Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this funding opportunity is to invite applications to participate in the NHLBI Precision Interventions for Severe and Exacerbation Prone Asthma (PrecISE) Network. This clinical trial network will conduct sequential, adaptive, phase II/proof of concept clinical trials with precision interventions in stratified patient populations. The Network will utilize patient phenotypes and/or endotypes, predictive, and monitoring biomarkers/profiles in sequential adaptive trials to evaluate the most effective precision intervention strategies for this hard to treat patient population. PrecISE will include multiple clinical centers and a single Data, Modeling, and Coordination Center (DMCC). This FOA invites applications for the Clinical Centers (CC) and runs in parallel with a companion FOA (RFA-HL-17-010) that invites applications for the DMCC.

Although asthma patients may present with similar clinical symptoms, there is significant heterogeneity in disease etiology, pathobiology, and manifestations. Wide variability in patients responses to therapeutics may be a consequence of such heterogeneity, however, our understanding of the complex interactions that result in differential population and individual therapeutic responsiveness is superficial. Treatment is challenging, particularly without clear and early indicators of therapeutic responsiveness. Moreover, an individual’s response to treatment may vary over time, and it is difficult to assess whether therapeutics affect the underlying disease pathology or prognosis.

An additional deficit in the care of patients with severe or exacerbation prone asthma is the intended purpose of available therapeutics which manage or improve the control of symptoms without modifying the underlying disease state or natural history of disease. Thus, even for patients who respond to therapy, their disease is merely controlled, subject to continued suppression with therapeutic agents. The underlying pathobiology may appear clinically quiescent, while the intrinsic disease process continues.

Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and exacerbations and distinct disease subtypes. These subgroups of patients with severe exacerbation-prone disease confirm the concept that disease results from interactions among multiple, diverse pathobiologic mechanisms over time, and provide the opportunity to leverage this evidence base to develop more precise, biologically based approaches for asthma management and modification.

The lack of informative data on the management of patients with severe asthma and the challenges of assessing treatment response and disease modification, necessitate the formation of a clinical network adept at sequential, adaptive clinical trial design to evaluate the safety and efficacy of precision interventions. Stratified patient populations, with specific phenotypes, and the use of predictive and monitoring biomarkers will enhance the flexibility and efficiency of trials as compared to single interventional approaches in large, heterogeneous patient populations.

The objective of this program will be to conduct early-phase clinical trials to test the safety and/or efficacy of interventions in stratified patient populations for the treatment of severe and exacerbation-prone asthma. The primary goal of the PrecISE Network is to accelerate the understanding of the use of precision based treatment approaches for management and secondary prevention of asthma in well-phenotyped patients with severe and/or exacerbation-prone asthma to improve patient outcomes and potentially modify disease expression. As well, it is expected that new knowledge will be generated regarding phenotypes, predictive and monitoring biomarkers, trial outcomes, the natural history of disease, and therapeutic responsiveness. Studies will use disease phenotypes, endotypes, and predictive and monitoring biomarkers in multi-stage, adaptive designs with precision interventions that may have the potential to abrogate disease pathobiology and determine the therapeutic response of individual patients.

The CCs are the scientific units of the PrecISE Network. As such, the CCs will:

• Collaborate to determine the scientific direction of the PrecISE Network;
• Actively implement each network-wide protocol approved by the Steering Committee (SC)
• Recruit and enroll severe and/or exacerbation-prone patient cohorts
• Propose phenotype and biomarker-driven adaptive clinical trials for the treatment of severe and/or exacerbation-prone asthma
• Collect and report highly detailed phenotype and endotype data to answer the primary outcomes of the PrecISE Network studies
• Conduct scientific analysis
• Interpret results

Over the project period, the PrecISE Network will conduct at least three targeted precision interventions, at least one of which is novel (not FDA approved), in severe and/or exacerbation-prone asthma patients using sequential, adaptive trial designs.

