Department of Health
and Human Services (HHS)
and Human Services (HHS)
EXPIRED
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
None
|
This FOA seeks applications that propose the establishment of a Hemophilia A Analytical Cohort Research Program (HARP) that will: 1) collaborate with an established consortium of clinical centers to support the recruitment, enrollment, and follow-up of an antenatal/neonatal/ pediatric cohort in severe hemophilia A; 2) provide data management, laboratory, and biospecimen support necessary for the establishment of a unique and sharable biospecimen resource annotated with robust intergenerational clinical and demographic data to enable future studies of FVIII immunogenicity; and 3) develop and implement protocols and procedures to conduct hypothesis-driven research studies utilizing data and biospecimens from the antenatal/neonatal/pediatric cohort. The role of HARP is to provide overall project coordination, administration, data and biospecimen management, research protocols and procedures development and implementation, biostatistics/data analytics support; as well as laboratory (including multi-omics) and biorepository expertise for development of this unique intergenerational cohort and resource. HARP, in collaboration with the consortium of clinical centers, will lead the scientific development, pragmatic implementation, and expert conduct of the hypothesis-driven protocols that will permit the establishment of the severe Hemophilia A intergenerational cohort, utilization of some of the cohort longitudinal data and biospecimens, and establishment of a shareable resource for the scientific community. |
30 days prior to the application due date
| Application Due Dates | Review and Award Cycles | ||||
|---|---|---|---|---|---|
| New | Renewal / Resubmission / Revision (as allowed) | AIDS | Scientific Merit Review | Advisory Council Review | Earliest Start Date |
| October 19, 2021 | Not Applicable | Not Applicable | March 2022 | May 2022 | July 2022 |
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
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.
Not Applicable
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.
Background
Hemophilia is a congenital X-linked rare bleeding disorder resulting from an absence or deficiency in clotting factor VIII (hemophilia A) or factor IX (hemophilia B). The Centers for Disease Control and Prevention (CDC) has ascertained an age-adjusted prevalence of 13.4 hemophilia cases/100,000 males and estimates that there are currently 20,000 individuals in the US living with hemophilia A or B. Among affected individuals, 80% have hemophilia A which universally affects 1 in 5,000 male births without racial or ethnic predilection. The CDC estimates that 400 babies with hemophilia A are born in the US each year (https://www.ncbi.nlm.nih.gov/pubmed/9840909; https://www.cdc.gov/ncbddd/hemophilia/data.html). Persons with hemophilia A exhibit significant phenotypic variability that is primarily attributable to genotypically determined baseline plasma levels of factor VIII (FVIII). The most severe phenotype, severe hemophilia A, accounting for 63% of all hemophilia A, results from absent or undetectable plasma FVIII (<1% of normal) and, in the absence of prophylactic clotting factor replacement, is associated with musculoskeletal, organ-related, and mucocutaneous hemorrhage provoked by normal activity or minimal trauma. Approximately 250 babies with severe hemophilia A are born yearly in the US. Two thirds have a family history of hemophilia; 30% of severe hemophilia A result from a de novo mutation identified primarily in the maternal carrier proband. For severe hemophilia A, the median age at diagnosis is < 1 mo. of age, prompted in 73% of cases by either known maternal carrier status or other family history (https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2516.2009.02074.x).
Approximately 70% of people with hemophilia in the US receive multidisciplinary, comprehensive care in a national network of ~140 federally-funded hemophilia treatment centers. Comprehensive care was found to decrease disease-related hospitalization and mortality when orthopedic disability from recurrent musculoskeletal hemorrhage and transfusion-transmitted viral infection (TTV) from HIV and Hepatitis B and C accounted for the most significant disease associated morbidity and mortality in persons with severe hemophilia A (http://www.bloodjournal.org/content/96/2/437.long?sso-checked=true).Virally- attenuated plasma-derived clotting factor concentrates in the 1980’s and the introduction of recombinant FVIII concentrates in the early 1990’s obviated TTV such that non-infected persons with severe hemophilia A born 1992 -2001 now have a median life expectancy of 71 years compared with 76 years in an unaffected Dutch male control cohort (https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2006.01776.x). Safe, efficient and advancing recombinant technology also facilitated the widespread early age adoption of the continuous (primary) prophylactic use of FVIII replacement in the US with the aim of preventing rather than treating hemorrhage. In an analysis of US treatment practices in 2010, 75% of persons with severe hemophilia A aged 2-19 years were receiving continuous prophylactic FVIII infusions, reducing yearly bleed rates to <5 and positively impacting joint health and quality of life (http://www.bloodjournal.org/content/129/17/2368.long).
