COLLABORATIVE PEDIATRIC CRITICAL CARE RESEARCH NETWORK

RELEASE DATE:  April 16, 2004

RFA NUMBER:   RFA-HD-04-004 - (Reissued as RFA-HD-08-025)

EXPIRATION DATE:  August 10, 2004

Department of Health and Human Services (DHHS)
 
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENT OF PARTICIPATING ORGANIZATION:  
National Institute of Child Health and Human Development (NICHD) 
 (http://www.nichd.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.865

LETTER OF INTENT RECEIPT DATE:  July 12, 2004
APPLICATION RECEIPT DATE:  August 9, 2004

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The National Institute of Child Health and Human Development (NICHD) invites 
applications from investigators willing to participate with the NICHD under a 
cooperative agreement (U10) to initiate a multi-center program designed to 
investigate the safety and efficacy of treatment and management strategies to 
care for critically ill children, as well as the pathophysiological bases of 
critical illness and injury in childhood.  This network will promote the 
efficient comparison of novel critical care treatment methods and management 
strategies of potential benefit for children who are critically ill. The 
objective of this Request for Applications (RFA) is to establish and maintain 
the infrastructure required for a network of approximately six clinical 
centers to perform multiple clinical trials as well as pertinent descriptive 
and translational research for children who are critically ill. An RFA for a 
Data Coordinating Center to support the network is separately published 
(RFA HD-04-015). The established network of academic centers will be able to 
study the required numbers of patients using rigorous common protocols and 
can provide answers more rapidly than individual centers acting alone. 

RESEARCH OBJECTIVES

Background 

Several convergent developments in critical care medicine, as well as in the 
larger medical, scientific, and national communities, underlie the decision to 
develop and maintain strong collaborative infrastructure in the form of a 
national pediatric critical care research network. The intent is to support a 
substantial range of research activities that reach across traditional 
disciplinary lines, transcending customary thinking and organizational 
structures in order to achieve innovative research in the care of the 
critically ill child. Modern critical care medicine has introduced a number of 
principles of management and innovative methodologies without rigorous use of 
the controlled observation necessary for their objective evaluation. A major 
problem has been the balance between assuring prompt implementation of new 
technologies, procedures, treatments, and drugs, and evaluation of their 
safety, efficacy, and cost/risk/benefit ratios. 

Indeed, because of the urgent demands of critically ill children, care is 
based on limited knowledge of new modalities not subjected to critical studies 
prior to introduction and use. In a critically ill child, for example, an 
innovative idea may be tried, which, if the child's condition improves, may 
rapidly start a new trend, and become the standard of care, expected and 
demanded by critically ill patients, their families, and the professionals 
caring for them. As a result, incorporation into the arsenal of critical care 
therapies frequently is based on limited experience, with efficacy and/or 
safety virtually unevaluated scientifically. 

Earlier attempts to address this need by the community of pediatric critical 
care investigators, while productive of smaller studies, suffered from under-
funded, non-sustainable infrastructure. Recent threats of bioterrorism, 
utilizing infectious and chemical agents to induce critical illness in diverse 
organ systems, and the potential for deployment of weapons systems which 
induce burns and trauma, have heightened the need for adequately powered 
studies that evaluate the efficacy and cost/risk/benefit ratios of innovative 
modalities and strategies in pediatric critical illness. Even in the instance 
that such events are rare (either occurring individually or in clusters) and 
unpredictable, an infrastructure to conserve and analyze data in critical 
illness in children is an essential research capacity; it is hoped that, for 
the needs of pediatric preparedness, this collaborative research network, will 
be an important national resource. 

Recent discoveries across a broad range of basic science research areas have 
greatly expanded the options for the critically ill child. Current advances in 
understanding of the molecular biology underlying organ system failure offer 
the possibility of manipulating otherwise poorly controlled processes, 
including inflammation, cell and organ death, and regeneration of tissues and 
functional organ system capacity. Modalities of mechanical ventilation, non-
invasive ventilation, circulatory support, organ transplantation, and 
extracorporeal life support have extended therapeutic options to children 
previously thought to be beyond the reach of state-of-the-art therapy.

The use of less invasive techniques in neurosurgery, general, orthopedic, 
reconstructive, vascular, and cardiovascular surgery, as well as the 
implementation of newer techniques of respiratory and circulatory support, 
have been central to the radical changes in mortality achievable with state of 
the art pediatric critical care medicine. As a result, children in higher risk 
groups who are victims of critical illness and/or injury, and those who might 
benefit from surgical interventions once not feasible, are benefiting from 
critical care in increasing number. 

