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 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) invites applications from investigators willing to participate with the NICHD under a cooperative agreement in an ongoing multicenter clinical program designed to perform interventional and observational clinical studies in newborn infants, particularly low birth weight infants. The model of multi-site clinical centers for research is the gold standard for conducting clinical research. The objective of this program is to facilitate the advancement of neonatal care by establishing a network of academic centers that, by rigorous patient evaluation using common protocols, can study the required numbers of patients and can provide answers more rapidly than individual centers acting alone to provide evidence to guide clinical practice.

The infrastructure is set up for randomized double-blinded placebo controlled and management trials with the ability to follow short term (clinical effect) and long term (neurodevelopmental outcome) measures. The infrastructure is also set up for observational, longitudinal studies in the neonatal intensive care unit setting. Many randomized clinical trials involve the need for baseline information regarding disease incidence and outcome, which is available from the generic database of neonates 22-28 weeks gestational age in the current Neonatal Research Network. This initiative will foster the conduct of multicenter trials in the neonatal population.

The NICHD Program Staff will assist Program Directors/Principal Investigators (PDs/PIs) of the Neonatal Research Network (NRN) and the Advisory Board in identifying research topics of high priority and in designing and implementing protocols in the evaluation of optimum management in the areas targeted for research. It is anticipated that 14 to 18 clinical centers will be involved in the program.

The primary objective of the Neonatal Research Network (NRN) is to advance the field of Neonatal-Perinatal Medicine by establishing and maintaining a network of academic centers that perform multi-center clinical protocols in a rigorous manner to investigate the safety and efficacy of treatment and management strategies to care for newborn infants, including low birth weight infants.

In an attempt to respond to the need for well-designed clinical trials in neonatal medicine, NICHD established a Neonatal Research Network in 1986.

There are a number of controversial issues in neonatology that might be clarified by multicenter collaborative research. Funded PDs/PIs will cooperate with the NICHD Program Scientist in identifying research topics of high priority and in designing protocols appropriate to the evaluation of superior or even optimal management in these areas. The participating Neonatal Research Network members will be designated as "Clinical Centers" which will recruit, assess and treat subjects under the supervision of the respective Clinical Center PD/PI as well as the research team assembled at the clinical center. The data coordinating center, which is funded under a separate FOA (RFA-HD-13-014), will have primary responsibility for data management and analysis for Network research in collaboration with the Steering Committee.

Ongoing studies in the NRN include:

• The Generic Data Base Study (GDB): Survey of Morbidity and Mortality in High Risk, Preterm Infants (see http://www.clinicaltrials.gov/ct2/show/NCT00063063)
• Follow-up of high Risk Infants at 18-22 months (see http://www.clinicaltrials.gov/ct2/show/NCT00009633)
• A Multi-center Randomized Trial of Laparotomy vs. Drainage as the Initial Surgical Therapy for ELBW Infants with Necrotizing Enterocolitis (NEC) or Isolated Intestinal Perforation (IP): Outcomes at 18-22 months Adjusted Age (see http://www.clinicaltrials.gov/ct2/show/NCT01029353)
• Effect of Hydrocortisone on Survival Without Bronchopulmonary Dysplasia and on Neurodevelopmental Outcomes at 18 - 22 Months of Age in Intubated Infants < 30 Weeks Gestation Age (see http://www.clinicaltrials.gov/ct2/show/NCT01353313)
• Inositol for Retinopathy of Prematurity (see http://www.clinicaltrials.gov/ct2/show/NCT01954082) - This study is currently co-funded by NEI.
• Neurodevelopmental Effects of Donor Human Milk vs. Preterm Formula in ELBW infants (see http://www.clinicaltrials.gov/ct2/show/NCT01232725)
• Do Antenatal Steroids Affect Maturation of the Amplitude Integrated Electroencephalogram in Late Preterm Infants? A Secondary Study by the NRN for the MFMU ALPS Trial (http://www.clinicaltrials.gov/ct2/show/NCT01222247)
• Transfusion of Prematures (TOP) Trial (http://www.clinicaltrials.gov/ct2/show/NCT01702805)- this study is currently co-funded by NHLBI.
• Preemie Hypothermia for Neonatal Encephalopathy (http://www.clinicaltrials.gov/ct2/show/NCT01793129)
• Hydrocortisone for Term Hypotension (http://www.clinicaltrials.gov/ct2/show/NCT01954056)
• Donor Milk versus Formula in Extremely Low Birth Weight (ELBW) Infants (http://www.clinicaltrials.gov/ct2/show/NCT01534481)
• Incubator Weaning of Moderately Preterm Infants (http://www.clinicaltrials.gov/ct2/show/NCT02160002)