Although the past few decades have ushered in unprecedented progress in the prevention of hemorrhagic and TTV complications of hemophilia and its treatment, they have also seen minimal mitigation, if not intensification, of a complication that has the potential to negatively impact the lifelong healthy outcomes that individuals with even severe disease and access to primary prophylaxis have come to expect routinely. This treatment-related complication is the development of a polyclonal neutralizing anti-FVIII IgG4 antibody that predominantly occurs in 25% to 30% of children with severe hemophilia A after a median number of 14.5 exposures to FVIII replacement therapy at a median age of 15.5 months (https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2012-09-457036).
While hemophilia shows no predilection based on race or ethnicity, antibody development disproportionately affects African American and Hispanic persons with hemophilia who develop anti-FVIII antibodies at twice the rate of Caucasians. These neutralizing anti-drug antibodies (ADA) bind to FVIII with type 1 kinetics, effectively inhibiting infused FVIII activity. These antibodies are therefore referred to as inhibitors. The increased morbidity and mortality, as well as additional burden and cost of treatment associated with high titer inhibitors that cannot be eradicated in a timely way, is particularly significant as health outcomes for persons with severe hemophilia A without inhibitors continue to rapidly exceed prediction and expectation. Although the licensure of novel therapeutics for the prevention of hemorrhage in persons with severe hemophilia A and inhibitors promises to mitigate hemorrhage-related morbidity, long term safety and efficacy data related to their use do not yet exist. Importantly, these novel agents neither eradicate nor prevent ADA formation.
The lack of an actionable knowledge about FVIII immunogenicity constitutes the major remaining speed bump on the innovation highway toward predictably healthy outcomes in severe hemophilia A. Navigating this speed bump will require a capacity for inhibitor prediction, prevention and/or early antibody detection and intervention. However, current understanding of the interaction between host and environmental risk factors triggering the immune system in the presence of immune danger signals is incomplete (https://journals.lww.com/hemasphere/Fulltext/2018/10000/Navigating_Speed_Bumps_on_the_Innovation_Highway.4.aspx).
With the release of funding opportunity announcement (FOA) (https://grants.nih.gov/grants/guide/rfa-files/RFA-HL-18-014.html) in 2017, NHLBI acknowledged the need for novel cross-disciplinary mechanistic study of FVIII immunogenicity and the identification of novel druggable targets for inhibitor eradication and tolerance induction. Multi-disciplinary pre-clinical research in response to this FOA is in progress. However, the biologic limitations of existing animal models for the in vivo study of the early human immune and tolerance response to FVIII, as well as the in vivo validation of druggable targets for antibody eradication and FVIII tolerance are well recognized. Consequently, a robustly annotated biobank of informative human biospecimens will be critical to the actionable translation of basic discovery on FVIII immunogenicity (National Blueprint for Future Basic and Translational FVIII Immunogenicity Research). The 2018 NHLBI State of the Science Workshop on Factor VIII Inhibitors (Executive Summary of the NHLBI State of the Science (SOS) Workshop) further recommended that this data and biospecimen resource be established through the intensive longitudinal interrogation of a de novo severe hemophilia A maternal/neonatal/pediatric cohort designed to leverage multi-omics, developmental immunology, clinical/demographic/ environmental data, and in silico modeling to elucidate mechanisms of protein immunogenicity and immunological tolerance to FVIII exposure (National Blueprint for Pregnancy/Birth Longitudinal Cohorts to Study Factor VIII Immunogenicity).
Research Objectives
This Funding Opportunity Announcement (FOA) seeks applications that propose to establish a Hemophilia A Analytical Cohort Research Program (HARP) to support the development of an Intergenerational Precision Medicine Program for the study of factor VIII immunogenicity in severe hemophilia A (i.e., Intergenerational Severe Hemophilia A Cohort or ISHAC) in collaboration with an established consortium of clinical centers. A major aim of this program is to establish an antenatal/neonatal/pediatric cohort in severe hemophilia A, conduct hypothesis-driven research studies utilizing some of the data and biospecimens collected longitudinally from the cohort, and make data and biospecimens from the cohort accessible to the broader research community within one year of maturity of this program. It is anticipated that about 100 pregnant women who are carriers of severe hemophilia A and 50 severe hemophilia A affected neonates would be enrolled over 3 years in this cohort, and that the neonates would be followed longitudinally for at least 2 years.