Often, in the present context of critical care, children with complex 
illnesses, combinations of medical, surgical, and traumatic processes are 
surviving to discharge from multidisciplinary critical care units. As 
mortality from pediatric critical illness and injury declines, survival of 
children with disabling residuals of the critical pathology increases, and 
chronic medical conditions become more common. In children, it is well known 
that such conditions make the risk of subsequent critical illness greater than 
that for age-peers who have not sustained such illness or injury. 

There are several reasons that a collaborative clinical research network would 
accelerate pediatric critical care research, and lead to evaluation of 
promising new approaches to life support and critical decision-making in 
complex illnesses. The heterogeneity of critically ill children makes it 
difficult to accumulate a large number of comparable patients in one center. 
Multi-center trials have the potential to reduce the number of patients needed 
at each clinical center, and allow subject accrual and meaningful research to 
be completed more rapidly. Further, common treatment protocols would reduce 
variables that contribute to patient outcome and allow valid comparisons 
between treatments. Finally, the Network approach will increase the number of 
comparative trials and meaningful translational descriptive studies that are 
conducted by providing a framework for rapid initiation of important studies, 
a focus on randomized studies, and efficient use of pooled clinical expertise 
and data management resources. 

Research Scope 

The Collaborative Pediatric Critical Care Network will achieve its objective 
through conducting clinical trials, as well as translational and descriptive 
studies.  Therapeutic trials may involve investigational drugs, drugs already 
approved but not currently used, and drugs currently used, as well as diverse 
innovative and more traditional management strategies. Patients might be 
randomized between different doses, as well as modes and techniques of novel 
treatment or novel treatment versus standard therapy. It is also recognized 
that not all studies can proceed directly to Phase III clinical trials.  Pilot 
clinical trials and adequately powered descriptive studies are essential to 
the development of the database necessary to conduct successful Phase III 
trials.  Indeed, the unique complexity of multiple organ system 
pathophysiology in the young is not well understood. 

Some examples of research appropriate for this RFA include, but are not 
limited to, the following: 

o Trials of methods of ventilatory support in various critical illnesses, 
including less invasive methods. 

o Trials of agents and strategies which may prevent progression of respiratory 
infection or compromise to respiratory failure. 

o Descriptive studies of the epidemiology of the complications of critical 
care which may be disabling, and the relationship of such complications to 
critical care methodologies: agents, technical apparatus, and strategies. 

o Descriptive studies of the epidemiology of critical illness among specific 
high risk populations (for example, neonatal intensive care survivors, 
disabled children, and children with ongoing chronic conditions such as asthma 
or diabetes). 

o Trials of innovative methods of circulatory support in defined populations 
of children where benefit is postulated: in overwhelming sepsis, 
cardiopulmonary arrest, or after complex surgical therapy. 

o Descriptive studies of the biological processes underlying critical illness 
in childhood, and progression to organ failure, such as genetic polymorphisms, 
and signal transduction. 

o Descriptive studies and trials that are directed at the critical care needs 
of pediatric oncology patients, especially those who have undergone bone 
marrow transplantation and chemotherapeutic agents. Examples include 
indications, modalities, and strategies for support in respiratory and 
circulatory compromise. 

o Trials of novel interventions and decision-making strategies for pediatric 
trauma patients, based on translational research, applying recent basic 
science findings to the bedside care of the critically injured child. 

o Trials of regimens or modalities of care that may prevent, ameliorate, or 
reverse the cascade of multiple organ system failure (MOSF) in children who 
are critically ill or injured. 

o Trials of novel interventions and strategies that may prevent or ameliorate 
the course of MOSF in children who are not critically ill, but are at 
increased risk to become unstable (immunocompromised and disabled children, 
children with genetic polymorphisms that place them at risk, trauma and burn 
patients who initially appear stable). 

o Descriptive studies and experimental trials of novel informatics-based 
decision making, to evaluate efficacy and safety in allocating resources for 
children with illness and injury whose future course is uncertain, and are at 
risk to become critically ill, or to be left with disability. 

o Follow-up studies to evaluate the link between acute interventions and 
chronic illness and disability. For example, various surgical and critical 
care modalities to correct congenital anomalies, critical injury and other 
situations where the risk of compromise of developmental outcome and/or 
functional success may be substantial. 

o Studies of transfusion therapy, including clinical trials, that evaluate the 
risk/benefit ratio of conservative and liberal transfusion in defined groups 
of critically ill and injured children. 

o Trials of new or more traditional immunosuppressive drugs, monoclonal 
antibodies, or cytokines in immunomodulation during sepsis and the systemic 
inflammatory response. 