The NICHD expects to enable the Network to initiate new protocols in the next award period. The topics of these protocols will be decided cooperatively by the Steering Committee with advice from the Advisory Board.

Areas of potential projects include but are not limited to:

• Trials of agents and strategies to improve short term and long term outcomes for infants (e.g. resuscitation strategies, medications, devices, preventive measures, management approaches, and so forth).
• Observational studies of areas where little or no evidence is available for clinical management (to include but not limited to infants born at the threshold of viability, nutrition, late preterm infant, infection, medical devices) or areas where there are gaps in knowledge.

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

Organizations should have academically-oriented divisions of neonatology and a minimum of 500 admissions per year in the neonatal intensive care unit. No more than 30 percent of infants should be outborn (i.e. at least 350 inborn infants per year). Large perinatal services will be given preference over combined services composed of small inborn unit(s) with a large transfer population. The need for continuous and active communication among centers dictates that only institutions in the United States are eligible to apply.

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 not 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.

PD(s)/PI(s) for the Clinical Centers should either be neonatologists certified by the American Board of Pediatrics, Neonatal-Perinatal Medicine Sub-Board; or if a current certification is not active, should provide evidence of previous certification(s) by the American Board of Pediatrics, Neonatal-Perinatal Medicine Sub-Board; or in neonatal-perinatal medicine by similar non-United States certifying entities as may be applicable; or provide descriptions of training, experience, research and publication history, and leadership so as to be widely recognized as academic neonatologists. The person designated as the Alternate PD/PI should meet the same criteria as the PD/PI as described in the preceding sentence. The Alternate PD/PI may be one of the named PD(s)/PI(s) on a multiple PD/PI application.

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

Only one application per institution (normally identified by having a unique DUNS number or NIH IPF number) is allowed.

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).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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:

Tonse NK Raju, MD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-5575
Fax: 301-496-3790
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.

Facilities and Other Resources:

Population Available for Clinical Trials

Participants must be based at level III/IV neonatal intensive care units that admit inborn and outborn infants. The application must contain information describing the available population for the NRN trials as well as a willingness to enroll eligible patients. Applicant clinical centers must have at least 500 NICU admissions per year. No more than 30 percent of admissions should be outborn (i.e. there must be at least 350 inborn infants per year). In order to provide peer reviewers with the specific neonatal population available for study at the clinical site(s), include information regarding admissions over the designated two-year period (2013-2014) in tabular format:

• Number of Births
• Number of NICU admissions
• NICU inborn admissions < 34 weeks
• NICU inborn admissions < 29 weeks
• NICU inborn admissions < 1500 grams birth weight
• NICU inborn admissions < 1000 grams birth weight
• NICU outborn admissions < 34 weeks
• NICU outborn admissions < 29 weeks
• NICU outborn admissions < 1500 grams birth weight
• NICU outborn admissions < 1000 grams birth weight
• NICU transport admissions
• Number of patients receiving CPAP only
• Number of patients receiving ventilator care
• Number of patients = 34 weeks receiving ventilator care
• Number of ECMO cases
• Number of surgical cases overall and specific subcategories including:
• Number of infants with congenital diaphragmatic hernia (CDH)
• Number of infants with congenital gastrointestinal malformations
• Number of patients with NEC with surgical intervention
• Number of patients with cardiac surgery excluding patent ductus arteriosus
• Number of patients with any retinopathy of prematurity (ROP)
• Number of patients with threshold ROP
• Number of patients with BPD
• Number of patients with necrotizing enterocolitis (NEC) using Bell's classification of = stage 2
• Number of patients = 36 weeks with hypoxic ischemic encephalopathy (HIE)
• Number of patients = 36 weeks with HIE treated with hypothermia at = 6 hours of age
• Number of patients 33-35 weeks with HIE