The established consortium of clinical centers will be referred to as the Consortium in this FOA and will not be funded by this FOA. It is anticipated that NHLBI will enter into a public-private partnership agreement with the Consortium engaging the Consortium to work with HARP prior to the start date of award. The Consortium will be responsible for identifying, consenting, and enrolling pregnant women who are known severe hemophilia A carriers and their babies diagnosed with severe hemophilia A into an antenatal/neonatal/pediatric cohort. The Consortium would also be responsible for conducting regular follow-up visits of the children with severe hemophilia A up to at least the age of 2. The Consortium, guided by protocols and procedures developed collaboratively with HARP will collect and transmit high-quality data to HARP, as well as collect, process, and ship biospecimens to HARP for storage and testing, per protocol.
HARP will be expected to work collaboratively with the Consortium to develop and implement protocols that will lead to the establishment of an antenatal/neonatal/pediatric cohort in severe hemophilia A with associated data and biospecimen collection; to conduct hypothesis-driven data and laboratory research studies; and to establish a well-annotated, shareable data and biospecimen resource. HARP will thus be expected to provide relevant scientific subject matter expertise to allow a collaboration with the Consortium for the development and establishment of the cohort, as well as the development and conduct of scientifically rigorous research protocols. HARP will also be expected to provide overall project coordination, administration, data and biospecimen management, and biostatistics/data analytical support for the program. Additionally, NHLBI expects that HARP will provide laboratory (including multi-omics) and biorepository expertise and provide the necessary procedures and data management systems to the Consortium and allow for the development of this unique resource. NHLBI expects that applicants will have demonstrated experience in the coordination, project management, and data and biospecimen management for multi-site clinical studies.
Through the development and implementation of maternal, perinatal, neonatal/pediatric immunology, and hemophilia event-driven neonatal/pediatric research protocols and associated procedures developed by HARP in collaboration with the Consortium, the Consortium will be able to: 1) Harness the federally-funded Hemophilia Treatment Center (HTC) infrastructure to build a national consortium of HTCs and community-based health care partners for optimal recruitment of severe hemophilia A carrier women who are pregnant and anticipating a male offspring; 2) optimize the consortium to collect biologic (including multi-omics), demographic, contextual, environmental, and psychological data, as well as biospecimens, on carrier mothers, by trimester and during labor and delivery, to include placental biometric data, blood and tissue collection; 3) initiate biometric and phenotypic data collection on affected neonates at delivery, as well as initial specimen collection from umbilical cord tissue/blood and meconium; 4) optimize the consortium to continue phenotypic data and biospecimen (including multi-omics) collection in the neonate and toddler to be focused on both non-hemophilia and hemophilia-related immunologic and inflammatory perturbations in the baseline state throughout the 2-year of highest risk period for anti FVIII antibody development; 5) collect biologic (including multi-omics), demographic, contextual, environmental, and psychological data, as well as biospecimens on the father, when available, and siblings, if scientifically appropriate, e.g., monozygotic twin and/or younger affected sibling born within the study recruitment period; and 6) potentially collect scientifically valid control data on male offspring unaffected by hemophilia, e.g., unaffected dizygotic male twin.
The implementation of feasible hypothesis-driven research protocols will drive the design of this de novo severe hemophilia A antenatal/neonatal/pediatric cohort and the research laboratory studies to be conducted during the life of the program. NHLBI expects that applicants will propose plans for generation of the shareable data and biospecimen resource. It is anticipated that the hypothesis-driven research developed by HARP in collaboration with the Consortium will also include:
Additional research protocols that propose to collect paternal data and biospecimens in the antenatal and perinatal period, when feasible, could potentially serve to interrogate the influence of paternal factors on maternal microbiome, and/or inform the inherited determinants of neonatal immunoreactivity and inflammatory responses to immunogens, particularly the FVIII immunogen.
Demographic data will be imperative to characterizing the role of social determinants and contextual factors, including ascribed race and ethnicity of the parents, in FVIII inhibitor development among male offspring affected by severe hemophilia A. Although hemophilia A does not exhibit incidence disparities across ascribed race or ethnicity, there are differences in the occurrence of FVIII inhibitor development across race and ethnicity (increased inhibitor development among African Americans and Hispanics), and limited understanding of those differences across other socio-demographic factors. This work will advance that understanding with strategic participant recruitment that will account for the need for diversity in research participation.
Program Structure
This FOA will utilize a bi-phasic, milestone-driven cooperative agreement mechanism of award (UG3/UH3) to facilitate completion of the project on time and on budget.
The HARP awardee will be expected to work collaboratively with the Consortium to develop and implement hypothesis-driven feasible research protocols with associated procedures. There will be a memorandum of understanding established at program inception to guide the collaboration between HARP and the Consortium for the 7-year duration of the project. The research protocols developed by HARP will 1) inform the study design underpinning the recruitment, enrollment, and follow-up of an antenatal/neonatal/pediatric cohort in severe hemophilia A; 2) produce data that will inform our understanding of the factors underpinning Factor VIII immunogenicity; and 3) populate the shareable data and biospecimen resource with relevant longitudinal data and biospecimens. HARP, in collaboration with the Consortium, will be responsible for the interpretation and dissemination of results specific to these protocols.