In addition, the Network will conduct patient management trials in 
collaboration with other research groups that have an interest in critically 
ill children:  for example, the cooperative cancer research groups and those 
groups studying ventilation strategies. These are examples only. Applicants 
are not limited to the subjects mentioned above, and are encouraged to submit 
proposals for other studies pertinent to the objectives of the RFA.

MECHANISM OF SUPPORT

This RFA will use the NIH Cooperative Clinical Research (U10) award mechanism. 
As an applicant you will be solely responsible for planning, directing, and 
executing the proposed project.  The anticipated award date is April 1, 2005.

The NIH U10 is a cooperative agreement award mechanism in which the Principal 
Investigator retains the primary responsibility and dominant role for 
planning, directing, and executing the proposed project, with NIH staff being 
substantially involved as a partner with the Principal Investigator, as 
described under the section "Cooperative Agreement Terms and Conditions of 
Award."  

FUNDS AVAILABLE

The NICHD intends to commit approximately $1 million in total costs [Direct 
plus Facilities and Administrative (F & A) costs] in FY 2005 to support up to 
six new grants in response to this RFA.  An applicant may request a project 
period of up to five years and a budget for direct costs of up to $100,000 for 
the first year and up to $450,000 per year thereafter.  Because the nature and 
scope of the proposed research will vary from application to application, it 
is anticipated that the size and duration of each award will also vary.  
Although the financial plans of the NICHD provide support for this program, 
awards pursuant to this RFA are contingent upon the availability of funds and 
the receipt of a sufficient number of meritorious applications. At this time, 
it is not known if this RFA will be reissued. 

ELIGIBLE INSTITUTIONS

You may submit an application if your institution has any of the following 
characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments 
o Eligible agencies of the Federal government 
o Domestic 
o Foreign institutions are not eligible to apply 

Applications may be submitted from organizations located in the United States 
of America. This geographic constraint is necessary because of the need for 
close communication among members of the program, the requirement for frequent 
Steering Committee meetings, and the necessity of site visits for data 
verification.

Participants must be based in a multidisciplinary pediatric intensive care 
unit (or units), in an academically oriented department of pediatric critical 
care medicine, that admits both medical and surgical patients.

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with his/her institution 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 programs.   

The Principal Investigator must be a pediatric intensivist.

SPECIAL REQUIREMENTS

Organization of the Collaborative Pediatric Critical Care Research Network 

The Collaborative Critical Care Research Network (Network) will be a 
cooperative network of approximately six Clinical Centers, one Data 
Coordinating Center, and the National Institute of Child Health and Human 
Development (NICHD). Clinical Centers will be responsible for proposing 
protocols that are appropriate and feasible for adoption by the Network, 
guiding protocol development, enrolling patients, analyzing results, and 
disseminating research findings. All Clinical Centers will be required to 
participate in a cooperative and interactive manner with one another and with 
the Data Coordinating Center. Divisions and departments of pediatric critical 
care medicine have the option to form a consortium and apply as a single 
entity for a Clinical Center award. In the case of a consortium, there will be 
one Principal Investigator who will serve on the Steering Committee and 
represent the other centers, and the maximum direct costs per year will be 
limited to $100,000 ($450,000 in Years 02 -05).

Participants must be based in a multidisciplinary pediatric intensive care 
unit (or units), in an academically oriented department of pediatric critical 
care medicine, that admits both medical and surgical patients. Physician 
staffing of the Clinical Center should include at least four full-time board-
certified pediatric intensivists. Complete descriptions of the training and 
qualifications of each in both clinical care and research should be provided. 
The Principal Investigator should be a practicing pediatric intensivist: 
her/his clinical, academic, administrative, and research commitments should be 
described in detail.