A central protocol will be developed that will utilize specific patient phenotypes/endotypes and predictive and monitoring biomarkers, based on a biologic and/or clinical rationale, to direct the choice of precision interventions. At least three different patient phenotypes and at least three precision interventions will be used in a sequential, adaptive design. If a particular intervention is safe and the patient is responsive, as determined by individual interim analyses utilizing monitoring biomarkers/profiles that are biologically based or composite, the patient will continue to the end of the study with the specific intervention. At that time, predictive and monitoring biomarker results will be integrated with a clinical outcome(s). Alternatively, if a specific patient is deemed unresponsive to a specific intervention, via statistical modeling using data derived from monitoring biomarker assessments, the patient will be crossed-over into another arm of the protocol where another targeted precision intervention will be employed, again determined by phenotype and predictive biomarkers/profiles. Patients will continue to enter and progress through the protocol with treatment arms guided by the use of initial phenotype, predictive biomarkers/profiles, and continuation or crossover guided by monitoring biomarkers and statistical modeling of outcomes, until the entire cohort has completed the study.

During the project period, the PrecISE Network will conduct at least one sequential, adaptive clinical trial protocol, with at least three precision interventions. Associated phenotyping, endotyping, validation, and longitudinal follow-up studies will be conducted, as appropriate and relevant to the interventions performed. It is anticipated that, depending on the precision interventions used, possible required washout between arms, and longitudinal follow-up of up to 12 months, the entire protocol may take up to three years to complete.

The PrecISE SC (described below) will evaluate the proposed protocols. Protocols conducted during the project period may be one of those proposed by the funded CC investigators or may be a modified or combined version of one of the proposed protocols. The decision to fund a particular CC will not commit PrecISE to develop that applicant’s proposed protocol. All CCs are expected to participate in all protocols put forth by the SC for the project period.

A stratified cohort of 800 patients will be used for the execution of the protocol. The phenotypes/endotypes used for stratification will be sufficiently represented in the overall severe and/or exacerbation-prone patient population as to allow for screening and recruitment of the cohort in an 18-month period, and as is feasible within the constraints of the network resources. It is anticipated that each CC will have the ability to enroll 100 severe and/or exacerbation-prone asthma patients over an 18-month period.

The protocol will be flexible and scalable such that if interim analyses and modeling conducted by the DMCC, indicate that adding or eliminating phenotypes and/or interventions is necessary, the Network will be able to respond in the appropriate manner. Additionally, as the intent of PrecISE is to inform the conduct of future clinical trials and help create a new treatment paradigm that uses precision interventions in specific patient strata, it is anticipated that biospecimens will be practical and accessible (e.g., induced sputum, blood, urine, nasal brushings, imaging, etc.) to enable translation to the clinic.

The NHLBI intends to conduct an evaluation of the effectiveness of PrecISE during the project period and reserves the right to suspend enrollment and/or trial execution during the evaluation if deemed necessary for the ultimate success of the overall network enterprise.

Research Examples

NHLBI intends to support protocols that are feasible as a multicenter trial, address issues of clinical significance, and have a high potential to inform future clinical trial design and clinical practice. Applications that propose protocols that are powered for biologic responsiveness to specific predictive and monitoring biomarkers, and clinically important endpoints for an integrated, composite endpoint that reflects individual patient response on a biologic and clinically relevant level, are strongly encouraged.

Examples of research topics include, but are not limited to, the following:

• Use of biomarkers predictive of redox dysregulation to identify severe asthma patients most likely to respond to mimetics or inhibitory agents that restore redox activity to validate biomarker and assess effects on a clinical asthma outcome(s).
• Use of TNF-alpha inhibitors and cytokine levels to predict augmented corticosteroid responsiveness to validate biomarker and effects on a clinical asthma outcome(s).
• Use of non-invasive biomarkers to identify asthma phenotypes most likely to respond to targeted therapeutics of specific inflammatory pathways to validate biomarkers and assess effects on a clinical asthma outcome(s).
• Use of non-Th2 biomarkers (e.g., metabolic, Th1) to identify asthma phenotypes most likely to respond to specific therapeutic interventions in non-Th2 asthma.
• Use of -Omics analyses to interpret the biologic and clinical significance of treatment response.

Applicants are not limited to the topics listed and are encouraged to submit other topics pertinent to the objectives of this FOA.

