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 objective of this program is to investigate mechanisms of ventilatory control that contribute to instability of oxygenation and risk of morbidity and mortality in premature infants during and after the Neonatal Intensive Care Unit (NICU) using a prospective observational cohort. This is an important step toward the identification of new opportunities for preventive interventions for high risk premature infants.

Chronic respiratory disease impacts thousands of premature infants annually in the U.S. leading to prolonged stays in Neonatal Intensive Care Units (NICUs), increased mortality, and respiratory morbidity. With improved neonatal care, many survivors of extremely low gestational age birth develop bronchopulmonary dysplasia (BPD) defined by instability of oxygenation and persistent needs for respiratory support as they prepare for discharge home from the NICU at 36 weeks postmenstrual age (PMA). This inability to maintain oxygenation during the NICU course and at 36-40 weeks PMA is managed with a range of supportive measures including low to high flow nasal cannula, varying concentrations of oxygen, nasal continuous airway pressure, and mechanical ventilation.

Preterm birth can interrupt not only the rapid increase in surface area for alveolar-capillary gas exchange that takes place during the late stages of pregnancy, but also may interrupt neurodevelopment and maturation of ventilatory (neurorespiratory) control. The ventilatory control system is required to regulate ventilation and provide oxygen to tissues and remove carbon dioxide. Neurons in the brainstem and higher centers in coordination with input from mechanoreceptors and chemoreceptors constitute the ventilatory control system. More than half of premature neonates have apnea of prematurity with significant episodes of interrupted breathing, resulting in significant hypoxemia and life-threatening bradycardias. Immature breathing mechanisms in the postnatal environment may contribute to BPD and/or result in respiratory decompensation, need for resuscitation, and mechanical ventilation. The trajectory of maturation of neurorespiratory control in premature babies is not clear, and how this contributes to acute and chronic respiratory outcomes of premature infants including BPD is unknown.

Despite the use of continuous cardiorespiratory monitoring in the NICU, episodes of periodic breathing and intermittent hypoxic periods are not captured even by the sophisticated monitors. Some episodes may accompany bradycardia. In premature infants, because of the intermittent nature of apnea, bradycardia, and desaturation episodes, events are infrequently recorded or reported. Clinical care givers often use physiologic responses to evoked challenges, such as titrating inspired oxygen concentrations to make a diagnosis of BPD, but better tests for this condition are lacking. Mathematical modeling algorithms that can utilize continuous recordings as input data from ICU monitors could inform the detection and analysis of breathing patterns in the premature. The ultimate goal is to gain greater insight into the pathogenesis of chronic respiratory disease of the premature, identify novel BPD phenotypes and physiological biomarkers, and discover targets for new prevention and treatment strategies, to improve outcomes for very vulnerable children at the beginning of life.

Prospective observational cohorts from each research center will inform site-specific and multicenter investigation of the maturation of ventilatory control in premature infants in the NICU and its role in respiratory outcomes to near term and 3 months corrected age. Multi-disciplinary teams are strongly encouraged with clinical research expertise in neonatology, respiratory and neural biology/physiology, sleep medicine, and/or computational modeling.

The program will consist of up to five Clinical Research Centers (CRCs) (described in RFA-HL-16-015) and one Leadership and Data Coordinating Center (LDCC). The first six months of the grant period will be for intensive collaborative planning by the LDCC and CRCs to conduct the necessary activities so that enrollment of premature infants begins no later than the end of Year 1.

Leadership and Data Coordinating Center (LDCC): The applicant to this LDCC FOA will provide statistical leadership and expert assistance in concept development and feasibility assessment of the multicenter protocol, but will not be responsible for statistical leadership of CRC specific applications. The LDCC will facilitate all aspects of recruitment including harmonization of data collection and cardiorespiratory monitor download and transfer across sites, consent form templates, development and programming of case report forms (CRFs), preparation of materials for submission to local IRBs, manuals of operation, oversight of protocol and protocol amendments, web-based data entry, serious adverse event reporting, coordinator and other staff training, common phenotyping elements, and clinical database management. The LDCC will provide the data management system that facilitates multicenter and single center data collection, retrieval, data sharing, and analysis. The LDCC will provide an open data system so that single research centers can add data elements/CRFs needed for single center projects and ensure the data are readily accessible. The LDCC will create and manage a DNA biorepository (trios of subject and parents) of samples from multicenter subjects and facilitate access for future genetic projects. The LDCC will also organize meetings and calls of the Steering Committees, Observational Safety Monitoring Board (OSMB), and program joint bi-annual meetings; design and maintain written materials and a website to support the program. The LDCC will provide relevant reports to the NHLBI and OSMB. The LDCC should have appropriate expertise for neonatal studies.