A centralized Data Coordinating Center will support the activities of the 
Network. The functions of the Data Coordinating Center will include developing 
protocol data management aspects, devising novel comparative study designs, 
providing sample size calculations and statistical advice, developing data 
forms, performing data analyses, coordinating the activities of the Steering 
Committee, Protocol Review Committee, and Data and Safety Monitoring Board, 
and overall study coordination and quality assurance. In addition, in order to 
hasten accrual in Network studies, the Data Coordinating Center, along with 
NICHD and the Steering Committee, will have the responsibility to identify 
qualified and interested investigators at non-Network centers who wish to 
enroll patients in these studies. Arrangements for data collection and 
reimbursement of trial-related data collection costs at non-Network centers 
will be the responsibility of the Data Coordinating Center. 

Awards for a Clinical Center and a Data Coordinating Center to support the 
network will not be made to the same Principal Investigator to ensure that 
data analysis is conducted independently of data acquisition. The same 
institution may apply for both a Clinical Center and the Data Coordinating 
Center award, but the applications for each must be from different 
individuals.

A Steering Committee will be the main governing body of the Network and, at a 
minimum, will be composed of the Principal Investigators of the Clinical 
Centers and the Data Coordinating Center and the NICHD Project Scientist. The 
structure and role of the Steering Committee are described below under 
Cooperative Agreement Terms and Conditions of Award. 

The costs of travel to Washington DC (up to six times per year) for the 
Principal Investigator should be included in the application budget request. 
In addition, funds should be budgeted to provide for travel of the research 
nurse to two of the Steering Committee meetings per year.

Data collection will be monitored in a manner consistent with NICHD Policy for 
Data and Safety Monitoring (http://www.nichd.nih.gov/funding/datasafety.htm).  
A Data and Safety Monitoring Board (DSMB) will monitor the activities of the 
Network semi-annually. As a part of its monitoring responsibility, the DSMB 
will submit recommendations to NICHD regarding the continuation of each study, 
and prepare a report for Principal Investigators to provide to their 
institutional review boards (IRBs).
 
It is anticipated that each protocol will be implemented in all of the 
Clinical Centers. As specific protocols are developed, support will depend on 
the availability of funds, and per patient (capitation) funding made 
available. All the Clinical Centers must be willing to pursue this funding 
arrangement for each new protocol conducted. Clinical protocols must be 
approved by local IRBs and the Protocol Review Committee before initiation. 
The exact number of protocols supported in the five-year program will depend 
on the nature and extent of the investigations proposed by the Steering 
Committee. Both short- and longer-term projects should be considered.

Required Expertise and Institutional Resources

Each clinical center selected will be supervised by a Principal Investigator 
who is a pediatric intensivist.

The disciplines and expertise that will be sought for the research undertaken 
in this program include but are not limited to the areas of pediatric critical 
care medicine, pediatric surgical critical care, pediatric trauma, 
biostatistics, bioengineering, informatics, immunology, pulmonology, 
cardiology, pharmacology, therapeutic development, and clinical trials 
management. Organizations should have academically-oriented divisions of 
pediatric critical care medicine. 

The Clinical Center must be located in an institution with a full spectrum of 
pediatric specialists and subspecialists in medicine and surgery to support 
the activities of Network studies. Because assessment of outcomes in survivors 
is so central to the Network purpose, all of the specialties involved in 
pediatric critical care should be available. These should include (but are not 
limited to): pediatric rehabilitation or general pediatric long term follow-
up, pediatric surgery and trauma surgery, pediatric cardiovascular surgery, 
pediatric neurology and developmental medicine, pediatric cardiology, 
pediatric pulmonology and pediatric immunology.  A history of cooperation 
between pediatric critical care medicine and surgery towards excellence in 
clinical care, maintenance of a database, and research productivity should be 
documented.

A pediatric surgeon, neurosurgeon, or cardiothoracic surgeon interested in 
pediatric critical care research willing to participate in the Collaborative 
Pediatric Critical Care Research Network should be designated. Such 
individuals must commit to serve as consultants, and possibly as 
collaborators, in Network research. The research productivity of the surgical 
consultants should be documented.

Applicant Clinical Centers should have a full range of state-of-the-art 
facilities, clinical capabilities, and excellent support staff. Laboratory 
facilities, imaging capabilities, research pharmacies, and qualified staff in 
respiratory therapy are essential requirements that should be documented in 
the application.

Patient Population Requirements

Clinical Center applicants should include a table in their applications 
providing the number of non-neonatal (older than 28 days) critically ill 
children at their institution.  The table should include a breakdown by age of 
surgical (trauma and non-trauma), medical, oncology, and bone marrow 
transplant admissions to the pediatric critical care unit in 2003.  An example 
of such a table can be found at 
http://www.nichd.nih.gov/RFA/HD-04-004/HD-04-004.htm.

