet FDA requirements as a drug development tool for use in future Phase III Randomized Clinical Trials
  • Identification of molecular pathways that can lead to therapeutic targets
  • Comparative studies of newborn-screened cohorts diagnosed with an HLBS disease that receive prescribed standards of care versus those who do not and the factors (e.g., socioeconomic, geographic) that contribute to their health outcomes
     

Prior to submission of an application in response to this FOA, applicants are strongly encouraged to consult with the Scientific Research Contacts. Early contact is encouraged, as this provides an opportunity for NHLBI staff to provide information and guidance to a potential applicant.

Eligible Studies

Awards made under this FOA are intended to support hypothesis-driven research that:

  • Enrolls a sufficient number of participants with rare or related rare HLBS diseases, disorders, conditions, or syndromes according to the NIH and FDA criterion (disease prevalence of fewer than 200,000 persons in the U.S.) to address key research questions with at least 85 percent power. Related rare diseases, disorders, conditions, or syndromes are based on shared pathogenesis, affected biochemical, cellular or physiological features, or organ system involvement. Studying related rare diseases within the same cohort could help elucidate subtle variations, and knowledge gained from one disease could accelerate the advances in related diseases. For example, investigators may propose to study hemoglobin disorders rather than only sickle cell anemia or thalassemia.
  • Enrolls most participants from a U.S. based patient population. Enrollment of participants at international sites would be permitted (with the sites as sub-contractors to U.S. domestic institutions) to increase diversity of demographics and clinical characteristics and to enable enrollment of and follow-up on as many subjects as feasible.
  • Enrolls de novo participants or participants from previous registries, clinical trials, or extant cohorts. Previously-studied cohorts may be enriched by adding new participants to reflect the diversity and demographics of the condition under study. Enrichment in the case of follow-up on clinical trial populations is especially important due to exclusion criteria in trials that often eliminate patients based on age criteria or co-morbidities. Enrichment enables adding new technologies and patients that are now available for study.
  • Includes collaboration with patient advocacy group(s) (if any) as full partners in the research program, including the application phase and throughout the study. The interaction with patient advocacy group(s) requirement aligns with the FDA’s Patient-Focused Drug Development Program; aids in identification of unaddressed research questions and clinically-relevant outcomes of importance to patients; and facilitates engagement and recruitment of patients and families.
     

Program Structure
This is a cooperative research program in which Research Centers will establish, re-establish or continue extant longitudinal cohorts in rare HLBS disorders. Partners in this Program include Research Centers funded under this RFA and the NHLBI. The project period for this program will be a biphasic award funded for a maximum of six years.

Milestones

Delineation of milestones by the applicant for the UG3 and UH3 phases is a key characteristic of this FOA. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. This FOA will support applications that propose a series of milestones including expected enrollment goals in the UG3 and UH3 phases and a plan for accomplishing the completion of key milestones on-time and on-budget. Applications that address contingency plans to proactively confront potential delays or disturbances in meeting the milestones are strongly encouraged. Satisfactory completion of UG3 milestones will be assessed administratively by NHLBI to determine eligibility to transition to the UH3 phase. It is expected that the performance of critical milestones such as expected enrollment goals, will be shared on a regular basis through an NHLBI clinical dashboard database.

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

Phases of Award

The UG3 Phase will support infrastructure building, formalizing collaborations with patient advocacy groups, establishment and convening the study’s Observational Study Monitoring Board (OSMB), refinement of protocols, completion of regulatory requirements, contracting with other sites, and demonstration of feasibility. The UG3 Phase will also support case-finding and tracking potential subjects and enrollment of at least 10 subjects. This phase will help demonstrate feasibility by enrolling initial subjects and helping to determine if sites can achieve research goals. Satisfactory completion of UG3 milestones will be assessed administratively to determine eligibility to transition to the UH3 implementation phase. If mutually agreed upon milestones cannot be achieved, funding will be phased-out by the NHLBI. The UH3 Phase will support full enrollment in the cohort, data collection and management, as well as data analysis and dissemination of results. Monitoring during the UH3 Phase will focus on recruitment and retention milestones, completeness of data, scientific questions answered, adherence to the data and safety monitoring plan (DSMP) and, if applicable, biospecimens collection and storage. It is expected that each research center will provide logistical and administrative support to coordinate regular phone calls of the study Steering Committee, other subcommittees (as appropriate) and an Observational Safety and Monitoring Board (OSMB), and create and maintain meeting records.