If there is an anticipated increase or decrease in the birth rate or the number of NICU admissions for the upcoming cycle (2016-2021), this should be indicated at the time of application.

For centers with more than one clinical site, please include each site's information in a separate section or column. Large perinatal sites are ideal and may be given preference over multi-site arrangements. If a multi-site center has a long standing, well-documented collaboration and interaction among institutions, this should be clearly stated in the application including the investigator responsible at the collaborating site. Centers with neonatology staff at more than one clinical site must provide evidence of collaboration on recent trials.

Maternal Fetal Medicine Unit

The clinical center(s) should be located in an institution with a maternal fetal medicine service for delivery of high-risk pregnancies. Perinatologists should be active in clinical research and a history of collaboration between Neonatology and Perinatology towards excellent clinical care, database accessibility, and research productivity should be included in the application.

The application must include in tabular form the following information from 2013-2014 detailing maternal population for potential neonatal studies:

• Number of deliveries
• Number of C-sections
• Number of multiple pregnancies delivered
• Number of patients with diabetes (include gestational diabetes as well as patients with diabetes prior to pregnancy)
• Number of patients with pregnancy induced hypertension or chronic hypertension
• Number of deliveries that are low birth weight (< 2500 grams), very low birth weight (<1500 grams), and extremely low birth weight (<1000 grams).
• Number of antenatal consults performed by neonatology service (may include inpatient and outpatient consults as well as high risk fetal consults)

Subspecialty Information -- In the upcoming cycle of the NRN, three studies requiring specific subspecialty involvement are approved and will be underway.

• The inositol for retinopathy study requires ROP final outcome information. A description of collaboration with ophthalmology to insure availability for examination and procedures for obtaining outpatient eye exams must be included in the application.
• A randomized trial of laparotomy versus peritoneal drain for necrotizing enterocolitis with perforation is in progress. Applicants should detail involvement and willingness of Pediatric Surgeons and Neonatologists to participate in this ongoing randomized trial of surgical intervention in the NRN. Additional surgical trials may occur in the 2016-2021 cycle as determined by the Steering Committee.
• The hydrocortisone for bronchopulmonary dysplasia has a cardiac secondary study to evaluate echocardiograms in enrolled infants. A description of involvement of pediatric cardiology in neonatology research should be described in the application

Clinical Capabilities

The applicant clinical center is expected to have a full range of perinatal subspecialists, clinical capabilities and support staff, including an active research coordinator. A detailed description of the clinical attributes of the Neonatal-Perinatal Program must be provided. This should include antenatal fetal testing, intrapartum diagnosis, laboratory testing, availability of subspecialists, and perinatal pathology. Other institutional components related to the NRN must also be described. In particular, the neonatal intensive care unit(s) and ambulatory facilities for follow up care must be presented, including the established policies and procedures for conducting clinical research in these facilities. Also, the availability of an institutional pharmacy, nutrition support, and respiratory therapy capable of supporting clinical research must be documented. A description of whether, and how, policies and procedures may have been modified to support clinical research in the past must be provided.

The application should describe the site's staffing and experience in clinical care and research.