HARP will provide expertise in relevant subject matter science, laboratory (including multi-omics) methodology, biorepository science, data science, bioinformatics, complex statistical (including trans-omics) analyses, project management, coordination and administrative support. HARP applications will be expected to demonstrate the required scientific and laboratory expertise and response capability to coordinate and provide the procedures needed to the Consortium to enable the latter’s rapid collection, quality control (QC), as well as implementation of scientifically-prioritized data, tissue, and blood biospecimen acquisition protocols and storage and distribution procedures. Responsive applications will emphasize on-site and/or collaborative scientific and laboratory expertise in multi-omics, immunology, microbiology and coagulation science; expertise in biorepository science (collection, processing, shipping, storage of all types of liquid and tissue biospecimens); expertise in the management and microtechnological assay of small volume specimens derived from neonates and children; and the capability to dispatch and oversee expert specimen collection, as well as timely processing in the field.
HARP will also provide centralized, facilitated approaches to complex data management and integration, QC procedures, data integrity and security, and the necessary statistical support to ensure the conduct of well-designed precision medicine studies and timely large data (including trans-omics) analysis. The data collection overseen by HARP will be expected to adhere to FAIR (Findable, Accessible, Interoperable, Reusable) principles to ensure transparency, reproducibility, and reusability (Wilkinson MD, et al., Scientific Data 2016) to use standard protocols supported through the NIH PhenX toolkit (https://www.phenxtoolkit.org), and to incorporate appropriate well -validated patient-reported outcome (PRO) measures supported through, or comparable to, those supported through the NIH Toolbox.
HARP applications will therefore be expected to demonstrate the requisite subject matter, data science, bioinformatics, analytic (including integrative omics analytics) and epidemiological expertise, as well as experience in coordinating the conduct of multicenter studies in maternal/fetal, neonatal and/or pediatric populations. Responsive applications must also demonstrate relevant biostatistical expertise and experience in Protocol and Manual of procedures development, designing of intergenerational studies, and integrative analyses of large datasets that include multi- omics data; project management expertise in coordinating and managing large multicenter studies; laboratory and biorepository science expertise; the requisite IT expertise and support for complex big data and biospecimen tracking and management; and the capacity for development and maintenance of a study coordination web site.
Phases of Award
Phase 1 (UG3): The UG3 phase (up to three years) is intended to support HARP developmental/establishment activities in collaboration with the Consortium including, but not limited to: 1) providing overall coordination and administrative support to the program; 2) developing, in collaboration with the Consortium, the scientific and operational ISHAC protocols; 3) developing and helping the Consortium implement the ISHAC’s Operating Procedures; 4) developing and maintaining data and biospecimen management and tracking systems for the program; 5) developing a Program’s internal and public web sites; 6) developing manual of procedures and didactic preparation of sites to implement feasible scientific and operational procedures for data collection and quality control; 7) developing manuals of procedures and didactic preparation materials to implement feasible scientific and operational procedures for biospecimen collection, processing, testing, shipping, and storage; 8) developing and implementing procedures to provide data, laboratory, and biospecimen management support to clinical sites (coordinated by the Consortium) that will be enrolling and following participants during the first phase; 9) developing and conducting laboratory research studies including pilot studies, as appropriate; 10) providing bioinformatics and biostatistical support; 11) developing a shareable data and biospecimen resource dissemination plan; 12) coordinating and convening steering committee and subcommittees; and 13) ensuring that all necessary administrative and regulatory clearances including IRB approval(s) have been obtained before implementation of research protocols.
Phase 2 (UH3): The UH3 phase (up to four years) is intended to support HARP coordination, administrative support, continued biospecimen and data collection activities in collaboration with the Consortium including, but not limited to: 1) continuing to provide overall project coordination and administrative support to the program including support of steering committee and subcommittees meetings/calls; 2) ensuring that all necessary administrative and regulatory clearances have been obtained; 3) continued implementation of all procedures to provide support to clinical sites that will continue to enroll and follow participants, as well as collect data and biospecimens; 4) maintenance of all data and biospecimen management and tracking systems; 5) completing collection of the research protocols data and biospecimens; 6) final building of a shareable, fully annotated biorepository; 7) providing bioinformatics, biostatistical and data analysis support;8) implementing the data and biospecimen resource dissemination plan; and 9) helping with the dissemination of findings through presentations and publications.