An annual meeting will convene all FOA awardees in Bethesda, MD to report on their progress and to share procedures that may facilitate conduct of the research such as Quality of Life assessment tools or the collection of common data elements.

See Section VIII. Other Information for award authorities and regulations.
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. See Section VI.2 for additional information about the substantial involvement for this FOA.
Application Types Allowed
New
Resubmission

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Clinical Trial?
Not Allowed: Only accepting applications that do not propose clinical trials

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

NHLBI intends to commit total costs of up to $1,430,000 for FY2020, $4,025,000 in FY2021, $5,525,000 in FY2022, $6,125,000 in FY2023 and FY2024, $5,525,000 in FY2025, and $2,525,000 in FY2026.

NHLBI expects to fund up to 3 new awards in FY2020 and 2 new awards in FY2021, for a total of up to 5 new awards.

Award Budget

Application budgets may not exceed direct costs of $460,000 in Year 1, $605,000 in Year 2, $790,000 in Years 3 through 5, and $542,000 in Year 6. Budgets should reflect the actual needs of the proposed project.

Award Project Period

The maximum period of the combined UG3 and UH3 phases is 6 years, with up to 2 years for the UG3 phase and up to 4 years for the UH3 phase. The scope of the proposed project should determine the requested project award period.

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

1. Eligible Applicants

Eligible Organizations

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
Foreign Institutions

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 allowed. 
Required Registrations

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) – 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.
  • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration , but all registrations must be in place by time of submission. 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.

Eligible Individuals (Program Director/Principal Investigator)
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.

2. Cost Sharing

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

3. Additional Information on Eligibility

 

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)

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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

Letter of Intent

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
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

Page Limitations
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed
Instructions for Application Submission
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.
SF424(R&R) Cover
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Project/Performance Site Locations
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Other Project Information
All instructions in the SF424 (R&R) Application Guide must be followed.


Other Attachments: The attachments listed below must be completed and attached or the application will not be peer reviewed, with the exception of the "Biospecimen Plan," which must only be provided if applicable.

1. Participant Assessments (no more than 5 pages)

Without duplicating information already provided in the PHS Human Subjects and Clinical Trials Information Form, a brief description of the data that will be collected during any visits should be provided as an attachment using the filename "Participant assessments.pdf" and may not exceed 5 pages. Examples of data that may be collected on participants may include, but are not limited to, the following:

  • Demographics (e.g., education, residential and occupational history);
  • Clinical characteristics and basic diagnostic information (e.g., anthropometry, functional status, medication history, laboratory measurements);
  • Co-morbidities and disease phenotyping (e.g., medical history, imaging, environmental exposures, perinatal events, family history);
  • Clinical endpoints (e.g., treatment response and/or side effects, progression/recurrence, overall and cause-specific survival, quality of life or patient-reported outcomes such as physical functioning, daily activities, sleep habits, social functioning, pediatric anxiety, pain impact); and
  • Repeated or longitudinal measurements to support scientific hypotheses, if applicable (e.g., circadian fluctuations).


2. Cohort Management (no more than 5 pages)
A description of how the proposed cohort will be managed must be provided as an attachment using the filename "Cohort management.pdf" and may not exceed 5 pages. Provide details for each bullet below:

  • Training/monitoring: Describe how training and monitoring of study sites and staff will be managed;
  • Data management: Describe how study data will be managed, including data cleaning and analysis, quality control, and database management approaches. Describe how clinical events will be adjudicated
  • Data: Describe plans for data collection, metadata generation, and adoption/use of data standards or common data elements. If any of these activities are not possible or feasible for the proposed study, applicants must explain why;
  • Innovative approaches: If applicable, describe the planned use of innovative approaches to data management/standards, data collection, and/or participant follow-up/surveillance; and
  • Surveillance: Describe plans for active and/or passive participant follow-up or surveillance.
     