Follow-up Program

The application should include a description of neonatal follow-up capabilities for the center. A designated facility for follow up with experience in tracking and retaining patients must already be in place at the clinical center. A Follow-up Investigator (can be the PD/PI) must be designated in the application. A minimum of 80 percent follow up rate at 2 years of age is required. For infants enrolled in observational studies and clinical trials with primary or secondary outcome of approximately 2 year follow-up, a follow-up rate of 90% is highly desirable. The number of clinic visits in 2013 and 2014 need to be included in the application, as well as criteria for follow-up (e.g. LBW, ELBW, neurological issue, ECMO, etc.) and post conceptual age at which the children are seen in clinic visits. Applicants should describe in detail mechanisms in place to insure compliance and assistance with neonatal follow-up including procedures for identifying infants for follow-up while in the nursery, maintaining contact with families, scheduling appointments, actions taken for missed appointments, number of home visit appointments including staff participating in home visits, and creative measures instituted at the center to insure excellence in follow-up rates and compliance with clinical research study protocols. The follow-up portion of the clinical capabilities must include expertise in performing Bayley Developmental assessments, neurological examinations, and hearing and vision assessments. The current system of follow-up assessment including data collection, population demographics, compliance rates, schedule of follow-up visits, funding sources, policies and procedures for conducting research in the follow-up setting and appropriate specialist involvement in the follow-up program should be delineated in the application.

Currently, the NRN has one protocol with school age follow up (6-7.5 years of age). Information regarding longer term follow-up of infants enrolled in clinical trials must be provided in the application.

Perinatal Data System

An established electronic perinatal data system must be in place to collect and analyze patient information. A detailed description of variables collected, quality control, and management of the data system must be provided. An illustration of the use of the system for a recent clinical research application should be included in the application. All successful applications must provide complete, accurate and timely transmission of data to the Neonatal Research Network Data Coordinating Center. Applicants should describe their process for responses to data entry edits and queries should they be necessary.

Other Support

Applications should include a list of funded clinical research that has augmented NRN as well as non-NRN neonatal clinical research. This includes but is not limited to financial support from NIH, granting agencies, and institutional support. Given the fiscal limitations and costs of clinical research, applicants with a record of obtaining extramural funding for NRN as well as non-NRN neonatal clinical studies or projects will be given high consideration.

Special Strengths

Applicants are encouraged to describe special or unique strengths that may be relevant to NRN research. This can include state-of-the art scientific capabilities such as modern imaging and assessment techniques, neuro-intensive care capabilities, proteomics, genomics, genetics, clinical pharmacology, respiratory therapy, and so forth, which may be shared or may be available to develop and expand the scientific productivity of the NRN.

In addition, special administrative strengths or experience as well as participation in administrative aspects of clinical research (institutional review board, data safety monitoring committee, advisory board for clinical research, clinical research committees and so forth) should be highlighted. Level and support of clinical trials can be described.

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

The PD/PI should be a practicing neonatologist and should describe his/her clinical, research, administrative and academic commitments in the Biosketch. One neonatologist must be designated as an Alternate PD/PI who is able to serve in the absence of the PD/PI. Biographical sketches should be submitted with the application for the Alternate PD/PI and site neonatologists participating in NRN studies.

At least two additional neonatal-perinatal medicine physicians should be included as Senior/Key persons. Biosketches must be provided for those individuals.

A full-time clinical research Coordinator must be designated, with a biographical sketch included as part of the application.

The clinical center(s) should be located in an institution with a maternal fetal medicine service for delivery of high-risk pregnancies. The application should include a biographical sketch of at least one maternal fetal medicine collaborator.

There must be a Follow-up investigator (can be the PD/PI) designated in the application with an included biosketch.

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

Each applicant should submit base budget estimates for all years. The first year budget at the time of application will be limited to a BASE BUDGET with maximum allowances as follows:

• Program Director/Principal Investigator (PD/PI): 1.2 person-months (10 percent) effort
• Alternate PD/PI, Follow Up PD/PI, additional investigator or additional PD/PI support: up to 2.4 person-months (20 percent) effort each
• Research Coordinator: 12 person-months (100 percent) effort
• Data Entry Clerk: 6 person-months (50 percent) effort
• Supplies and small equipment (itemized and justified): Not to exceed $5,000
• Travel: A total of 10 trips to DC metro area per network team, as appropriate. Steering Committee meetings are held in the Washington, DC metro area four times per year. The PD/PI or designee is required to attend the meetings in their entirety. Research coordinators are expected to attend at least 2 meetings per year. Follow Up investigators meet twice yearly.
• Other costs (itemized and individually justified): Not to exceed $3,000

Total funding for clinical centers depends on the base awards and reimbursements for approved protocol-related expenses from the Data Coordinating Center (DCC). The overall provision of money for the NRN is subject to the availability of NICHD funding.