While consideration of the applicant Center's qualification in census will be 
an important criterion for inclusion in the Network, relevant expertise and 
productivity will be evaluated as well.

The capacity to follow children and capture data about their status for up two 
years after admission is strongly recommended for all applicants, and will be 
central in the review of the proposed Center's qualifications; no applications 
will be considered where the capacity to follow children as outpatients and 
capture pertinent outcome data is not evident. Specific plans to work 
collaboratively with professionals in pediatric rehabilitation, general 
pediatrics, and pediatric subspecialty disciplines providing care to children 
with special health care needs are specifically solicited.

Applications should also indicate the willingness of the pediatric critical 
care and pediatric surgical divisions to work collaboratively.

Participation in Studies

It is the intent of this network that multiple trials and descriptive studies 
will be conducted during the five-year project period. It is anticipated that 
in the initial year, one trial will be selected from the studies proposed by 
the successful applicants. However, a decision to fund a particular Clinical 
Center will not commit the Network to develop that center's clinical protocol. 
Nevertheless, awardees must agree to actively enroll patients in at least one 
Network trial and/or descriptive study in the first year after the award. 
Applicants should plan that, after the first year, at least three studies will 
begin enrolling patients each year.

All applicants should propose a strategy to streamline protocol development 
and acceptance among centers, given this ambitious pace for initiating 
studies. Initiation of trials in future years will depend on satisfactory 
progress in previous trials. Additionally, eligibility for clinical centers 
includes provision for the evaluation of outcomes in children surviving 
critical illness and injury.

Cooperative Agreement Terms and Conditions of Award

The following Terms and Conditions will be incorporated into the award 
statement.  They are to be followed in addition to, and not in lieu of, 
otherwise applicable OMB administrative guidelines, HHS grant administration 
regulations at 45 CFR Parts 74 and 92, and other HHS and NIH grant 
administration policies.

The administrative and funding instrument used for this program will be the 
U10, an "assistance" mechanism (rather than an "acquisition" mechanism), in 
which substantial NIH scientific and/or programmatic involvement with the PI 
is anticipated during performance of the activities. Under the cooperative 
agreement, the NIH purpose is to support and/or stimulate the PI's activities 
by involvement in and otherwise working jointly with the PI 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 PI for the project as a whole, although 
specific tasks and activities may be shared between the awardee and the NICHD 
Project Scientist.  Facilities and Administrative cost (indirect cost) award 
procedures apply to cooperative agreements in the same manner as for grants.  
Business management aspects of these awards will be administered by the NICHD 
Grants Management Branch in accordance with HHS and NIH grant administrative 
requirements.

1.  Awardee Rights and Responsibilities

The Collaborative Pediatric Critical Care Research Network (Network) will be a 
cooperative network of approximately six Clinical Centers, one Data 
Coordinating Center, and the National Institute of Child Health and Human 
Development (NICHD). Clinical Centers will be responsible for proposing 
protocols that could be adopted by the Network, guiding protocol development, 
enrolling patients, analyzing results, and disseminating research findings. 
All Clinical Centers will be required to participate in a cooperative and 
interactive manner with one another and with the Data Coordinating Center. 

All awardees are required to submit annual progress reports to NICHD, as 
appropriate, and to provide study and site performance information as 
stipulated by NICHD.  

A centralized Data Coordinating Center will support the activities of the 
Network. Functions of the Data Coordinating Center include advice and 
assistance in developing protocols, devising novel comparative study designs, 
providing sample size calculations and statistical advice, developing data 
forms, performing data analyses, coordinating the activities of the Steering 
Committee, Protocol Review Committee, and Data and Safety Monitoring Board, 
and overall study coordination and quality assurance. In addition, in order to 
ensure accrual in protocols, the Coordinating Center will have the 
responsibility to identify to the NICHD and the Steering Committee, qualified 
and interested investigators at non-Network clinical centers who wish to 
enroll patients in Network studies, or to propose protocols for consideration 
by the Steering Committee. Arrangements for data collection and reimbursement 
of trial-related data collection costs at non-Network centers, once approved 
by the Steering Committee, will be the responsibility of the Data Coordinating 
Center. 

o Development of Network Research Agenda and Protocols

It is the responsibility of the awardee(s) to develop the details of the 
research design, including definition of objectives and approaches, the 
planning, implementation, and analysis of studies, any modification of study 
design, quality control, collaboration with other investigators, 
interpretations, and conclusions of studies, unless otherwise provided for in 
these terms or by action of the Steering Committee. Modifications of study 
protocols will be approved by the Data and Safety Monitoring Board. Ancillary 
studies will not be funded by this grant mechanism.

o Coordination and Internal Oversight of Network Activities

Awardee(s) agree to the governance of the study through a Steering Committee. 