3. Biospecimen Plan (must be provided if applicable to the study proposed, 5 pages)
If applicable, and without duplicating information provided in the PHS Human Subjects and Clinical Trials Information Form, a Biospecimen Plan should be provided as an attachment using the filename "Biospecimen Plan.pdf" and may not exceed 5 pages. Provide details for each bullet below:

  • Brief description of which biospecimens will be or were collected (e.g., blood, urine, disease-impacted tissues) and, if applicable, plans for repeated or longitudinal biospecimen collection to support scientific hypotheses (e.g., microbiome sampling);
  • How study biospecimens will be or were collected, processed, analyzed, managed and tracked, and stored;
  • Plans for adherence to Good Laboratory Practices (GLP) and use of current best practices for biospecimen management and quality control (e.g., the National Cancer Institute's Best Practices for Biospecimen Resources) and for submission to the NHLBI BioLINCC; and
  • Assurance that specimens from extant cohorts meet data and genomic data sharing policies, and requirements for broad consent.
SF424(R&R) Senior/Key Person Profile
All instructions in the SF424 (R&R) Application Guide must be followed.

Multiple PDs/PIs are encouraged for this application. Key personnel should demonstrate strong administrative, technical, and management expertise in the areas that are critical to the success of the application, including experience with working productively in collaborative environments; and experience with administrative management of resource-based operations.

The PD/PI submitting this application is encouraged to be a biomedical researcher experienced in the conduct of multicenter longitudinal cohort studies in a rare disease. The application should propose a multidisciplinary team, which may include a clinical informatician or bioinformatician with experience in “Big Data” analysis, physicians, biostatisticians, data managers, study coordinator(s), etc., and other individuals required to facilitate the implementation of all aspects of the study, including recruitment and retention of subjects. Applicants proposing multiple sites must identify a Lead to oversee each site. All Key Personnel who are major contributors to the Research Centers must provide an NIH Biosketch whether or not they are budgeted.
 

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

Applicants shall include funds for travel to Bethesda, MD for an annual in-person Investigators Meeting with one overnight stay for up to three project staff.

R&R Subaward Budget
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Cover Page Supplement
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Research Plan
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:


Specific Aims: Provide Specific Aims and research hypotheses for the establishment, re-establishment or continuation of the cohort.

Research Strategy:

UG3 Phase

  • Describe plans to support infrastructure building, formalize collaborations with patient advocacy groups, establish and convene the study’s Observational Study Monitoring Board (OSMB), refine protocols, complete regulatory requirements, contract with other sites, and demonstrate feasibility.
  • Clearly define the study design (e.g., family, trio, or population) and statistical analysis plan, heritability, and what a priori information (e.g., for genetic research linkage or GWAS information) has been completed to date for participants. Clarify the targets of the exploration and whether extant knowledge of networks and pathway can focus initial investigations.
  • Delineate plans for case-finding and tracking potential subjects and enrollment of at least 10 subjects.
  • Describe the research questions being investigated and how the major findings will be of relevance to rare HLBS disorders. If applicable, provide a rationale and justification for including related rare diseases within the cohort. Clearly indicate the need for and timeliness of the cohort study with emphasis on how the proposed cohort will advance our knowledge, methods, or management of rare HLBS disorders. Describe the scientific rationale underpinning the need for the cohort.


UH3 Phase

  • Describe plans to support full enrollment in the cohort, data collection and management, and data analysis and dissemination of results.
  • Provide a plan for ongoing monitoring during the UH3 Phase, including recruitment and retention milestones, completeness of data, scientific questions answered, adherence to the data and safety monitoring plan (DSMP) and, if applicable, biospecimens collection and storage.
     

Letters of Support: A statement of commitment from each participating institution or organization must be provided.

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

The following modifications also apply:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Consistent with achieving the goals of the program, applications are expected to describe planned internal and external data and biospecimen sharing policies. Applicants may contact NHLBI staff to discuss any concerns about sharing study data from their proposed cohort.