Research topics that will NOT be considered responsive to this FOA:

• Clinical trial protocols that do not propose use of specific patient phenotypes/endotypes to stratify patients for therapeutic interventions.
• Clinical trial protocols that do not propose predictive and monitoring biologic biomarkers to assess early responsiveness to a specific intervention.
• Clinical trial protocols that do not propose sequential, adaptive designs with at least 3 interventions, at least one of which has not been used before for the treatment of severe and/or exacerbation prone asthma.
• Clinical trial designs that are traditional phase II designs using undifferentiated, heterogeneous patient populations without the use of predictive and monitoring biologic or biologic/clinical composite biomarkers in a sequential, adaptive design.
• Phase III clinical management trials.

PrecISE will be a cooperative network of CCs, a DMCC, and the Division of Lung Diseases, NHLBI.

Clinical Centers

CCs are responsible for conducting the research (subject recruitment and implementation of all study procedures) and disseminating research findings. CCs will be responsible for the planning and collection of high-quality biospecimens that will permit the appropriate interim and longitudinal analysis of therapeutic responsiveness, biomarker effectiveness, effects of interventions on disease modification and natural history, and disease stratification. In conjunction with the DMCC, CCs will be responsible for finalizing and prioritizing protocols, developing common definitions and standardization across protocols, and analyzing and interpreting research results. Each CC will be required to participate in a cooperative and interactive manner with all other CCs and the DMCC in all aspects of the network. CCs will also participate intellectually in all aspects of the Network, including developing Network procedures and subcommittees, finalizing clinical trials protocols and costs, developing a collaborative IRB process, and writing template informed consents.

Data, Modeling, and Coordination Center (DMCC)

The DMCC will play a major research role in the development of the clinical protocol(s), and interim and final analyses of data, and will participate in and support protocol finalization, execution, and final analyses to help determine the best predictive and monitoring biomarkers for use in specific patient phenotypes, development and statistical modeling, analysis of early responsiveness and formulation of stopping rules, final analysis of composite biologic and clinical outcomes, and group effect analyses. During protocol execution, the DMCC will utilize real-time information from clinical and biologic data to model protocol effectiveness in the context of the phenotypes, monitoring biomarkers, and integrated biologic and clinical endpoints. These data will be used to inform SC evaluation and recommendation of protocol modifications with regard to specific phenotypes, biomarkers, and/or precision interventions that may need to be added or eliminated for successful execution of the protocol and the overall success of the Network enterprise.

The DMCC will perform traditional network coordination and support activities such as, but not limited to: editorial and meeting coordination for manuscript preparation, coordination of the activities of the SC, DSMB, drug acquisition and distribution, and overall study coordination and quality assurance. The DMCC will also initiate and coordinate activities to promote standardization of asthma research vocabularies and methodologies and coordinate PrecISE activities with NHLBI bioinformatics programs. Patient-related costs (e.g., clinical costs that are not part of usual care--tests, sample and data collection, supplies, drugs) will be distributed from the DMCC budget. See RFA-HL-17-010 for more details on the responsibilities of the PrecISE DMCC.

NHLBI

The NHLBI is responsible for organizing and providing overall support for PrecISE. The NHLBI Program Office and Office of Grants Management are responsible for the overall management of PrecISE. In addition to regular grant stewardship, the NHLBI Project Scientist(s) will be involved substantially with the awardees as an NHLBI partner, consistent with the Cooperative Agreement mechanism. The NHLBI will appoint the Data and Safety Monitoring Board, and the SC Chairperson (SC Chair).

Steering Committee (SC)

The SC is composed of the PD(s)/PI(s) of the CCs and the DMCC, and the NHLBI Project Scientist will comprise the main governing body of PrecISE. The SC Chair will be independent of the CCs and the DMCC to preside over SC meetings and serve as the SC representative. All major scientific decisions will be determined by majority vote of the SC. It is anticipated that the SC will meet at least twice a month by conference call and up to six times a year in the greater Washington DC area for in-person meetings. The SC will have primary responsibility for the general organization of PrecISE, finalizing clinical protocols and budgets, facilitating the conduct and monitoring of the studies, reporting study results in a timely manner, and working with the NHLBI to promote dissemination of the findings. The SC will be responsible for creating a plan for biospecimen banking and public availability, according to NHLBI policies, during the first year of the program. Subcommittees of the SC will be established to perform specific functions such as publications and presentations, equipment, quality control and assurance, and conflict of interest policy. The SC will monitor disclosures of financial interests and potential conflicts of interest among investigators and clinic coordinators according to NHLBI conflict of interest policies. Awardee members of the SC will be required to accept and implement policies approved by the SC.