Scope of Activities for the LDCC

The LDCC will provide leadership of a multicenter research protocol using NICU cardiorespiratory monitor data, clinical data, biospecimens, and administrative and data coordination for Pre-Vent program activities.

In support of the activities of Pre-Vent, the LDCC will

(1) propose a research plan that investigates mechanisms of ventilatory control that contribute to respiratory outcomes and utilizes NICU cardiorespiratory monitor data (from CRC sites) from at least 500 premature infants (at least 75% of which are <29 weeks gestation)

(2) collaborate with CRCs in the development, implementation and monitoring of the common multicenter protocol and harmonization with CRC-specific research data collection

(3) provide statistical leadership and expert assistance in concept development and feasibility assessment of the multicenter protocol

(4) facilitate all aspects of recruitment including data collection, consent form templates, development and programming of multicenter and single center CRFs, preparation of materials for submission to local IRBs, manuals of operation, oversight of protocol and protocol amendments, web-based data entry, serious adverse event reporting, coordinator and other staff training, common phenotyping elements, and clinical database management.

(5) facilitate cardiorespiratory monitor data download and transfer from CRCs to LDCC core for interpretation and analysis

(6) provide data management, including preparation of data and safety reports for the OSMB and preparation of data reports for Pre-Vent subcommittees, CRCs and public data files

(7) collaborate in the analysis of data and publication of results of the Pre-Vent multicenter studies

(8) provide the logistical support necessary to running an efficient and productive multicenter program including coordination with the clinical centers for cardiorespiratory monitor data and DNA collection and transfer to the LDCC.

(9) collect and file all Institutional Review Board (IRB) reports and communications;

(10) provide logistical support for in person meetings, teleconferences, of the steering committee, subcommittees, and OSMB, including expenses for Steering Committee Chair and OSMB members.

(11) provide support for DNA biospecimen collection, storage, management, and facilitate access for future genetic projects;

Clinical Research Centers (CRC) (described in RFA-HL-16-015): Each CRC awardee will investigate specific hypotheses of ventilatory control mechanisms (e.g. chemoreceptor, mechanoreceptor, developmental, etc.) that contribute to instability of oxygenation and risk of morbidity and mortality in premature infants. Methods to test these hypotheses should include novel approaches to examine how ventilatory control influences the inability to maintain oxygenation at 36 weeks postmenstrual age and acute/chronic respiratory compromise through at least 3 months corrected age. CRCs will include prospective assessment of control of breathing in a premature cohort at 2 or more time points to assess maturational changes of ventilatory control. Applicants are encouraged to include evoked phenotypes (e.g., medication induced, hypoxia/hyperoxia induced, etc.) to examine vulnerabilities and/or resilience of these respiratory control processes to the development of or resolved need for respiratory support at 36 weeks postmenstrual age and during infancy.

A CRC can be a single institution or group of institutions with the capability of recruiting and retaining at least 100 premature infants, (at least 75 of which are <29 weeks gestation) during the NICU course and through at least 3 months corrected age to ensure robust pathophysiologic studies of ventilatory control maturation and its role in acute and chronic respiratory disease risk.

