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 DMCC and runs in parallel with a companion FOA that invites applications for the Clinical Centers (CC) (RFA-HL-17-009).

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.

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 continue 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 Steering Committee (SC) consisting of all funded PDs/PIs 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.

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 . Each clinical center is expected 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.

An independent Data and Safety Monitoring Board (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 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.

The DMCC will have a dual coordination/support and research role in PrecISE. Coordination/support activities will include:

• Providing expert assistance in concept development and feasibility assessment, protocol design and analysis plans, and implementation of multicenter, adaptive, precision intervention, Phase II/ proof of concept, and biospecimen analyses in adult and pediatric populations with asthma.
• Management and distribution of funds to CCs for finalized protocols selected by the SC.Database development; document management; data entry and verification; data validation (data checking and query resolution); coding and reporting adverse events; integration of core laboratory data and data from other external sources across clinical studies; database quality control/improvement; and archival, storage and distribution of documents and biospecimens.
• Development of procedures for quality control/improvement, training and certification, and data management at Clinical Centers.
• Establishment and maintenance of a computer system and software needed for storage and interrogation of study data. It is anticipated that data will include demographics, medical history, medications, results of clinical laboratory tests, outcomes, and responses to questionnaires and patient-centric diaries, as well as extensive genetic, phenotypic and omics-based datasets. Security provisions must be implemented to prevent unauthorized access or release of study data. A backup electronic copy of study data shall be maintained off-site. Biomedical informatics support is expected to be innovative and flexible to support operations, administration and research activities, including a strategy for continual assessment of informatics performance across PrecISE and with external partners/collaborators.
• Monitoring and evaluation of quality of data received from CCs and provide relevant reports to NHLBI, SC and DSMB.
• Monitoring and evaluation of protocol execution and subject accrual for studies and provide relevant reports to NHLBI, SC and DSMB.
• Initiation of changes in training/procedures in response to issues/protocol changes that emerge during trials.
• Planning, arranging, and providing support to meetings of the SC and its subcommittees, and DSMB. Preparation and distribution of minutes of SC meetingsPreparation of draft minutes of open sessions of DSMB meetings and teleconferences, and submit to NHLBI.
• Negotiation of clinical agreements with third parties with NHLBI concurrence and obtaining IND and/or IDE approval from FDA; subcontract to external laboratories/biospecimens repositories; coordinate with suppliers of drugs, and arrange for the preparation and packaging of medications for delivery to CCs.
• Development and maintenance of a secure high-availability web site for the distribution of study documents, forms, and information, including metrics (textual and graphical) of study progress and performance (e.g., expected versus actual subject accrual indexed by CC). Development and maintenance of an open-access web site to provide information about PrecISE to the public and prospective research subjects. NHLBI expects that such information includes a summary of study aims, design, schedule, and eligibility criteria; a link to study registered in ClinicalTrials.gov; a listing of the Clinical Centers with contact information; and a link to the NHLBI public web site. The public web site must comply with all applicable Federal regulations, including Section 508 of the Rehabilitation Act of 1973 (29 USC 794d). See http://www.section508.gov and http://www.nih.gov/icd/od/ocpl/resources/wag/.
• Promoting collaboration across PrecISE to identify core constructs for developing clinical asthma history and phenotype ascertainment instruments, standardized procedures and outcome measures, and when possible harmonized phenotypes for adults and children to facilitate translational science.
• Development of a comprehensive framework for evaluating the effectiveness of PrecISE, including the identification of specific metrics for the PrecISE achieving proposed goals.
• Preparation of public-use files for archiving and sharing results of each study according to NIH and NHLBI policies.
• Preparation of public-use files for disseminating research resources, such as methods of procedures, study manuals, case-report form templates, patient-centric diary templates, and phenotype ascertainment instruments.
• Registration and updating of protocols with ClinicalTrials.gov.
• Submission of manuscripts accepted for publication to PubMed Central according to Federal and NIH policy (http://publicaccess.nih.gov/).
• Tracking of progress of publications, including PubMed Central reference number, and presentations of findings.

The DMCC will play a major research role in the development of the clinical protocol(s), and interim and final analysis of data. The DMCC is expected to include expertise in integration of multi-stage testing in targeted, adaptive clinical trial designs, and the combination of individual patient data to give group treatment effect estimates. The DMCC will participate in all parts of protocol development, execution, and final analyses to help determine the best predictive and monitoring biomarkers for use in specific patient phenotypes, development and statistical modeling and analysis of early responsiveness and formulation of stopping rules, and final analysis of composite biologic and clinical outcomes, and group effect analyses. De novo modeling, using systems and machine learning approaches, will be a major and required component of the DMCC. These approaches will be utilized prior to beginning the protocol to project phenotypic responsiveness to monitoring biomarkers and overall feasibility. During protocol execution, the DMCC will utilize real-time information from clinical and biologic data to project 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 PrecISE Network enterprise.