NHLBI Expectations for Data Sharing: De-identified data collected under this FOA are expected to be widely shared through the NHLBI BioLINCC repository and/or other NIH-designated repositories. Metadata, protocols, manuals of procedures, algorithms for calculated data elements, and other documentation necessary to describe the study and resultant data to investigators not affiliated with the study are also expected to be widely available. Applicants proposing to submit biospecimens will follow the timeline and requirements in the NHLBI Guide to Building Biospecimen Collections for Study and Future Research Use. Biospecimens of subjects from previous studies will be required to meet regulatory requirements for reconsent and broad use for research.

Genomic Data Sharing

If proposing to generate large-scale human genomic data, applications are expected to also describe a genomic data sharing plan per the NIH Genomic Data Sharing (GDS) Policy. Even if applications do not propose to conduct genomic or other -omic analyses, these types of analyses may occur during future data collection cycles; as such, applicants may wish to anticipate the potential for these types of studies by incorporating relevant language regarding genomic data collection, analysis, and sharing into their informed consent process.

The NIH has developed several guidance documents to assist applicants with the NIH GDS Policy. Applicants are encouraged to review the following resources and to contact NHLBI staff to discuss any concerns about genomic data sharing:

Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
PHS Human Subjects and Clinical Trials Information
When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.4 Inclusion of Women, Minorities and Children

Power calculations for the proposed sample size, minor allele frequency, disease prevalence and penetrance, and transmission model should also be provided if applicable to determine whether the proposed study has sufficient statistical power to achieve its aims.

2.5 Recruitment and Retention Plan

The Recruitment and Retention Plan should address: 1) the expertise of the individual(s) responsible for screening, approaching and consenting potential participants; 2) engagement of patient advocacy groups (if one exists); 3) the process for identification and screening of study participants; 4) primary and back-up recruitment strategies (e.g., use of electronic health records); 5) implementation of the consent and/or assent process(es); 6) participant retention and adherence strategies; 7) possible competition from other clinical studies or clinical trials for study participants; 8) engagement of the clinical community(ies) that will play a critical role in the recruitment and retention; 9) enrollment goals and number of potential participants available at the site.

2.7 Study Timeline

Applicants must include both a description and a table or graph of the overall study timeline and key milestones. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, measurable, results-focused and time-bound. Milestones must address timing of overall recruitment/enrollment and retention goals.
 

Milestones and UG3/UH3 Transition: Applicants must plan and submit the application for both a UG3 and a UH3 phase. The section describing the research to be conducted under the UG3 must include a description of an entry point and the milestone(s) that will be reached at the end of this phase. The application should provide quantifiable metrics to determine success of the UG3 phase. Additional milestone(s) may be negotiated before or after funding decisions have been made.
 

Milestones of particular interest during the UG3 phase may include but are not limited to:

  • Complete finalized study protocol;
  • Final Informed consent(s) and, if applicable, assent form(s);
  • Agreements in place for product supply (if applicable);
  • Agreements and sub-contracts with participatory clinical sites, patient advocacy groups and/or laboratories (if applicable);
  • Comprehensive laboratory plan (if applicable);
  • Pharmacy/Laboratories Identification (if applicable);
  • Contracts/Third Party Agreements (if applicable);
  • Training of study staff;
  • Final Management/Communication Plan;
  • Final IRB-approval and Observational Study Monitoring Plan;
  • Site Performance Plan;
  • Data Completeness and Quality Monitoring Reporting Plan;
  • Completion of regulatory approvals (if applicable);and
  • Initial enrollment of the first 10 or more participants.
     

The application should also include a series of milestones for the completion of the specific aims of the UH3 phase. Milestones and timelines for the UH3 phase may need to be revised and finalized at the time of the UG3/UH3 transition meeting. Milestones of particular interest during the UH3 phase include but are not limited to:

  • Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study participants, including women, minorities and children (as appropriate);
  • Assessment of study protocol implementation performance;
  • Collection of data related to primary and secondary endpoints and database lock;
  • Data cleaning and lock for analysis; and
  • If applicable, final plan for active and/or passive follow-up of participants.  