Multicenter Collaborative Project: In addition to individual CRC studies this collaborative program will develop a LDCC-coordinated multicenter project that will investigate ventilatory control mechanisms in outcomes of instability of oxygenation, acute and chronic morbidity. The multicenter protocol will leverage readily available NICU cardiorespiratory monitor data from at least 500 premature subjects (75% of which are below 29 weeks gestation) enrolled across participating sites. To investigate the role of maturation of ventilatory control on outcomes of premature infants, the LDCC will include a computational modeling expert to develop a protocol, which will be finalized with Steering Committee member input that utilizes at a minimum respiratory rate and rhythms, pulse oximetry, and heart rate. The multicenter project will answer whether algorithms using readily available clinical NICU cardiorespiratory monitoring data can detect ventilatory control instability and predict acute or chronic respiratory disease after 36 weeks PMA. This could lead to a new strategy for detection of ventilatory control contributions to chronic respiratory outcomes of the premature that could be implemented for research and clinical care.

Steering Committee (SC): The SC is composed of CRC PDs/PIs, the LDCC PDs/PIs, SC Chair, and the NHLBI Program Scientist. The SC will have responsibility for developing the overall scientific direction of the program; assuring compliance with program policies and procedures; selecting topics for investigation; designing study protocols; implementing studies; ensuring data quality and completeness; participating in the analysis and interpretation of data; and reporting results in presentations and publications. The SC will be chaired by an outside expert selected by the NHLBI. The Chair will have one vote, as will each of the CRCs, the LDCC, and the NHLBI Project Scientist.

Each SC member must work intensively in a cooperative and interactive manner with the LDCC awardee so that enrollment begins no later than end of year 1. The awardee is expected to attend an in-person 2-day Steering Committee meeting on July 28-29, 2016 in Bethesda, MD, in order to develop the multicenter protocol. The SC will meet by conference call monthly, and will meet in person at least twice a year throughout the project period.

Within 6 months of award, the SC will: 1) identify harmonized clinical data to be collected, 2) develop common respiratory phenotypes at approximately 36 weeks PMA, 3) develop common respiratory outcomes to 3 months corrected age, 4) develop a protocol for cardiorespiratory monitor data transfer to LDCC for analysis, 5) determine what biospecimens will be collected and stored on subjects for later analysis through additional funding outside this FOA, and the procedures for collection, storage, and access, and 6) develop a data sharing plan for the data and biospecimens collected including a long-range plan for subsequent studies of the cohort as they age to maturity. Note that biospecimen collection will not be permitted until the final protocols are reviewed and approved by the Observational and Safety Monitoring Board (OSMB) and IRBs.

Single CRC protocols have unique study objectives and are likely to include distinctive data collection that may not be required in the multicenter protocol. These should be harmonized with and not conflict with multicenter objectives. SC members must reach the following milestones in the first year before enrollment begins: finalize the multicenter protocol within 6 months, OSMB and IRB review and approval, development of Manual of Operations, data management system launched, and staff training.

Safety Oversight: Protocols (single CRC and multicenter) will be reviewed by Institutional Review Boards and an OSMB with expertise to evaluate risk and current accepted clinical practices. The OSMB will provide overall monitoring of progress, interim data and safety issues and will be appointed by NHLBI. Therefore, applicants should not appoint OSMB members in advance of the peer review, or even inquire about the interest of possible OSMB members, because anyone so contacted would not be eligible to serve as a member of the peer review committee that will evaluate the applications for scientific merit. An NHLBI scientist other than the NHLBI’s Pre-Vent Program Scientist will serve as the Executive Secretary to the OSMB. The OSMB will meet approximately semi-annually by teleconference call or in-person meetings in the Greater Washington D.C./Baltimore region.

The NHLBI will be substantially involved with the awardees in a partnership. The NHLBI Program Scientist will monitor patient recruitment and study progress, ensure a policy for the disclosure of conflicts of interest, and assure adherence to NHLBI policies.

Selected Research Examples

Research examples include, but are not limited to:

• How does caffeine stabilize ventilatory responses to hypoxia in premature infants?
• How do nasal cannula flow rates modify ventilatory responses in premature babies with hypoxemia at 32 and 36 weeks PMA?
• What are the ventilatory responses to room air challenges that predict infants at risk of life threatening episodes of apnea and cyanosis after NICU discharge?
• How does upper airway obstruction impact ventilatory responses to hypoxia?
• What components of ventilatory responses during feeding predict resilience and survival without morbidity?