Milestones
A key characteristic of this FOA is completion of core milestones. A core 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 performance-based to achieve completion of the Intergenerational Precision Medicine Program on time and on budget.
The research protocols underpinning the establishment of this Intergenerational Precision Medicine Program are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible. Applicants are strongly encouraged to employ project management principles as appropriate. Applications that address contingency plans to proactively confront potential delays or disturbances in meeting the milestones are strongly encouraged.
Investigators and NHLBI will review and mutually agree upon final revised milestones that will be included in the Terms and Conditions of the grant, if awarded (see Research Plan section for description of core milestones). The overall planned enrollment expected during the first three years (UG3) will be agreed upon between the grantee organization (or recipient) and the NHLBI prior to the UG3 award being made.
Transition to and funding of the UH3 award is predicated on NHLBI funding availability and the successful completion of the milestones proposed and peer-reviewed, and mutually agreed upon per the Terms and Conditions of the grant, if awarded. Completion of the core milestones will be ascertained by review of the program’s progress on a regular basis by NHLBI and NHLBI administrative reviews conducted towards the end of UG3, about 30 months into the project. Slower than anticipated progress towards meeting core milestones in the first phase (UG3) of the program will result in a re-evaluation of the award by NHLBI including whether the program objectives can be met on time and on budget. If milestones have not been satisfactorily met, subsequent funding years may not be approved and may lead to phasing out of the award.
Milestones and timelines for the UH3 phase may be revised and finalized at the time of the UG3 to UH3 transition. Slower than anticipated progress towards meeting milestones in the second phase will result in a re-evaluation of the award by NHLBI including whether the program objectives can be met on time and on budget. If milestones have not been satisfactorily met, subsequent funding years may not be approved and may lead to phasing out of the award.
NHLBI policies regarding milestones and relevant clinical research/studies policies are described in the following: NHLBI Accrual of Human Subjects (Milestones) Policy, NHLBI Policy for Inclusion of Women and Minorities in Clinical Research, NHLBI Policy for Data and Safety Monitoring of Extramural Clinical Studies, and NHLBI Data Sharing Policy.
See Section VIII. Other Information for award authorities and regulations.
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.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.
Not Allowed: Only accepting applications that do not propose clinical trials.
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NHLBI intends to commit total costs of up to $1,702,000 in FY 2022 to fund 1 award.
Applications budgets should reflect the actual needs of the proposed project.
The maximum period of the combined phases of the award is 7 years, with up to 3 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.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
For-Profit Organizations
Local Governments
Federal Governments
Other
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.
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.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Number of Applications
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:
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.
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:
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
Facilities and Other Resources: Describe the facilities and resources available for the coordination and laboratory/biospecimen support of multi-site clinical data and biospecimen collections including the establishment of a deeply phenotyped data and biorepository resource, and project and data/biospecimen management tools that will be used. Describe how the infrastructure at the HARP will facilitate the efficient operation of the proposed Intergenerational Cohort and Biospecimen Program.
Other Attachments: The attachments listed below must be completed and attached or the application will not be peer reviewed.
1. Protocol Development Plan (no more than 9 pages)
A Protocol Development Plan must be provided as an attachment using the filename "Protocol Development Plan.pdf" and may not exceed a total of 9 pages.
Describe the proposed process by which the protocols and procedures leading, to the establishment of the cohort, compilation of relevant data and biospecimens, laboratory testing of biospecimens, and establishment of a well characterized shareable data and biospecimen resource will be achieved, in collaboration with the Consortium. Describe the proposed procedures for expert review of the protocols before they are finalized and provide the details of the proposed study design and statistical analysis plan for the cohort and resulting resource. Address how the following four hypothesis-driven research protocols drive the cohort study design and statistical analysis plan, and the generation of the resource: 1. the maternal antenatal research protocol; 2. the perinatal research protocol; 3. the neonatal/pediatric multi-omics and immunology research protocol; and 4. the hemophilia event-driven neonatal/pediatric multi-omics and immunology research protocol.
2. Cohort and Resource Management Plan (no more than 6 pages)
A Cohort and Resource Management Plan must be provided as an attachment using the filename "Cohort and Resource Management Plan.pdf" and may not exceed 6 pages.
Describe plans for how the proposed severe hemophilia A antenatal/neonatal/pediatric cohort and resource generation project will be managed, including the strategy that will be used throughout the project to ensure that management activities of the cohort and resource are met. Outline intended project management activities which should include, but are not limited to, directly supporting the needs of study leadership to identify barriers, make timely responses, and optimize the allocation of limited resources to meet predefined study objectives. Describe the management strategy for overall program coordination, administration, data and biospecimen management, biostatistics/data analytics support, as well as laboratory (including multi-omics) and biorepository support to develop and establish the cohort and associated data and biospecimen resource, in collaboration with the Consortium. Include the following in the description:
All instructions in the SF424 (R&R) Application Guide must be followed.