Data and Safety Monitoring Board (DSMB)

An independent DSMB, established by the NHLBI in accordance with NIH policies, will conduct interim reviews of trial data to monitor patient safety and review study performance and overall progress. The DSMB will also monitor the need to modify protocols. The DSMB will consist of a chair, clinicians with expertise in asthma management, scientists with expertise in asthma clinical trials, bioethics, and biostatistics and adaptive, precision clinical trial design and coordination. An NHLBI scientist other than the NHLBI’s PrecISE Project Scientists will serve as the Executive Secretary to the DSMB. The DSMB will meet approximately semi-annually by conference call or in-person meetings in Bethesda, MD. The DSMB will review serious adverse event reports on an ongoing basis, according to NHLBI policies. Following each meeting, the DSMB will submit recommendations to NHLBI regarding the continuation of each study. The NHLBI will address the recommendations and prepare a report for PD(s)/PI(s) that can be provided to their institutional review boards.

See Section VIII. Other Information for award authorities and regulations.

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

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

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

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

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

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

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

The Project Director/Principal Investigator (PD/PI) or contact PD/PI should have strong expertise in adult and pediatric asthma (children >11 years of age).

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

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

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

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

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

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

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

The letter of intent should be sent to:

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)
Telephone: 301-435-0270
Fax: 301-480-0730
Email: [email protected]

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

The 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. Applicants may propose to participate as a CC made up of two or more satellite recruitment and protocol implementation sites (that is, additional recruitment sites at a different location than the CCs).

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

Facilities and Other Resources: Applications from institutions that have a Clinical and Translational Science Award (CTSA) should identify the resources that could be available to support the proposed PrecISE Clinical Center, commenting particularly on those aspects that will enhance their programmatic and scientific efficiency. In such a case, a description of the GCRC or CTSA and how the applicant proposes interacting with it should be included.

Other Attachments: Attachments listed below must be provided or the application will be incomplete and will not be peer reviewed, with the exceptions of the "Recruitment Collaboration Plan" and "Biospecimen Core", which must only be provided if applicable.

Upload each attachment as a separate pdf file with the names specified below.

1. Protocol and Consent (required)

A single attachment must be included that contains the full protocol and template consent. This should be a single PDF file with the name "PrecISE protocol.pdf".

2. Recruitment Collaboration Plan (if applicable)

The filename "Collaboration Plan.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

Patient recruitment may rely on collaborations with other groups (e.g., other health care providers in the community such as pulmonary/allergy practices, primary care practitioners, pediatricians, and health maintenance organizations) in addition to the applicant’s institution. If links with other groups are anticipated, the application should include a plan that describes: (1) how the applicant CC will link to and operate with the other groups; and (2) how the CC will monitor the quality of the other group s performance (recruitment and, if applicable, patient visits and data collection).

3. Biospecimen Core (maximum 1 page; if applicable)

The filename "Biospecimen Core.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

A CC may propose to function as a core for the banking and analysis of biospecimens that may need to be collected and analyzed during the execution of the clinical protocol. Describe successful biospecimen core history in potential relevant areas and a plan for biobanking and analyses, sample preparation, storage and capacity, including quality control.

All instructions in the SF424 (R&R) Application Guide must be followed. The following additional guidance should also be followed:

Key personnel must have demonstrated expertise in the recruitment and retention of severe and/or exacerbation prone asthma patients in clinical research studies, and in the conduct of longitudinal clinical trials in asthma patients. Inclusion of expertise in adaptive clinical trial design is strongly encouraged. Additional expertise is required in asthma phenotyping and endotyping, the collection and analysis of biospecimens, and the use of predictive and monitoring biomarkers in patient populations. Other demonstrated expertise may be needed in omics, imaging, molecular and/or cellular biology, immunology, physiology, etc., depending on the specific protocol proposed. Key personnel must have all expertise necessary for feasibility of executing the protocol. If a CC is proposing the serve as a biospecimen core, relevant expertise must be included

For CC’s proposing more than one site, the responsible investigator(s) at the collaborating site(s) should be named as Senior/Key Personnel.