This FOA is intended to support only human studies and test a hypothesis. Descriptive studies alone will not be considered responsive. Applications that include animal studies or model systems will not be considered responsive. Patient registries and retrospective studies will not be considered responsive. Clinical trials are not the intent of this FOA.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) 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 PD/PI or multiple PD(s)/PI(s) together must possess a doctoral degree in a relevant field such as statistics, biostatistics, computational modeling, or epidemiology and must commit no less than 2.4 person-months (20 percent) combined effort to the LDCC activities of the Pre-Vent program. The PD(s)/PI(s) must have multicenter clinical study, administrative, and statistical expertise. Active participation of the PD(s)/PI(s) is expected during all phases of a clinical research study. . Applications for the LDCC may be submitted by individuals located at the same institution as an applicant for a CRC site grant submitted under RFA-HL-16-015, but an individual may not be the PD/PI of both a CRC and the LDCC.

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

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, 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
National Institutes of Health
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.

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

Facilities and Other Resources: Institution descriptions should include information about the data management system including computers, firewalls, and back-up systems and Information Technology/Institutional support and experience with data transfer for the multicenter project.

All instructions in the SF424 (R&R) Application Guide must be followed. Profiles should specify PD/PI expertise in statistics, biostatistics, computational modeling, and/or epidemiology and the extent to which key personnel have clinical research expertise in neonatology, respiratory and neural biology/physiology, and/or sleep medicine.

One individual must be designated as an alternate PD/PI who is able to serve in the absence of the other PD(s)/PI(s).

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

Applications should budget for the following:

• LDCC PD(s)/PI(s) will be required to declare a minimum effort of 2.4 person-months (20 percent) effort per year. Applications proposing Multiple PD(s)/PIs(s) must have a minimum combined PD/PI effort of 2.4 person months.
• Computational modeling expertise for multicenter protocol development that includes plans for collecting, transfer, and processing cardiorespiratory monitor data and analysis
• Arrangement of logistical services for protocol-specific costs, including subcontracts and supplies
• Support for the activities of the Steering Committee, Steering Committee Chair, and the OSMB through provision of materials/documentation support, meeting planning and logistics and conference call coordination
• In-person travel of at least the PD(s)/PI(s) to Bethesda, MD at least twice a year throughout the project period for two-day meetings, including the launch meeting which has been scheduled for July 28-29, 2016 in order to develop the multicenter protocol.
• Administrative management of subcontracts with the clinical sites for disbursement of capitation costs
• Budget years 2-5 should include costs for site cardiorespiratory monitor data and biospecimens transfer to the LDCC.

Expertise and Effort Table

To justify the personnel component of the budget, in addition to the standard biosketches including the tailored individual statement for key personnel, the applicant should include a table outlining the role the individuals in the project and effort proposed for the LDCC. Effort should differ during Year 1 startup (protocol writing, LDCC operations, data base preparation) and Year 5 close down (finalizing data bases, final manuscripts, transferring data and biospecimens to NHLBI). Expertise typically needed for a LDCC includes project management, research coordinator, biostatistics, computer expertise including data base creation and management, website development. For this FOA, computational modeling expertise for processing cardiorespiratory monitor data and analysis, as well as biobanking is needed.

Recommended Travel:

Year 1:

• 4 LDCC staff and 1 SC chair attending 2 SC meetings to be held in Bethesda/Washington DC region.
• 7 people (including 2 LDCC staff and 5 OSMB members attending 1 OSMB meeting in Bethesda, MD.

Years 2 through 5:

• 5 LDCC staff and 1 SC chair attending 2 SC meetings each year.
• 2 LDCC staff visiting 5 clinical centers each year for oversight and quality assurance.
• 7 people (including 2 LDCC staff and 5 OSMB members attending 1 OSMB meetings each year

Other costs to be included but not limited to:

• Costs for meeting space for SC and OSMB meetings.
• Reasonable costs for consultants serving on OSMB should be proposed.
• The SC Chair will be selected from outside the LDCC personnel. The LDCC will be responsible for reimbursing the Chair: consultant budget at 1.2 person months (10% full-time professional effort) should be included and will be restricted for this use.
• Administrative costs including teleconferences, webinars, binder production etc.