Section 3 - Protection and Monitoring Plans
3.5 Overall Structure of the Study Team
Applicants must provide, but are not limited to, the following:

  • A description of the applicant's role in the cohort in the overview of organizational structure;
  • A description of key committee structures needed to manage the cohort;
  • If applicable, a description of the oversight and coordination of any sites proposed;
  • If applicable, a description of the role of patient advocacy groups and any subcontractors;
  • How the committees/structures/sites proposed will be integrated with the organizational framework of the Research Center;
  • A plan to promote collaborations among investigators affiliated with the cohort.
Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form
All instructions in the SF424 (R&R) Application Guide must be followed.

 

3. Unique Entity Identifier and System for Award Management (SAM)

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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.

7. Other Submission Requirements and Information

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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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

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

See more tips for avoiding common errors.

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

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease, sickle cell disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a "Common Data Element (CDE) Resource Portal" (https://www.nlm.nih.gov/cde/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.
Post Submission Materials
Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

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

 

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

Specific to this FOA

To what extent will the project advance our understanding, knowledge, methods, and/or management of rare HLBS disease(s)? How likely is it that the proposed project will significantly advance the field of rare disease research by contributing to foundational knowledge while addressing a well-recognized challenge in rare HLBS disorders?

 

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

Specific to this FOA

Do the investigators collectively have a record of expertise in all relevant subject matters, including clinical, biostatistical and bioinformatical expertise, knowledge of cohort management, and collaboration with patient advocacy groups? What are the strengths and weaknesses of the research team members participating in the project in terms of their experience in related studies? Is the inclusion of the team members adequately justified? How strong is the application in demonstrating that the PDs/PIs and Key Personnel have the experience and capability to conduct the proposed research and meet the milestones and timelines? What evidence is provided to ensure that the clinical sites will employ the appropriate personnel to recruit subjects and implement the protocol? How strong is the coordination and project management team at the participating institutions to facilitate the implementation of all aspects of the project? Are roles and responsibilities well-defined?

 

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

 

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

Specific to this FOA

How will the recruitment strategy enable achievement of the research aims? Is the study population adequately defined? Does the power analysis adequately justify the proposed enrollment? If related disorders are being studied in the cohort, how well is the scientific rationale explained and justified? How will the study designs and methods, including data science methodologies and data analysis, advance our knowledge or methods in addressing critical gaps for this rare disease? Are common data elements (CDEs) appropriately considered? What are the strengths and weaknesses of the participant assessments in addressing the key research questions? How will achievement of the milestones ensure a successful transition from the UG3 phase to the UH3 phase? Are the milestones appropriate for the project and are the milestones adequately defined across the project period? If applicable, what are the strengths and weaknesses of the applicant's plan for collecting, processing, analyzing, managing and tracking, and storing study biospecimens? Is the proposed statistical data analysis plan appropriate for the research questions being posed?

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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

 

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

Specific to this FOA

What are the strengths and weaknesses of the institutional support, equipment and other physical and environmental resources available to the investigators in accomplishing the specific aims of the project proposed?
Additional Review Criteria
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.

 

For research that involves human subjects but does not involve one of the 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 categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

 

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

 

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

 

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

 

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

 

Not Applicable

 

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

 

Not Applicable

 

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

 

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

 

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

 

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), 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; and
  • Will receive a written critique.
Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.
Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Heart, Lung, and Blood Advisory Council. The following will be considered in making funding decisions:
  • Scientific and technical merit of the proposed project as determined by scientific peer review;
  • Availability of funds;and
  • Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

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

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

1. Award Notices

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.

2. Administrative and National Policy Requirements

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

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 Part 75, 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) assume(s) responsibility and accountability to the applicant organization officials and to the NHLBI for the performance and proper conduct of the research supported by the UG3/UH3 award in accordance with these terms and conditions of the award. As such, the awardee PD(s)/PI(s) will be responsible for all aspects of the study and cohort, as well as any modification(s), unless otherwise provided for in these terms or by action of the study Steering Committee.
 