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 DMCC must have key investigators (PDs/PIs) from at least three different areas of expertise. Demonstrated expertise in predictive, statistical modeling, and analysis in targeted, multi-stage, adaptive clinical trial designs, and a track record of major roles in the conduct of such trials is required. There must also be demonstrated expertise, and a track record of major roles, in the coordination and support of asthma clinical trials and studies, at least some of which had longitudinal components. Additionally, expertise in asthma phenotyping/endotyping and biomarker analysis is required.

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 7214b
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)

Phone: 301-435-0270
Fax: 301-480-0730
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

Other Attachments: Applicants must provide a detailed table listing the characteristics of trials that the demonstrate experience in trial coordination of multi-center asthma clinical trials and clinical trials or studies with longitudinal components in the last 5 years. The table must be provided as an attachment called "Clinical Trial Experience.pdf" and may not exceed 3 pages.

The table columns must include:

Column A: clinical trial title

Column B: applicant's role in the trial

Column C: a brief description of the trial design

Column D: planned enrollment

Column E: actual enrollment

Column F: number of sites

Column G: whether the trial(s) were completed on schedule or not

Column H: publication reference(s)

All instructions in the SF424 (R&R) Application Guide must be followed. The DMCC must have key investigators (PDs/PIs) with sufficient effort from at least three different areas of expertise: 1) management of complex clinical trials and studies in asthma with longitudinal components, 2) asthma phenotyping/endotyping and biomarker analysis, and 3) the design and analysis of predictive, multi-stage, adaptive clinical trial design. Staff of the DMCC must have experience and qualifications in clinical trial management.

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

To justify the personnel included in the budget, in addition to the standard biosketches including the tailored individual statement for key personnel, include a table outlining the expertise and effort proposed for the DMCC. Effort should differ during Year 1 startup (protocol writing, network operations, data base preparation) and Year 6 close down (finalizing data bases, final manuscripts, transferring data and biospecimens (if relevant) to a public biorepository). Expertise needed for the DMCC includes biostatistical expertise in predictive statistical modeling and the design and execution of predictive, sequential, adaptive clinical trial designs, expertise in the asthma clinical trials and clinical longitudinal studies, expertise in asthma phenotyping/endotyping and biomarkers, project management, computer expertise including data base creation and management, and website development.

Suggested Travel

Year 1

• Up to three DMCC staff to attend up to six SC meetings to be held in the Bethesda, MD general geographic area.
• Nine people (including two DMCC staff and seven DSMB members) to attend one DSMB meeting in Bethesda, MD

Years 2 through 6

• Up to three DMCC staff to attend up to six SC meetings each year.

Year 5

• Up to 10 experts in precision, adaptive clinical trial design, and severe and/or exacerbation prone asthma with expertise in clinical, longitudinal, and targeted asthma care for evaluation of the network in Bethesda, MD.

Other costs to be included but not limited to:

• Costs for meeting space for SC and DSMB meetings.
• Reasonable costs for consultants serving on the DSMB should be proposed (to include travel for year 1 meeting and $200 honorarium per member for each meeting/teleconference). In addition, the SC Chair will be selected from outside the CC personnel. The DMCC will be responsible for reimbursing the Chair: consultant budget at 1.8 person months (15% full-time professional effort) should be included and travel for up to 6 SC meetings per year will be restricted for this use.
• Administrative costs including teleconferences, webinars, etc.
• Applicants proposed budgets should not exceed $600,000 in fiscal year 2017, and $900,000 directs costs, exclusive of indirect costs associated with consortia, in fiscal years 2018 through 2022 for the DMCC infrastructure costs.
• For all patient care costs, the DMCC budget must include a line item for reimbursement for patient capitations to be paid to the CCs. Direct costs amounts for patient capitations are limited as follows: Year 1 $96,000; year 2-$11,673,000; year 3-$12,037,000; year 4-$12,037,000; year 5-$11,837,000; year 6-$5,921,000. These should include costs for reimbursement to CCs functioning as biospecimen cores for patient samples. For planning purposes, assume up to four cores with biospecimens such as blood, urine, sputum, EBC, imaging. The final cores, collection, analyses, storage, and associated costs will be determined by the clinical protocols via the SC. However, the DMCC should present a realistic vision based on prior experience with asthma clinical trials/studies. These funds will be restricted for this use only.