Cardiorespiratory Monitor Data (CRM) Core:

The LDCC budget must include costs for logistical management of cardiorespiratory monitor (CRM) data collection from CRCs, including protocol development, manual of procedures and training for data transfer to LDCC CRM core, and data quality review, cleaning, linkage to clinical data, and analysis.

Data Management System (DMS):

A budget should be proposed that includes a DMS with flexibility to support single center research needs and data access for CRC single center studies.

Biospecimen Core:

A budget should be proposed to support a central biospecimen core. This should include sufficient labor to establish procedures that meet quality standards of the NHLBI Biorepository (BioLINCC https://biolincc.nhlbi.nih.gov/home). Costs include sample collection kits assuming several types of biospecimens that would be useful for DNA genotyping (trios of subject and parents), shipping containers and shipping costs for the CRCs, costs for storage at the LDCC biorepository, and costs for final shipping to the NHLBI biorepository. Costs for quality assurance (QA) should be described. This biospecimen collection plan will be finalized by the SC, but the LDCC should present a vision and budget for the biospecimen collection. A subcontract may be proposed for the biospecimen core.

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: Applicants for the LDCC should propose specific hypotheses of ventilatory control mechanisms that contribute to instability of oxygenation, and risk of morbidity and mortality in premature infants. The multicenter application should leverage readily available NICU cardiorespiratory monitor data from at least 500 premature subjects (75% of which are below 29 weeks gestation) enrolled at the CRCs in response to RFA-HL 16-015. The LDCC-proposed multicenter protocol will be finalized with Steering Committee member input that utilizes at a minimum respiratory rate and rhythms, pulse oximetry, and heart rate. The multicenter project should answer the extent to which algorithms using readily available clinical NICU cardiorespiratory monitoring data can detect ventilatory control instability and predict acute or chronic respiratory disease after 36 weeks PMA. This could lead to a new diagnostic strategy for detection of ventilatory control contributions to chronic respiratory outcomes of the premature that could be implemented for research and clinical care.

The LDCC multicenter research application should include the hypotheses or questions to be addressed, background, rationale, and significance of the anticipated results, preliminary data, patient group to be studied, the number of patients per group, the interventions and methods (including power and statistical analysis of endpoint to be studied). Clinically meaningful acute and/or chronic respiratory endpoints to at least 3 months corrected age are expected.

In addition to a Research Strategy with the usual headings for a multicenter application , the LDCC applicant should describe their plans for carrying out the duties involved in overseeing a multicenter prospective observational protocol.

Some of the duties are listed below:

• Maintain a common data set, and provide a platform for sites to collect and manage CRC specific data.
• Provide data management, including quality control and development of forms.
• Provide data analysis plans and other statistical support for the multicenter protocol.
• Develop needed databases and implement a web-based system to coordinate program activities that serve the multicenter protocol as well as the single center research.
• Provide support in designing and conducting joint protocols.
• Provide support for and monitor CRC start up procedures.
• Maintain quality control and monitor performance of the Clinical Research Centers and other central units.
• Provide procedures and training to clinical center staff, answer questions as needed, and take a leadership role in resolving issues and problems as they arise during the study.
• Monitor that all clinical centers use informed consent documents that contain all necessary elements and that informed consent is obtained properly for all participants.
• Prepare and distribute reports (e.g., adverse event report compilation and distribution; clinical center recruitment performance).
• Provide coordination of OSMB, Steering Committee, and Research Site subcommittee teleconferences, meetings, and reports as needed.
• Provide support for preparing and submitting joint presentations and joint publications.
• Provide plans for biospecimen collection and storage in collaboration with Steering Committee input.

LDCCLDCC

A LDCC application should provide evidence of the applicant's ability to cooperate with multiple sites involved in clinical study design, execution, data collection and data analysis resulting in publication particularly in the area of neonatal-perinatal medicine.

The Research strategy section may include any other information that the applicants deem important for determination of merit.

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
• Clinical data collected by the CRCs will be deposited with the LDCC which will be responsible for adhering to the NIH data sharing policy.