Meetings of the Steering Committee will ordinarily be held in the Washington, 
D.C. metropolitan area or by telephone conference call. The Steering 
Committee, with the assistance of the Data Coordinating Center, is responsible 
for coordinating protocol development, descriptive study design, protocol 
submission, study conduct, quality control and study monitoring, drug 
ordering, data management, statistical analysis, protocol amendments/status 
changes, adherence to requirements regarding investigational drug management 
and federally mandated regulations, and protocol and performance reporting. 
The Data Coordinating Center will be responsible for communication with the 
appropriate NICHD staff.

The Steering Committee Chairperson, who will be someone other than an NICHD 
staff member and may be someone other than a Principal Investigator, will be 
selected by NICHD. The Clinical Centers, the Data Coordinating Center, and 
NICHD each will have one vote. The Chairperson will vote in the case of ties. 
The Steering Committee may meet as often as three to six times in the first 12 
months of the Network, and two to four times per year thereafter. All major 
scientific decisions will be determined by majority vote of the Steering 
Committee.

The Steering Committee will have primary responsibility for the general 
organization of the Network, finalizing common clinical protocols, 
facilitating the conduct and monitoring of the studies, and publishing study 
results. Topics for the protocols will be proposed and prioritized by the 
Steering Committee; protocols from the wider pediatric critical care community 
of investigators may be submitted for Steering Committee review as well. For 
each protocol, one investigator (or small group) will take the lead 
responsibility for drafting the protocol along with the Data Coordinating 
Center, although the Steering Committee will provide input and will be 
responsible for assuring development of a common protocol to be implemented by 
the network's Clinical Centers, as well as centers or consortia from outside 
the network.
 
Some of the major considerations relevant to protocol review by the Steering 
Committee include: (a) the strength of the scientific rationale supporting the 
study, (b) the medical importance of the question being posed, (c) the 
avoidance of undesirable duplication with other ongoing studies, (d) the 
appropriateness of study design including interim monitoring plans if 
appropriate, (e) a satisfactory projected accrual rate and follow-up period, 
(f) patient safety, (g) compliance with federal regulatory requirements, (h) 
adequacy of data management, (i) appropriateness of patient selection, 
evaluation, assessment of toxicity and risk, response to therapy and follow-
up, (j) adherence to NIH guidelines.

Subcommittees of the Steering Committee will be established as necessary; for 
example, it is envisioned that a Publications and Presentations Committee will 
prioritize, facilitate, and supervise preparation and review of manuscripts 
prior to submission for publication. Subcommittees to oversee study protocol 
development in regard to the complications of critical care treatments, such 
as pneumothoraces, line erosion and placement complications, and nosocomial 
infection are also envisioned. 

o Network Compliance with Federally Mandated Regulatory Requirements

The Network must comply with all FDA regulatory requirements for studies 
involving investigational devices and agents and NIH policies applying to the 
conduct of research involving human subjects and be consistent with Office of 
Human Research Protections guidelines http://www.hhs.gov/ohrp/. 
These regulations include but are not limited to CFR 21 Parts 50, 56 and 312 
and CFR 45 Part 46. 

o Data Collection and Management

The Network shall establish and implement mechanisms for data collection and 
management that are: (a) adequate for quality control and analysis, and (b) as 
simple as possible in order to encourage maximum participation of physicians 
entering patients and to avoid unnecessary expenses. Awardees are required to 
follow Network procedures for data collection and management, which will be 
developed by the Steering Committee. 

o Study Monitoring and Quality Assurance

The Network shall establish and implement mechanisms for study monitoring and 
quality assurance, as well as policies and procedures for protocol 
implementation. Awardees are required to follow Network procedures for study 
monitoring. The Network is responsible for assuring accurate and timely 
knowledge of the progress of each study through:

a. tracking and reporting of patient accrual and adherence to defined accrual 
goals;

b. ongoing assessment of case eligibility and availability;

c. timely medical review and assessment of patient data;

d. rapid reporting of treatment-related morbidity and measures to ensure 
communication of this information to all parties;

e. interim evaluation and consideration of measures of outcome as consistent 
with patient safety and good clinical trials practice;

f. timely communication of results of studies; and

g. an on-site monitoring program. 