All instructions in the SF424 (R&R) Application Guide must be followed. CC budgets must reflect support for personnel and infrastructure costs of the center. The CC budget must include the effort required for network participation, including regular teleconferences for discussion of protocols and other network committees including regular SC conferences, CC group meetings, and activities related to IRB approval and updates, manuscript preparation, and travel costs for in-person meetings. Other costs may include a travel budget for up to six SC meetings (2 days, 1 night) per year for two investigators. Applicants may budget for one trip per year for one research coordinator and one trip per year for one junior faculty member. Modest administrative support and supply budget may be proposed.

CCs should request funds for protocol set up and implementation that include personnel required for initial activities of network and protocol set up and implementation, support for the ongoing infrastructure and daily administrative and personnel needs.

The first year budget should be lower than subsequent years. In year 1, infrastructure support is expected to consist of the following: 40% total FTE for the combined leadership of Program Directors/Principal Investigators (PD(s)/PI(s)) and other key personnel in adult and pediatric asthma. In year one, it is not expected that one clinical coordinator will exceed 25% FTE. When patient recruitment begins (years 2-6), coordinator effort may increase to 100% FTE, and the combined effort of the Program Directors/Principal Investigators (PD(s)/PI(s)) and key personnel may increase to 60% FTE. Infrastructure direct costs are suggested not to exceed $210,000 in year 1, $275,000 in years 2-5, and $250,000 in year 6, exclusive of indirect costs associated with consortia.

As part of the budget justification, applicants should support the protocol budget requests by estimating the total direct costs of implementing the protocol on a per patient basis. Include estimated hours for enrollment (screening and consent) for PD/PI and coordinator, and estimated hours for protocol implementation (execution).

Include costs of obtaining and shipping biospecimens to a CC biorepository, as well as the estimated cost of analyzing the specimens. Costs associated with equipment that may be unique to the proposed protocol must be included.

Estimated budgets for Protocol and Biospecimen Core should be provided, as final costs will not be known until the Steering Committee selects and develops common protocols. Patient-related costs (e.g., clinical costs that are not part of usual care--tests, sample and data collection, supplies, drugs) will be distributed from the DMCC budget.

Enter the estimated costs for the proposed protocol(s) as line items in Section F. Other Direct Costs:

• Line 8 should be identified as protocol costs should be entered under Funds Requested ($) in this line.

If an application includes a Biospecimen Core:

• Line 9 should be identified as Biospecimen Core and the corresponding total costs should be entered under Funds Requested ($) in this line.

Applicants should label subsections of the Budget Justification appropriately (e.g. Infrastructure, Patient Care Protocol, Biospecimen Core, Equipment,.

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:

A. Clinical Center Overview

In this narrative subsection discuss the CC's overall research goals and the strategic plan to achieve those goals. The research goals should address important clinical problems in and should be put into the context of the current state of knowledge of severe and/or exacerbation-prone asthma phenotypes, biomarkers, and predictive, adaptive clinical trial designs. In addition, the Overview subsection should address the following areas:

Qualifications and Experience: Describe plans to leverage the experience and expertise of the CC team to achieve collaborative conduct of multi-center asthma clinical trials and longitudinal studies, discovery and/or validation of severe and/or exacerbation-prone asthma phenotypes, endotypes and biomarkers. CCs must have an established research program in the scientific areas of interest, appropriate expertise, ability to carry out clinical protocols, an established infrastructure that supports multi-center studies, a track record of successful collaborative research, and demonstrated access to a sufficient number of patients to accomplish their portion of the proposed protocols.