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: In lieu of a standard Research Strategy as described in the SF424 (R&R) Application Guide, the applicant must present a discussion of the planned approach to coordination and administration, development and finalization of protocols, data management, biostatistical support, and data analysis and dissemination support for the complex clinical trials-based PrecISE Network. Applicants must describe:

• Capacity to develop novel, cost-effective, and innovative predictive, targeted, adaptive clinical trial designs and predictive statistical modeling and analysis of data. Include the use of predictive monitoring biomarkers, early stopping rules with crossover to subsequent intervention(s), and modeling of group effect data. Include relevant examples from applicant’s previous clinical trials. Describe the potential to significantly improve the way phase II and/or proof of concept trials are performed in asthma patients. Approaches described should be flexible and able to adapt to interim analyses results such that phenotypes and/or precision interventions can be added and/or eliminated.
• Approach toward and capacity for asthma phenotyping/endotyping and biomarker analysis. Include relevant examples from applicant’s previous clinical trials.
• Plans for the administrative structure of the proposed DMCC and how this structure facilitates communication and cooperation among the CCs, the DMCC, and the NHLBI. Explain how the proposed structure will be able to react quickly to unexpected events.

Methods for clinical data collection and data integrity.

• DMCC team history of interactions with regulatory agencies and with obtaining and holding Investigational New Drug (IND) permits.
• Strategy for monitoring quality assurance of clinical trial data at CCs.
• Ideas for monitoring and improving enrollment and retention in trials.
• Plans for oversight and operation of a clinical trials network including
• computer and data systems
• public and private website creation and maintenance
• quality and safety oversight
• CC staff training and monitoring
• drug preparation
• preparation of data sets for committees and for placement in a public data repository
• study drug blinding and distribution
• meeting and minutes organization

other activities that will demonstrate the capabilities of the applicant

Letters of Support: Provide letters of support, including a letter indicating institutional willingness to participate in a 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 exacervation prone asthma.

Applications that do not include the above elements will be considered incomplete.

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.

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 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 NOT-OD-13-030.

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

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

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

Significance

Does the proposed Center address the needs of the research network that it will coordinate and administer? Is the scope of activities proposed for the Center appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research network?

Investigator(s)

Are the PD(s)/PI(s) and other personnel well suited to their roles in the Center? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing clinical research? Do the investigators demonstrate significant experience with coordinating collaborative clinical research? If the Center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach, governance, plans for conflict resolution, and organizational structure appropriate for the Center? Does the applicant have experience overseeing selection and management of subawards, if needed?

Specific to this FOA

Does the research team include demonstrated expertise, with sufficient effort, in the following areas: management of complex clinical trials and studies in asthma with longitudinal components? expertise in asthma phenotyping/endotyping and biomarker analysis? expertise in the design and analysis of predictive, multi-stage, adaptive clinical trial design? experience and qualifications in clinical trial management?

Innovation

Does the application propose novel management strategies in coordinating the research network the Center will serve?

Specific to this FOA

Have innovative clinical trial designs and statistical modeling and analysis plans been described? Is there the potential to significantly improve the way phase II and/or proof of concept trials are performed in asthma patients?

Approach

Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the research network the Center will serve? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the network, as appropriate for the work proposed? If the network is in the early stages of operation, does the proposed strategy adequately establish feasibility and manage the risks associated with the activities of the network? Are an appropriate plan for work-flow and a well-established timeline proposed?

Specific to this FOA

Have novel, cost-effective approaches to clinical trial design, data collection, training, CC oversight, and information sharing been described? Are the approaches flexible and able to adapt to interim analyses results such that phenotypes and/or precision interventions can be added and/or eliminated?

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?

Environment

Will the institutional environment in which the Center will operate contribute to the probability of success in facilitating the research network it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the Center proposed? Will the Center benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling?

Specific to this FOA

Are strong letters of institutional support included? Is the institution's 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) 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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• The DMCC PD/PIs will be responsible for the overall function of all PrecISE research activities. The DMCC PD/PIs will be responsible for oversight of protocol development, including predictive modeling of biologic responsiveness to specific interventions, formulation and implementation of early stopping rules; drug acquisition and distribution; data collection; data safety and confidentiality, quality assurance; data analysis, both individual and group effect; coordination of data distribution, and implementation of all data sharing plans. The DMCC may also be responsible for filing and holding of INDs, as necessary. The DMCC will be responsible for the distribution of protocol funds to the CCs (see RFA-HL-17-009). The DMCC will be responsible for coordination of manuscript preparation, activities of the Steering Committee, and Data and Safety Monitoring Board.
• 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 applicable NIH, and NHLBI policy concerning third party agreements.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

The 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 Steering Committee (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 Chair will have one vote in case of a tie. Note that although CCs and/or the DMCC may choose to utilize the multi-PI mechanism, each CC and the DMCC will have only one vote in all SC and relevant subcommittee meetings. 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 Scientists, shall serve as Executive Secretary to the DSMB.

Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

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: support@grants.gov

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

Patricia Noel, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0202
Email: noelp@nih.gov

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

John Bucheimer
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0166
Email: bucheimerj@nhlbl.nih.gov

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

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