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:

Specific Aims: Describe specific aims for the center.

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

• Neonatal Research Staffing -- The application should describe the respective roles of staff and a management plan for how staff interact with the neonatal-perinatal medicine subspecialists and other individuals listed under Senior/Key Persons.

As many protocols require patient recruitment at night and on weekends, plans for availability for staff must be included in the application.

Management plans including supervision, training, in-service, certification, data handling, quality assurance, cost effective management, and communication are required for centers with > 1 clinical site.

• Patient Population -- Applications should describe the eligible subject populations and actual enrolled study subjects. Eligibility and enrollment in previous clinical trials should also be included in the application. Ability to recruit, retain and follow up infants in clinical trials and observational studies is critical to being an effective member of the NRN. Large eligible populations with low numbers enrolled in trials are considered less favorably than smaller populations that have higher enrollment rates. Capabilities for patient recruitment on nights and weekends must be described in the application.

The patient population served by the NRN must be characterized by demographics, obstetric parameters, and payment status. Indications must be given of the proportions of various subgroups, including minorities that have been eligible and actually have been randomized in previous or current clinical trials.

Centers with ongoing clinical trials should report those patients actually eligible for NRN studies (not competing with institutional research). If awarded, it is anticipated that NRN research studies will be given high priority.

If there are ongoing or pending studies/trials that will limit availability of patients for NRN trials, these must be described in the application. If there is to be a projected increase or decrease in subjects eligible for study, this should be described in the application.

• Academic Productivity -- Provide evidence of research productivity by the clinical center in previous or ongoing clinical studies and trials, especially those of a cooperative or multicenter design. Contributions in key areas of research development and design, patient recruitment, retention and study completion, data collection and analysis, and track record of publications should be included in the application.
• Progress Report for Renewal Applications -- Current Neonatal Research Network members should describe their participation and contribution to the network in detail including patient enrollment in studies, involvement in trials and their particular contribution to the trials (PD/PI at center, trial subcommittee), standing subcommittee activities including chairmanship or vice chairmanship, and publications.
• Preliminary Studies for New Applications -- New applicants must describe their recent experience and participation in clinical studies and trials. Specific roles (PD/PI, participating site, steering committee, writing committee, trial design and development) should be described for each study. Publications should be listed that resulted from participation in the studies.

Integration of research programs --

If the institution submits applications in response to both the Neonatal Research Network FOA and the Maternal Fetal Medicine Unit FOA (RFA-HD-16-019), the applicant must describe how the two research programs will be integrated.

Progress Report Publication List: Renewal applications should include any publications supported in the prior project periods.

Letters of Support:

• The departmental and institutional commitments to participate in NRN research should be clearly documented with letters of support from appropriate individuals. Evidence of past support can also be cited. Support in areas of grants management, personnel provision and management, space allocation, procurement, equipment as well as general support of the research should be described as well as evidence of past research support.
• There must be a clearly expressed intent to participate in a cooperative manner with other NRN clinical centers, the NICHD and the data coordinating center in all aspects of research as outlined in this FOA. Centers are expected to participate in all trials unless they describe trials that currently conflict with ongoing network trials as part of their application for this FOA. NRN projects are given priority at awarded clinical sites; a statement that NRN protocols will be given priority must be included in the application.
• The clinical center(s) should be located in an institution with a maternal fetal medicine service for delivery of high-risk pregnancies. The application should include a letter of commitment from at least one maternal fetal medicine collaborator, who should also be included among the Senior/Key Persons.
• A letter of assurance of cooperation with the policy for capitation of research costs as outlined below should be provided from the departmental and institutional offices of sponsored research programs.
• The DCC will be responsible for issuing payments for the NRN -approved protocol expenses including a per-patient capitation. These funds can be used to fund staff positions listed above as well as other research staff and expenses. To receive reimbursements, a funded clinical center must set up an agreement with the DCC.
• Participating sites will be required to accept protocol budgets for those studies underway in the Network. Clinical site researchers are encouraged to assist in the development of protocol budgets. The protocol budgets will consist of specific protocol-related allowances, capitated per subject enrolled in each study. Capitation funds can be utilized to fund key personnel.
• The clinical center PD/PI or designee will be required to help the DCC manage protocol costs. The PD/PI or designee should propose estimates of recruitment efforts for each protocol to the DCC and update these at least annually.
• The DCC may establish a recruitment limit. If a clinical center investigator believes that their site(s) is able to exceed the limit then permission to do so must be obtained from the DCC.
• The clinical centers' F&A rates on the initial competitive awards will not be adjusted in future years due to changes in their negotiated rate agreements.
• Applications from institutions that have a Clinical and Translational Science Award (CTSA) funded by NIH or other funded perinatal-neonatal research centers as resources for conducting the proposed research should provide a letter of agreement that identifies the level and type of support from the PD/PI or the CTSA program director.

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 submitted for the January 25, 2015 due date or after are expected to comply with the NIH Genomic Data Sharing Policy as detailed in NOT-OD-14-111, as applicable.
• Applicants are expected to deposit biospecimens in the NRN Repository for storage and use, consistent with achieving the goals of the program. NICHD holds the exclusive authority to enter into agreements with outside parties for the purpose of sharing data and biospecimens in accordance with NIH policies. Therefore, awardees shall not enter into any third party agreements directed to aspects of an active study with any outside party, during the course of the study.
• 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 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 components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

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

For review of this FOA, please note the following:

• Review of the UG1 application will emphasize the overall research environment, capabilities, and experience of the center and center personnel. Assessing the merit of the application should include how well the center can carry out research projects with particular emphasis on recruitment, retention, and follow up in clinical trials as well as collaboration with other centers in the Neonatal Research Network.

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? Is there a significant track record of productivity in clinical research by the investigators and the clinical team in the recent past? Do the investigators have the scientific, administrative, clinical and academic qualifications to conduct successful clinical research? Does the research team at the center have the institutional support and capabilities including the patient population to participate fully in the Neonatal Research Network? Do the key personnel have the knowledge and experience in areas relevant to the conduct of collaborative clinical research, especially randomized clinical trials, including experience in research design, in neonatal medicine? Is there commitment of staff time for the satisfactory conduct of the studies? Do the investigators have experience as well as qualified team members who would be responsible for data quality and management activities?

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

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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 appropriate populations available for enrollment into NRN studies? Is there evidence of commitment to prioritize NRN studies? Does the application demonstrate willingness to work and cooperate with other NRN centers and the NICHD in a manner summarized in this FOA? What has been the quality of the unit's participation in randomized clinical trials? Does the applicant have the ability to recruit, retain and follow up infants in clinical trials and observational studies? What is the recent track record in clinical research?

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? Is there a culture of clinical research evident in the application as demonstrated by staff and institutional commitment to recruit, retain and follow up infants enrolled in clinical trials and studies? Is there institutional assurance to provide support to the study in such areas as fiscal administration, personnel management, space allocation, procurement, planning, and budgeting? Are there appropriate administrative, clinical, and data organizational management facilities as described in the requirements?

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 five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. 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

For Renewals, the committee will consider the progress made in the last funding period. What has been the quality of the unit's participation in the most recent NRN cycle?