It is anticipated that the PD/PI/PM (or Multi-PDs/PIs/PMs) of the HARP will be experienced in the development, coordination and management of multi-center clinical research studies as well as central laboratory services, including success in meeting milestones and timelines. The experience and scientific expertise of each PD/PI/PM and all Key Personnel need to be carefully documented and roles and responsibilities must be well-defined. The HARP requires a multidisciplinary team and the application should reflect the team's hands-on involvement in HARP functions, including coordination, relevant scientific expertise, study protocols and manuals of procedures development, biorepository development, laboratory testing services and management, sample tracking, logistics and administration, communications, data management (including quality control), data security and IT infrastructure (including development of public and secure study websites), regulatory support, and bioinformatics/biostatistical/analytical support. Applications must include personnel and corresponding biographical sketches for the HARP . All Key Personnel who are major scientific contributors to the Program are encouraged to provide an NIH Biosketch whether or not they are budgeted.
R&R Budget
All instructions in the SF424 (R&R) Application Guide must be followed.
Provide detailed annual budgets necessary to enable the HARP to meet proposed milestones.
If parts of the costs of the resource are to be provided by sources other than NHLBI, these contributions must be presented in detail in the budget justification. Third Party support of the proposed research activity (if approved) will be incorporated as a Special Award Condition. Applicants are reminded that although Cost Share is not required, if these types of costs are included in the research application and peer reviewed, it is expected that these costs will not be covered by NHLBI.
The HARP budget should include support of a Steering Committee Chair at 10% effort to be chosen by NHLBI. Additionally, the HARP budget should include all costs associated with IRB reviews of the Program protocol(s) and corresponding coordination and administration support.
HARP should include in their budget all costs associated with monitoring of adverse events including independent medical monitor review, and Observational Study Monitoring Board (OSMB) activities. This includes the costs for preparing reports for the OSMB and meeting/calls reimbursement for the OSMB members. HARP should also include a plan for assessing OSMB member conflict of interest, and put associated costs in the budget. Additionally, if the OSMB is convened by NHLBI, HARP should include in their budget coordination of support for regular OSMB calls as needed (by teleconference or videoconference).
Include budget support for two Steering Committee in-person meetings every year including budget for personnel to travel to each of the twice a year in-person Steering Committee meetings. One of the Steering Committee in-person meetings will be held in the Washington, D.C. area. Include budget for personnel to travel to scientific meetings as appropriate. All in-person meetings may be held virtually if deemed more appropriate.
Include budget support for publications, data sharing, and dissemination of results.
The HARP budget should request only the costs that will be required for the activities to be performed in a given year.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Research Strategy:
Describe plans for providing the needed scientific expertise to permit the development of research protocols in collaboration with the Consortium to establish the cohort, conduct the proposed research, and establish a shareable data and biospecimen resource. Detail the plans for providing expert assistance in project coordination and communications; administration; study designs; biospecimen acquisition, processing, shipping, and storage; laboratory (including multi-omics) testing; feasibility assessments; data and biospecimen management and tracking; and bioinformatics/biostatistics/data analytics support for the Program.
The following criteria must be addressed:
Significance: Explain why the chosen approach is optimal to support the successful establishment of the cohort and resulting shareable resource to answer key scientific questions to enable studies of FVIII immunogenicity and tolerance.
Investigators: In addition to strong expertise and well-defined roles and responsibilities, describe governance, organizational structure, leadership approach, and plans for conflict resolution.
Innovation: Describe plans to employ unique or novel methodologies that will enhance the Program’s design, management, or methods of data analysis. Describe how HARP plans to utilize current best practices to improve the knowledge and/or skills of the Program that it will support.
Approach: Describe how the Program will be coordinated, including plans for developing and implementing research protocols and corresponding procedures, and providing administrative, operational support, plans to monitor accrual, laboratory (including -omics) support, biospecimen science support, and data management and validation support including data management systems, methods of data entry and cleaning, event tracking and logistics, case report forms, and methods for monitoring the quality and consistency of data collection, data confidentiality and subject privacy, adjudication of events (as needed), and data reports. Explain the communications strategy, including how HARP proposes to interact with the Consortium of clinical centers, how data will be transmitted in an accurate and timely fashion, biospecimen plan(s) including collection, processing, storage, cataloguing and preparation for distribution, how laboratory testing (including -omics) will be identified and managed, and how HARP will establish accessible and secure methods of communication, including development and maintenance of a secure internal and external project website.