Collaboration: Describe support of collaborative research and interaction with other CCs, the DMCC and the NHLBI in all aspects of the PrecISE program. Include a plan to ensure the maintenance of close cooperation and effective communication among members of the applicant’s team and evidence of the capability of the applicant’s organization to participate and interact effectively in cooperative multi-center research. Discuss capability to participate in a distributed data entry system to transmit and edit data from the DMCC. Recognizing the wide interest in changing the asthma treatment paradigm, particularly in severe and or exacerbation-prone asthma, this may involve domestic and/or international collaboration and/or 3rd party agreements. Describe how unique strengths will be leveraged to contribute to the collaborative effort (e.g., precision-based and/or adaptive clinical trial designs, genetics/genomics/proteomics, bioinformatics, team leadership, multi-disciplinary or multi-national teams, patient recruitment, retention, and adherence strategies).

For CC’s proposing more than one site, plans for collaboration and interaction among institutions should be clearly described in the application. Centers with more than one clinical site should provide management plans that include descriptions of supervision, data handling, quality assurance, cost effective management, and communication.

B. Research Project

Describe the key objectives, design features, and integration of the complete protocol and related biospecimen analyses with timeline at the beginning of this section. The research project plan must include a proposal for one innovative targeted, sequential, precision- and, biomarker-based, adaptive clinical trial protocol that includes at least three distinct interventions, one of which is novel (not FDA-approved for the treatment of severe asthma or severe exacerbations) for the treatment of severe and/or exacerbation prone asthma. Each intervention should be targeted to a specific patient stratum, the phenotype of which is described in clinical and biologic detail, a predictive biomarker (may be composite but must have a biologic rationale) for therapeutic responsiveness, and interim biologic responsiveness should be proposed based on the use of a monitoring biomarker specific for each proposed intervention. Describe feasibility of using proposed biomarkers for prediction and therapeutic responsiveness based on obtaining necessary biospecimens in a minimally invasive, reproducible, cost-effective, and efficient manner. Up to three phenotypes should be proposed with treatment arms for each that includes crossover to an alternative intervention if the interim analysis predicts futility for that specific patient. Describe an analysis plan for proposed predictive and monitoring biomarker(s) and include precision-based, adaptive algorithm design, interim analyses for biomarker response, composite (biomarker and clinical response) endpoint(s), and possible analysis of group effects derived from individual results. Include success and failure criteria in the interim analyses to determine which individuals will continue with the current intervention and which will progress to the next intervention. Describe primary (a composite of biologic and clinical endpoints), and secondary (if appropriate) outcomes for each intervention, with appropriate statistical support. Describe relevant longitudinal follow-up for up to 12 months to determine long term outcomes, if appropriate.

Describe with rationale the biospecimen analyses which may include additional biomarker and/or target discovery and validation; phenotyping and endotyping; and longitudinal follow-up. Studies should be directed at elucidating biologic or biologic/clinical composite data that will further inform the utility of the phenotypes, predictive and/or monitoring biomarkers, composite outcomes being used in the protocol, and the possible intervention effects on modification of the specific pathobiology and natural history of the disease phenotypes and endotypes being used. Describe how the proposed research will be cost-effective and efficient with the ultimate goal of informing future clinical trial design. Include a description of how the proposed study(ies) have the potential to change clinical management paradigm of severe and/or exacerbation-prone asthma patients resulting in a personalized approach with precision-based interventions that improve outcomes and/or modify disease progression.

Note that these studies should not be mechanistic, hypothesis-driven questions of pathobiology. The PrecISE SC will evaluate the proposed analyses. The exact number of analyses supported will depend on the nature and extent of the investigations. Analyses may be selected from the studies proposed by successful applicants in response to this FOA, but a decision to fund a particular Research Center will not commit the PrecISE network to develop that applicant’s proposed analyses. Final analyses will be prioritized on the ability to best inform the execution and success of the protocol and the feasibility to perform collection and analyses within the network parameters.