Specific responsibilities include:

  • Defining objectives and approaches of the research;
  • Defining the research plan and goals;
  • Project design and protocol development;
  • Obtaining all requisite study and protocol approvals;
  • Participant recruitment and follow-up;
  • Data collection and quality control;
  • Data statistical analysis;
  • Safety and data monitoring;
  • Oversight of study activities, such as data analysis and interpretation, manuscript preparation, and dissemination of study results;
  • Overseeing/performing other scientific activities of the research plan;
  • Monitoring the completion of the supported activities and taking corrective actions, if needed;
  • Cooperating with NHLBI programmatic, technical, and administrative staff;
  • Administratively managing the award;
  • Developing collaborations with and making data accessible to external investigators; and
  • Ensuring submission of reports to the OSMB  

The awardee will be required to provide updated descriptive and meta-data to the NHLBI upon request, including cohort characteristics, study protocols, basic counts of study participants, enrollment progress, biospecimen availability, and study variable definitions.

Awardees will be expected to evaluate and document compliance with NCI's Best Practices for Biospecimen Resources for collection, processing, and storage of future and previously collected biospecimens (http://biospecimens.cancer.gov/bestpractices). 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 HHS, PHS, and NIH policies.
Awardees agree to the governance of the study through a study Steering Committee and to accept and implement decisions approved by the study Steering Committee (see "Joint Responsibilities" section below).

Awardees are expected to make their data widely available to other investigators per NIH and NHLBI data sharing policies (https://www.nlm.nih.gov/NIHbmic/nih_data_sharing_policies.html, https://www.nhlbi.nih.gov/grants-and-training/policies-and-guidelines/nhlbi-policy-for-data-sharing-from-clinical-trials-and-epidemiological-studies). If awardees propose to generate large-scale genomic data, they are expected to comply with the NIH Genomic Data Sharing Policy (https://osp.od.nih.gov/scientific- sharing/genomic-data-sharing/). Study investigators are strongly encouraged to publish and disseminate results, tools, resources, and other products of the study, in accordance with the study protocols and governance. It is expected that all methods, analyses, software, and algorithms will be made available in a timely manner to the scientific community.

Support or other involvement of industry or any other third party in the study may be advantageous and appropriate. Participation by the third party; involvement of study resources; citing the name of the study or NHLBI support; or special access to study results, data, findings, or resources requires notification of and concurrence by NHLBI. Except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification to and concurrence by NHLBI.
NHLBI staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

A designated NHLBI Project Scientist(s) will have the following responsibilities:

  • Participating in the activities of the study's Steering Committee, as well as any subcommittees as appropriate, and helping to address issues that come before these committees;
  • Facilitating collaborations between the awardees and other NHLBI-sponsored programs, investigators, or organizations that may contribute to the study's goals;
  • Assisting in the interaction between the awardees and investigators at other institutions, as appropriate for the cohort;
  • Promoting collaborative research efforts that involve interactions with other NIH-supported projects, programs, and centers and helping with the coordination of such efforts;
  • Facilitating data and biospecimen resource optimization;
  • Participating in study meetings;
  • Providing technical assistance and advice to the awardees as appropriate;
  • Organizing an annual in-person meeting of awardees of this FOA;
  • Assisting with the development of research protocols;
  • Monitoring participant recruitment and study progress; and
  • Ensuring disclosure of conflicts of interest and adherence to NHLBI policies.

A cohort-specific Observational Study Monitoring Board (OSMB) will be established to provide overall monitoring of data and safety issues in accordance with NHLBI DSMB/OSMB policy (https://www.nhlbi.nih.gov/grants-and-training/policies-and-guidelines/nhlbi-policy-data-and-safety-monitoring-extramural-clinical-studies ). Meetings of the OSMB will be held via teleconference/videoconference.

In addition to the Project Scientist, a separate NHLBI Program Official will be responsible for the normal program stewardship of the cooperative agreement, and will be in the Notice of Award. However, the NHLBI may elect to have a dual-role approach where a single individual may act as both the NHLBI Project Scientist and Program Official. Final decision-making authority on matters of budgetary and funding actions, grants management actions, and management of intellectual property issues is assigned to NHLBI staff other than the Project Scientist. The responsibility for final decision making may reside with Senior Institute management, separate organizational components, and/or oversight committees. Because it is anticipated that the Program Official will participate in activities that rise to a level of involvement (i.e., additional role as Project Scientist) that results in conflicts of interest (e.g., co-publication), other staff members such as direct line supervisor and/or other Senior NHLBI Program management staff may serve as agency Program Officials and will be responsible for the normal scientific and programmatic stewardship of the award. Additional NHLBI staff members may be designated to have substantial involvement in the study.