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. Applicants should note their intention to adhere to NRN policy; this will satisfy the expectation to provide a 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 NICHD, 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 Advisory Child Health and Human Development (NACHHD) 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 OMB administrative guidelines, HHS 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:

• Identification of Priority areas for research
• Developing and implementing the network protocols including meeting recruitment goals based on information provided at the time of application
• Collection and transmission of the data to the data-coordinating center
• Analysis of data and publication of results of the NRN trials
• The Data Coordinating Center is funded through a separate solicitation as a cooperative agreement (U10).
• All parties will agree to accept the coordinating role of the group and the participatory and cooperative nature of the group process.
• The individual NRN members will be required to project patient enrollment for a specific protocol during a specified time frame; continuation and level of funding will be based on actual recruitment.
• The NRN Steering Committee will retain custody 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:

NICHD Project Scientist

The NICHD Project Scientist will provide technical assistance and participate as one voting member of the Steering Committee. Specifically, the NICHD Project Scientist will:

• Assist with the identification of important areas of study.
• Assist in the development of study protocols.
• Assist in the development and review of capitation-based budgets, including the identification of study costs and special institutional needs.
• Assist in the review and evaluation of each stage of the program before subsequent stages are started, in conjunction with the Steering Committee and the Advisory Board.
• Assist in reporting results in the community of investigators and health care recipients.
• Assist in the conduct of the trials, including ongoing review of progress; possible redirection of activities to improve performance and cooperation; and frequent communication with other members of the Steering Committee.
• Participate on the Steering Committee and all active subcommittees.

NICHD Program Official

The NICHD will appoint a Program Official, apart from the Program Scientist, who will:

• Carry out continuous review of all activities to ensure that the objectives are being met and that all regulatory, fiscal, and administrative matters are handled according to NIH guidelines.
• Perform other duties required for normal program stewardship of grants.
• Assure the scientific merit of the trials, including the option to withhold support of a participating center if technical performance requirements such as protocol compliance, enrollment targets, or randomization of subjects are not met.
• Initiate a decision to modify or terminate a study based on the advice of the data center, Data Safety and Monitoring Committee, and/or Advisory Board.

Areas of Joint Responsibility include:

The management of the Neonatal Research Network includes committees with the following functions:

Steering Committee

A Steering Committee will be responsible for protocol development. The Steering Committee will have primary responsibility for the conduct of protocols and the preparation of publications. The Steering Committee will be composed of all PD(s)/PI(s), one representative from the data center, and one NICHD staff. Participating NICHD staff will include the Pregnancy and Perinatology Branch NRN Program Scientist. The NRN Program Scientist will be the only voting NICHD staff member of the Steering Committee. A member of the NICHD Grants Management Branch advises the Steering Committee on funding matters. An outside chairperson, who is not participating as a PD/PI, will be selected by the NICHD Director.

Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

Advisory Board

The Advisory Board assists the Steering Committee in the identification and prioritization of topics for perinatal research. The advisory board is selected by the NICHD Director and consists of individuals with expertise in clinical trials, biostatistics, epidemiology, perinatology, and neonatology, along with the Chairperson of the Steering Committee and the NRN Program Scientist. Additional members will participate based on the need for specific expertise.

Data and Safety Monitoring Committee

A Data and Safety Monitoring Committee (DSMC) monitors the safety of ongoing clinical trials. The DSMC is established by the NICHD and reports to the Director of NICHD. The DSMC is composed of individuals with expertise in clinical trial design and conduct, perinatology, neonatology, basic science, and ethics.

In addition, the NICHD Neonatal Research Network has established policies and procedures that govern its operations, including publications. These policies and procedures can be amended by the Steering Committee and the NICHD.

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 arbitration. 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 regulations 42 CFR Part 50, Subpart D and HHS regulations 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 Commons Help Desk (Questions regarding 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)
Telephone: 301-710-0267
Email: [email protected]

Tonse N.K. Raju, MD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-5575
Email: [email protected]

Sherry Dupere, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-451-3415
Email: [email protected]

Grace Poe
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-7011
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 Parts 74 and 92.