A narrative describing the ability to enroll 100 severe and/or exacerbation prone asthma patients during an 18-month enrollment period should be included, with objective sources of data on the size of the available population(s) and demonstration of past experience in the successful recruitment and retention of severe and/or exacerbation prone asthma patients in clinical research protocols. A discussion must be included of the ability to enroll specific phenotypes which are both relevant to the precision interventions proposed and accessible within the network parameters (8 clinical centers, anticipated available resources). The study population must be described, with sample size estimates of expected frequency of the relevant phenotypes/endotypes and biomarker(s) in a geographically and ethnically and racially diverse population of 800 severe and/or exacerbation prone asthmatics, and an estimate of the expected distribution of female, minority participants, and children (12 years of age and older). The applicant should indicate for each protocol how many study participants are available in the applicant s center and how many will be required from the entire PrecISE network to conduct the protocol. In addition, a brief description of anticipated problems with recruitment and plans for addressing these problems should be included. Note that proposed solutions may not include requests for additional funds. It is the intent of PrecISE to enroll children 12 years of age and older. The proposed intervention protocol should include children with severe and/or exacerbation prone asthma, as appropriate. Applicants are encouraged to explore, within the context of their proposed protocols, new technologies and therapeutic interventions that could lead to improvements in prediction of therapeutic responsiveness treatments, monitoring of asthma control and disease progression, and significant improvements in asthma management, disease modification, or secondary prevention in specific patient strata.

For purposes of the application, investigators should use the 2014 American Thoracic Society (ATS)/European Respiratory Society (ERS) definition of severe asthma (ATS/ERS severe asthma definition). Additionally, if proposing an exacerbation prone population only, the definition in the 2009 ATS/ERS statement on severe exacerbations (ATS/ERS severe exacerbation definition) should be used, and documentation that patients experienced at least 2 severe exacerbations in the 12 months prior to being enrolled in PrecISE, will be required. Experience in retention of asthma patients in longitudinal studies or clinical trials with longitudinal follow-up must also be described.

Protection of Human Subjects: In this section, a detailed description of the patient population should be described, including phenotypes with biologic/clinical characteristics. Sources of documentation for frequent, severe exacerbations should be identified.

Letters of Support: Letters of institutional and departmental support for participation in PrecISE should be included in the application. The letters of support should demonstrate willingness to participate in PrecISE clinical trials, and in cooperative, central, or shared IRB models. In addition, support should be stated for participation in possible third-party agreements and/or collaborations within or outside the United States, in relation to phenotype- and biomarker-directed, adaptive clinical trials for the treatment of severe and/or exacerbation prone asthma.

Applications from institutions that have a Clinical and Translational Science Award (CTSA) must include a letter of agreement from either the GCRC/CTSA Program Director or PD/PI. The letter should indicate which CTSA resources will be used.

Applications that contain patient recruitment plans that rely on collaborations with other groups (e.g., other health care providers in the community such as pulmonary/allergy practices, primary care practitioners, pediatricians, and health maintenance organizations) should include letters of support from the identified groups.

If the application plans to address any anticipated problems with recruitment by utilizing additional groups, letters of support from those additional groups are required.

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

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Include a statement of assurance that the applicant will comply with all NIH policies and procedures regarding Resource Sharing including genetics and -omics samples and data and dissemination

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

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

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

Specific to this FOA

Does the proposed trial address important clinical problems in severe and/or exacerbation prone asthma? Does the proposed trial use innovative targeted, sequential, adaptive designs with precision-based interventions? Will completion of the proposed studies have the ability to substantially improve future clinical trial design and personalized clinical management for patients with severe and/or exacerbation prone asthma? Is there the possibility for significant improvement in outcomes and possible disease modification for such patients?

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

Specific to this FOA

Do the PD/PIs have experience in the conduct of clinical trials in asthma patients? Do the PD/PIs have experience in the successful recruitment and retention of asthma patients in longitudinal studies? Is there appropriate expertise on phenotyping/endotyping, biospecimen collection, and analysis? Does the team include experience in design and/or execution of adaptive clinical trials?

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

Do the proposed studies address important treatment questions that have not been addressed before? Are novel clinical trial designs and analyses proposed? Do the studies have the potential to change clinical management paradigm of severe and/or exacerbation prone asthma patients resulting in a personalized approach with precision-based interventions that improve outcomes and/or modify disease progression? Are the methods proposed efficient, cost-effective, practical, and do they have the ability to inform novel designs for future clinical trials and translate into the clinic?

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

Specific to this FOA

Are the studies proposed feasible from an organizational, budgetary, and statistical perspective? If proposing to function has a Biospecimen Core, has the applicant included the appropriate description with respect to protocol relevance, feasibility, and quality control?