The NICHD is responsible for ensuring that all participating sites receive 
routine audits by the Data Coordinating Center. In the event that an awardee 
fails to comply with these guidelines, the accrual of new patients to the 
Network's protocols at the affected site shall be suspended immediately upon 
notice of the determination. The suspension will remain in effect until the 
awardee conducts the required audit and the audit report or remedial action is 
accepted by the NICHD. The Data Coordinating Center and the Institute will be 
responsible for notifying any affected site of the suspension. During the 
suspension period, no funds from this award may be provided to the site for 
new accruals, and no charges to the award for new accruals will be permitted.

Awardees will retain custody of and have primary rights to the data developed 
under these awards, subject to Government rights of access consistent with 
current HHS, PHS, and NIH policies.

2. NIH Responsibilities

NICHD Project Scientist:

The NICHD Project Scientist will have substantial scientific-programmatic 
involvement during conduct of this activity, through technical assistance and 
participation as one voting member of the Steering Committee. 

NICHD Project Officer:

The NICHD will appoint a Project Officer, apart from the Project Scientist, 
who will:

o 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.

o Have the option to withhold support to a participating institution if 
technical performance requirements are not met.

o Perform other duties required for normal program stewardship of grants.

3. Collaborative Responsibilities

The management of the National Pediatric Collaborative Critical Care Research 
Network includes three committees whose functions are as follows:

o A Steering Committee will be responsible for protocol development and 
selection. Protocols that originate with investigators outside the Steering 
Committee may be presented for review as well, if two of the Principal 
Investigators and the NICHD Project Scientist concur. The structure of the 
Steering Committee is outlined above.

o An Advisory Board will advise the Steering Committee in the identification 
and prioritization of topics for Network research. The Advisory Board, chosen 
by the NICHD with the advice of the Steering Committee, will be composed of 
individuals with expertise in clinical trials, biostatistics, epidemiology, 
pediatric rehabilitation, pediatric pulmonology, developmental pediatrics, and 
pediatric surgery.

o A Protocol Review Committee will review and approve all clinical protocols 
before initiation.

4.  Arbitration Process

Any disagreements that may arise in scientific or programmatic matters within 
the scope of the award between grantees and the NIH may be brought to 
arbitration.  This special arbitration procedure in no way affects 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 regulation 
at 45 CFR Part 16.  An Arbitration Panel will help resolve both scientific and 
programmatic issues that develop during the course of work that restrict 
progress.  The Arbitration Panel will be composed of three members:  a member 
selected by the Steering Committee without NIH staff voting, a member selected 
by NICHD, and a member with expertise in the relevant area selected by the 
other two members.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants management 
issues:  

o Direct your questions about scientific/research issues to:  

Carol E. Nicholson, M.D., M.S.
Pediatric Critical Care and Rehabilitation Program
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 2A03, MSC 7510
Bethesda, MD  20892-7510
Telephone: (301) 435-6843
FAX: (301) 402-0832
Email: nicholca@mail.nih.gov

o Direct your questions about peer review issues to:  

Robert Stretch, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD  20892-7510
Telephone: (301) 496-1485
FAX: (301) 402-4104
Email: stretchr@mail.nih.gov

o Direct your questions about financial or grants management matters to:  

Chris Robey
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, 8A17, MSC 7510
Bethesda, MD  20892-7510
Telephone: (301) 435-6996
FAX: (301) 451-5510
Email: robeyj@mail.nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes 
the following information:  

o Descriptive title of the proposed research 
o Name, address, and telephone number of the Principal Investigator 
o Names of other key personnel 
o Participating institutions 
o Number and title of this RFA 

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.

The letter of intent is to be sent by the date listed at the beginning of this 
document.  The letter of intent should be sent to:  

Carol E. Nicholson, M.D., M.S.
Pediatric Critical Care and Rehabilitation Program
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 2A03, MSC 7510
Bethesda, MD  20892-7510
Telephone: (301) 435-6843
FAX: (301) 402-0832
Email: nicholca@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/. The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 
document is available at 
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
Email: GrantsInfo@nih.gov.
 