The NHLBI policy on authorship and manuscript review of NHLBI-sponsored extramural research protects against conflicts of interest with the Program Officer.

The NHLBI reserves the right to withhold funding or curtail the study in the event that any of the following occur:

  • Substantial shortfall in participant recruitment, follow-up, data reporting, or quality control;
  • Major breach of the protocol or substantive changes in the agreed-upon protocol, methodologies, and/or tools with which the NHLBI cannot concur;
  • Failure to develop or implement a mutually agreeable protocol;
  • Human participant ethical issues that may dictate a premature end of the award; and
  • Results that substantially diminish the scientific value of study continuation.
     

Areas of Joint Responsibility:

Each award established under this FOA shall have a study Steering Committee (SC) that serves as its main governing board for the study. The SC voting membership shall be determined jointly by the PDs/PIs and the NHLBI, but shall at a minimum consist of the study center PI(s), other site PI(s), the NHLBI Project Scientist(s), and subject matter expert(s). Additional members may be added per request of the NHLBI. Meetings of the SC will ordinarily be held by teleconference, videoconference, or in-person.
The appointed voting study Steering Committee members will be required to attend all Steering Committee meetings and tele/videoconferences, or to appoint a substitute who will be fully briefed on the issues at hand. Additional non-voting members to serve in an advisory capacity may be added to the Steering Committee as needed by a decision of the existing voting committee members. The study Steering Committee may also form an Executive Committee (EC) and/or subcommittees as needed. The NHLBI Project Scientist(s) may serve on the EC and on subcommittees as deemed appropriate. The Chair of the study Steering Committee will be the Project PI.

The study Steering Committee will have primary responsibility for:
 

  • Overseeing the overall organization of the study's core functions
  • Providing guidance on scientific and infrastructural issues pertinent to the cohort study
  • Contributing to the development of policies and processes pertinent to the cohort infrastructure
     

All investigators/staff within the study will be required to accept and implement the policies approved by the study Steering Committee to the extent consistent with applicable grant regulations.

Study Steering Committee may propose a common data model and data standards, including common data elements (CDEs), as well as biospecimen collection and storage standards consistent with the NHLBI Guide to Building Biospecimen Collections for Study and Future Research Use. Investigators may propose to use data standards such as those available at the NIH National Library of Medicine https://www.nlm.nih.gov/cde/, the PhenX Toolkit https://www.phenxtoolkit.org/, the NIH Patient Reported Outcomes site http://www.healthmeasures.net/, or similar.

NHLBI will partner with the PD(s)/PI(s) to ensure dataset and documentation preparation is congruent for submission to the Biological Specimen and Data Repository Information Coordinating Center (BioLINCC) as described in the NHLBI Policy for Data Sharing from Clinical Trials and Epidemiological Studies, and the Guidelines for Preparing Clinical Study NHLBI Data Sets for Submission to the NHLBI Data Repository. Large-scale genomic data generated by the awardee are to be deposited along with associated phenotype data into the database of Genomic and Phenotype Data (dbGaP, accessed at http://www.ncbi.nlm.nih.gov/gap) in accordance with the NIH Genomic Data Sharing Policy available at https://osp.od.nih.gov/wp-content/uploads/NIH_GDS_Policy.pdf.

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 study 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.

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.
A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

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

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
Application Submission Contacts
eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

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

Scientific/Research Contact(s)

Division of Blood Diseases and Resources

Andrei Kindzelski, MD, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0050
Email: kindzelskial@nhlbi.nih.gov  

Division of Cardiovascular Sciences

Eser Tolunay, PhD
National Heart, Lung, and Blood Institute (NHLBI) Telephone: 301-435-0560
Email: tolunaye@nhlbi.nih.gov  

Division of Lung Diseases

Lora Reineck, M.D., M.S.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0222
Email: lora.reineck@nih.gov
Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

Taryn Cobb
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8025
Email: taryn.cobb@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.
Authority and Regulations
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.


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