Has the applicant described the ability to enroll 100 severe and/or exacerbation prone asthma patients, pediatric and adult, during an 18-month enrollment period? Is this ability supported with objective data? Is a discussion included of the ability to enroll specific phenotypes which are both relevant to the precision interventions proposed and accessible within the network parameters (8 clinical centers, anticipated available resources)? Does the description of the study population include sample size estimates of expected frequency of the relevant phenotypes/endotypes and biomarker(s) in a geographically and ethnically and racially diverse population of 800 severe and/or exacerbation prone asthmatics, and an estimate of the expected distribution of female and minority participants?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

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

Are strong letters of institutional support included? Is the willingness to participate in a cooperative, central, or shared IRB indicated clearly?

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 six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

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

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

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

Not Applicable

Not Applicable

Not Applicable

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

Not Applicable

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

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NHLBI in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Heart, Lung, and Blood Advisory Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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

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

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

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

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

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

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.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) will have the primary responsibility for:

• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
• The PD(s)/PI(s) of the CC will have the primary responsibility for all aspects of the PrecISE studies, including proposing protocols, participating in their development, preparing protocol budgets in collaboration with the DMCC, modifying proposals if indicated, leading studies, recruiting study participants, conducting the research, assuring quality of study participant care and protocol adherence, assuring the accurate and timely transmission of data collected to the DMCC, analyzing and interpreting data, and preparing publications.
• Support or other involvement of industry or any other third party, within or outside of the United States, in the PrecISE studies may be advantageous and appropriate. Awardees must follow NHLBI policy concerning third party agreements.

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

The NHLBI Project Scientist will serve on the Steering Committee as a voting member. He/she or other NHLBI scientists may serve on additional committees, when appropriate. The NHLBI Project Scientist (and other NHLBI program staff may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees (e.g., recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, and preparation of publications). NHLBI Program staff, on behalf of the NHLBI, will have the same access, privileges, and responsibilities regarding the collaborative data as the other members of the Steering Committee.

The NHLBI reserves the right to phase out a PrecISE study (or an individual award) in the event of (1) failure to develop or implement mutually agreeable collaborative protocol; (2) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control; (3) major breach of a protocol or substantive changes in the agreed-upon protocol with which NHLBI cannot concur; (4) attaining of a major study endpoint before schedule with persuasive statistical significance; or (5) human subject ethical issues that may dictate an early phase out of a trial or the program.

Annual continuation and level of funding for the DMCC will be based on NHLBI review of actual recruitment and overall performance, determined as part of the NHLBI review of the annual non-competing continuation grant progress reports submitted by awardees. Additionally, an NHLBI program official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

The NHLBI reserves the right to modify or phase out the PrecISE network based on feasibility of achieving network goals as determined by recommendations, generated during the mid-program review, from external experts and NHLBI staff.

In addition to the above responsibilities, the NHLBI Project Scientists will also serve as Program Official, and be responsible to the normal program stewardship, consistent with the provisions of the Cooperative Agreement mechanism.

Areas of Joint Responsibility include:

• Awardees agree to the governance of the study through a SC. The lead investigator(s) from each CC and the DMCC a chairperson, to be appointed by the NHLBI, and an NHLBI representative will comprise the SC. All major scientific decisions will be determined by majority vote of the SC. Each CC, the DMCC, and the NHLBI Program Office will have one vote; the SC Chair will have one vote in case of a tie. Each CC has one vote, even if there are multiple PD(s)/PI(s). Note that if the CCs or DMCC choose to utilize the multi-PD/PI mechanism, the PD/PIs are expected to participate in all SC meetings and teleconferences; however, each Clinical Center has one vote. It is anticipated that SC meetings will be held at least twice a month by conference call and up to 6 times a year in person. The first year during network establishment and initial protocol selection, may require more frequent contact.
• An independent Data and Safety Monitoring Board (DSMB) will be appointed by the Director, NHLBI, to provide overall monitoring of study performance, interim data, and safety issues. An NHLBI scientist, other than the NHLBI Program Scientist, will serve as Executive Secretary to the DSMB.
• Members of the SC will be required to accept and implement policies approved by the SC.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: https://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726

Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Patricia Noel, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0202
Email: [email protected]

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

John Bucheimer
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0166
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.