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. The following information may be provided as a PDF file with the name (PD(s)/PI(s) name) Pre-Vent (XX).pdf":

• The study protocol
• Informed consent form
• A timeline for developing protocols for standardized clinical data collection, training, and data management system; a timeline for recruitment/sample/data collection; and a timeline for electronic cardiorespiratory monitor data collection, transfer and analysis with standardized clinical data from all participating research centers awarded through RFA-HL-16-015.
• Agreement to lead and collaborate in multicenter protocol development and implementation.

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

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

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. 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.

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.

For this particular announcement, note the following:

Complete applications must include:

• A timeline for developing protocols for standardized clinical data collection, training, and data management system
• A timeline for recruitment/sample/data collection
• A timeline for electronic cardiorespiratory monitor data collection, transfer and analysis with standardized clinical data from all participating research centers awarded through RFA-HL-16-015.
• Agreement to lead and collaborate in multicenter protocol development and implementation.

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? 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?

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? How well has the application documented that the PD(s)/PI(s) has(ve) expertise in statistics, biostatistics, computational modeling, or epidemiology? To what extent does the applicant have multi-disciplinary teams with clinical research expertise in neonatology, respiratory and neural biology/physiology, and/or sleep medicine? How experienced is the LDCC team with clinical study management?

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? To what extent are innovative approaches to clinical study design, data collection, cardiorespiratory monitoring data analysis, training, CRC oversight and information sharing been described?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Are economical and efficient means for communication with and among CRCs described? Is the plan for the DNA biospecimen core sufficient to result in high quality specimens? How feasible are plans for electronic cardiorespiratory data collection from CRCs and transfer to the LDCC? What is the quality of the plan for prospective analyses from a premature cohort of at least 500 neonates, <29 weeks gestation and an appropriate comparison cohort?

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? Are data management systems flexible enough to accommodate the needs of CRC research including specific single center data collection and access? Are facilities available for secure data and biospecimen storage?

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.

Not Applicable

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 Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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 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.

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.

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: the overall function of all Pre-Vent research activities. The LDCC PDs/PIs will be responsible for oversight of protocol development, data collection, data safety and confidentiality, quality assurance, data analysis, coordination of data distribution, and implementation of all data sharing plans. The LDCC PD/PI will be responsible for coordination of multicenter protocol manuscript preparation, activities of the Steering Committee, Protocol Review Committee, and Observational Safety Monitoring Board.

Support or other involvement of industry or any other third party in the Pre-Vent studies may be advantageous and appropriate. Awardees must follow NHLBI policy concerning third party agreements.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current 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 Pre-Vent Project scientist (PS) will participate in Steering Committee activities. Several procedures are in place to manage potential conflicts of interest by PS administering the cooperative agreement. PS will not seek lead authorship of primary publications and will obtain approval by Branch Chief to participate in secondary publications. 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 Project scientist, 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 negotiate milestones for study conduct in each year of an award and the right to phase out an individual award in the event of: (1) failure to develop or implement a 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 CRC 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, the NHLBI Program Official will be responsible for the programmatic stewardship of the award and will be named in the award notice

Areas of Joint Responsibility include:

Awardees agree to the governance of the study through a Steering Committee (SC). Up to two investigators from each CRC and the LDCC, 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 Clinical Research Center, the Leadership and Data Coordinating Center, and the NHLBI Project Scientist will have one vote; the Chair will have one vote in case of a tie. Note that although each Clinical Center may have multiple PIs, each Clinical Research Center has only one vote. It is anticipated that SC meetings will be held at least once a month by conference call and two times a year in person. The first year during PRE-VENT program establishment and initial protocol selection, may require more frequent contact

An independent Observational Safety Monitoring Board (OSMB) will be appointed by the Director, NHLBI to provide overall monitoring of study performance, interim data, and safety issues. An NHLBI scientist, other than the NHLBI Project Scientist, shall serve as Executive Secretary to the OSMB.

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)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-710-0267

Carol J. Blaisdell, M.D..
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0222
Email: [email protected]

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

Renee Livshin
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0174
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.