Environment: Describe available resources to support electronic information handling.
Core Milestones
Propose and justify milestones that will be subject to peer-review. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones should be relevant, measurable, results-focused and time-bound, and should address timing of overall recruitment/enrollment and retention goals.
Describe the milestones that will be met to address the specific aims of Phase I (UG3) and Phase II (UH3) as outlined above, that will ensure the successful establishment of the cohort, the completion of specific research protocols as outlined in the Protocol Development Plan, and the development of the shareable data and biorepository resource and its dissemination. HARP core milestones include, but are not limited to:
Phase I (UG3) Core Milestones
Year 1
Year 2
Year 3
Phase II (UH3) Core Milestones
Milestones and timelines for Phase II (UH3) may need to be revised and finalized at the time of the UG3 to UH3 transition meeting.
Letters of Support: Applicants are encouraged to provide a statement of commitment from each participating institution or organization.
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.
All applications, regardless of the amount of direct costs requested for any one year, must address a Data Sharing Plan.
Data and Biospecimen Sharing Plan:
Describe the Data and Biospecimen Sharing Plan, including submission to the NIH repository resources, to allow for use of the data and biospecimens by the research community within one year of completion of the resource.
Biospecimens, which will have been curated by interdisciplinary expert input for hematologic, inflammatory and immunological determinations, integrative trans-omics analyses, and exposome (https://www.cdc.gov/niosh/topics/exposome/default.html) ascertainment during the life time of the program, will allow for timely sequential studies that will inform important actionable mechanisms of FVIII immunogenicity, as well as future strategies for antibody eradication and prevention. Given the intent of the data and biospecimen resource sharing plan, the investigators are strongly encouraged to follow all requirements with respect to data and specimen acquisition, as well as the structure and quality control procedures that must be met for acceptance of a study dataset/repository into NIH-sponsored biorepository and data management resources.
Genomic Data Sharing Plan:
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. Applications will need to incorporate 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:
When involving human subjects research, clinical research, and/or NIH-defined 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.
Section 2 - Study Population Characteristics
2.1 Study Timeline
Include a table or graph of the overall study timeline. This is expected to be a visual representation (such as a Gantt Chart) of core milestones and key HARP project management activities. A narrative is not expected in this section.
The study timeline should include core milestones that need to be met throughout the lifecycle of the project to ensure its success, and the subtasks that will be used to reach the milestones. The period of time for the study duration is expected to be displayed in months and must include, but is not limited to, the following timepoints:
(a) the study opens to enrollment
(b) core milestones are met
(c) subtasks needed to reach the core milestones are completed
(d) resource is completed
(e) analyses of stand-alone research study(ies) data are completed
(f) submission for publication of study manuscript(s) describing the resource
Section 3 - Protection and Monitoring Plans
3.2 Data and Safety Monitoring Plan
Describe the process that will be utilized to identify unanticipated problems and describe procedures to mitigate risks.
3.3 Overall Structure of the Study Team
Applicants must provide, but are not limited to, the following:
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.
All instructions in the SF424 (R&R) Application Guide must be followed.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit 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 Office for Scientific Review (OSR) at the National Heart, Lung, and Blood Institute (NHLBI) and responsiveness by program staff at NHLBI, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
.
Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.
Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission 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.
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
How strongly does the proposed HARP application address the needs of the research program that it will support? To what extent the scope of activities proposed for the HARP likely to meet the needs of the research program that will be supported?
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
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?
Specific to this FOA
Where appropriate, does the proposed HARP demonstrate utilization of current best practices to improve the design and conduct of the multi-site clinical cohort and data and biospecimen resource it will support?
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?
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?
Specific to this FOA
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
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.
Core Milestones
Protections for Human Subjects
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.
Inclusion of Women, Minorities, and Individuals Across the Lifespan
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.
Vertebrate Animals
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.
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
Not Applicable
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; and (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).
Authentication of Key Biological and/or Chemical Resources:
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.
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 a special emphasis panel convened by NHLBI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.
As part of the scientific peer review, all applications will receive a written critique.
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.
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:
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 recipient's business official.
Recipients 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.
Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.
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, Recipients, 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 laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.
HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.
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.
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.
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, 2 CFR Part 200, 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 recipient 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below.
The PD(s)/PI(s) will have primary responsibility for:
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 award in accordance with these terms and conditions of the award. As such, the recipient PD/PI will have primary and lead responsibilities for the project as a whole, including overall project coordination, administration, data and biospecimen management, bioinformatics/biostatistics/data analytics support, as well as laboratory (including multi-omics) and biorepository support for the project.
Upon completion of the project, recipient are expected to put the resource data and biospecimen collection into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community (see section 3 below "Collaborative Responsibilities"). Third Party support of the proposed research activity (if proposed, accepted and approved) will be incorporated as a Special Award Condition in the Notice of Award (NoA). Recipients will be responsible for ensuring third party compliance and if the third party support is no longer available, and not replaceable in a timely fashion, negotiated phase-out of the award may occur. Cost share is not a requirement for this program; however, if cost share is proposed, peer reviewed and accepted by NHLBI it will become a Special Award Condition in the NoA.
The recipient 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.
Recipient 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). Recipient 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.
Recipient 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).
Recipient are expected to make the data and biospecimen resource available to the scientific community within one year of maturation (completion). If recipient 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 protocol and governance.
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:
The NHLBI Project Scientist and/ or Program Officer will assist with development of research protocols, monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies.
The NHLBI Project Scientist/Program Officer will serve on the Steering Committee and other study committees, when appropriate. The NHLBI Project Scientist/Program Officer may work with recipients on issues coming before the Steering Committee such as recruitment, protocol development, follow-up, quality control, adherence to protocol, possible changes to the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems, such as insufficient participant enrollment.
The Project Scientist/Program Officer will be responsible for the normal program stewardship of the cooperative agreement, and will be in the Notice of Award. 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/Program Officer. 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 Project Scientist/Program Officer will participate in activities that rise to a level of involvement that results in conflicts of interest, for example, co-publication, other staff members such as direct line supervisors and/or other Senior NHLBI Program management staff will serve as agency Program Officials and will be responsible for the normal scientific and programmatic stewardship of the award. The NHLBI policy on authorship and manuscript review of NHLBI sponsored extramural research protects against conflicts of interest with the Project Scientist/Program Officer.
A designated NHLBI Project Director (PD) and/or a Project Scientist(PS) will have the following responsibilities:
An independent Observational Study Monitoring Board (OSMB) will be established by NHLBI 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 ). The OSMB has the responsibility to review interim data and final data, and recommend whether the protocol should be modified, and, at each call/meeting, whether the study should be continued or should be terminated early. An NHLBI scientist other than the NHLBI Program Official or Project Scientist will serve as Executive Secretary to the Board. Because the OSMB serves as an independent group advisory to the NHLBI, study investigators shall not communicate with OSMB members regarding study issues, except as authorized by the Board's Executive Secretary. Meetings of the OSMB will be held via teleconference/videoconference.
The NHLBI reserves the right to phase-out or curtail the study (or an individual award) in the event of: (a) failure to develop or implement a mutually agreeable protocol, (b) substantial shortfall in subject recruitment milestones, core milestones mutually agreed upon by the recipient organization and PD/PI and the NHLBI, consortium participation and collaboration with other recipient, (c) substantive changes in the agreed-upon methodologies and tools with which NIH cannot concur, (d) human subject ethical issues that may dictate a premature termination, or (e) results that substantially diminish the scientific value of study continuation.
Areas of Joint Responsibility include:
The 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 Chair, HARP PI(s), the Consortium director(s) or PIs, the NHLBI Program Officer and/or Project Scientist(s), and subject matter expert(s). The Chair of the SC will be appointed by NHLBI and supported budget-wise by HARP. Additional members may be added per request of the NHLBI. Meetings of the SC will 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 Program Officer and/or Project Scientist(s) may serve on the EC and on subcommittees as deemed appropriate.
The study Steering Committee will have primary responsibility for:
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 that the data and biospecimen resource are established and documented to be congruent for submission to the appropriate NIH repository. For example, large-scale genomic data generated by the recipient 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 recipient. This special dispute resolution procedure does not alter the recipient'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.
Multiple PD/PI Dispute Resolution
If a conflict develops between PD(s)/PI(s) in a multiple PD/PI application, the following procedures will apply:
The Departmental administrators representing the PD(s)/PI(s) shall meet and attempt in good faith to settle any dispute, claim or controversy arising out of or relating to the interpretation, performance or breach of this disagreement. However, if the Departmental administrators fail to reach resolution in 30 days then NIH may invoke dispute resolution procedures as described in the above paragraph.
When multiple years are involved, recipients 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 recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten 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: [email protected] (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: [email protected]
Division of Blood Diseases and Resources
Shimian Zou, PhD
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute (NHLBI)
301-435-0065
Email: [email protected]
Andrei Kindzelski, MD, PhD
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute (NHLBI)
301-435-0065
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: 301-827-8014
Email: [email protected]
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 2 CFR Part 200, 42 CFR Part 52 and 45 CFR Part 75.