SUPPLEMENTARY INSTRUCTIONS:

Each applicant Principal Investigator for a Clinical Center should prepare an 
application that reflects two fundamental components:

1) the qualifications of the Principal Investigator and research nurse to be 
supported at the center, as well as the qualifications of the applicant 
institution to participate fully in the Network described in this RFA. In 
addition, it is appropriate to include support for a half-time administrative 
or data entry/collation employee.  

2) a proposal for an experimental or descriptive study to be implemented by 
the network within the first 18 months after award. The proposal must be for a 
study term of no greater than 18 months, so that the first Network study will 
be completed within 36 months of the award.  The budget for the study should 
reflect its implementation at all six centers.

USING THE RFA LABEL:  The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label 
could result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA title and 
number must be typed on line 2 of the face page of the application form and 
the YES box must be marked.  The RFA label is also available at: 
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten original of 
the application, including the Checklist, and three signed photocopies, in one 
package to: 

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application and all 
copies of the appendix material must be sent to:  

Robert Stretch, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD  20892-7510
Rockville, MD  20852 (for express/courier service)
Telephone: (301) 496-1485
FAX: (301) 402-4104
Email: stretchr@mail.nih.gov

APPLICATION PROCESSING:  Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an application 
is received after that date, it will be returned to the applicant without 
review.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within eight weeks.

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is, the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes from the 
previous unfunded version of the application.  

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NICHD.  Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration.  

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NICHD in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will: 

o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the National Advisory Child Health and 
Human Development Council.

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals:

o Significance
o Approach
o Innovation
o Investigator
o Environment 

The scientific review group will address and consider each of these criteria 
in assigning the application's overall score, weighting them as appropriate 
for each application.  The application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, an investigator may propose to 
carry out important work that by its nature is not innovative but is essential 
to move a field forward.

PROPOSED NETWORK STUDY:

SIGNIFICANCE:  Does this proposed network study address an important problem?  
If the aims of the study are achieved, how will scientific knowledge be 
advanced?  What will be the effect of these studies on the concepts or methods 
that drive this field?

APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?  Can the proposed study be completed within 36 months of 
the award?

INNOVATION:  Does the project employ novel concepts, approaches or methods?  
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?

INVESTIGATOR:  Is the investigator appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to the experience level 
of the Principal Investigator and other researchers (if any)?

ENVIRONMENT:  Does the scientific environment in which the work will be done 
contribute to the probability of success?  Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements?  Is there evidence of institutional support?

ADDITIONAL REVIEW CRITERIA:  In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

QUALIFICATIONS AND EXPERIENCE:  The expertise, training, and experience of the 
investigators and staff, including the administrative abilities of the 
Principal Investigator and Research Nurse; especially evidence that her/his 
time can realistically be devoted to the program for the effective development 
of the Network.

PEDIATRIC CRITICAL CARE STAFFING:  Quality of the clinical care and research 
experience of the physicians staffing the Clinical Center pediatric intensive 
care unit.

WILLINGNESS TO PARTICPATE IN A COLLABORATIVE RESEARCH NETWORK:  Applicant 
institution's history of collaborative research, the Principal Investigator's 
depth of commitment and ability to work with other Network Centers, NICHD, and 
the Network Data Coordinating Center. 

FULL SPECTRUM OF PEDIATRIC SPECIALISTS AND SUBSPECIALISTS IN MEDICINE AND 
SURGERY:  Evidence of staffing and collaboration of the full spectrum of 
pediatric medical and surgical specialists and subspecialists, as detailed 
under SPECIAL REQUIREMENTS.

A HISTORY OF COOPERATION BETWEEN PEDIATRIC CRITICAL CARE MEDICINE AND SURGERY 
TOWARDS EXCELLENCE:  Evidence and quality of collaborative activities and 
research productivity between the specialties involved in pediatric critical 
care, including the research productivity of the surgical consultants.

FACILITIES AND CAPABILITIES:  Quality of the support staff, laboratory 
facilities, imaging capabilities, pharmacies with research capability and 
experience, and qualified staff in respiratory therapy.  Capacity of the 
applicant Center to follow children as outpatients and capture pertinent 
outcome data for up to two years after admission.

PROTOCOL DEVELOPMENT:  Quality of proposed strategy to streamline protocol 
development and acceptance among Centers in the network.

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK:  The involvement of human 
subjects and protections from research risk relating to their participation in 
the proposed research will be assessed.  (See criteria included in the section 
on Federal Citations, below.)

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans 
to include subjects from both genders, all racial and ethnic groups (and 
subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below.)

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.

ADDITIONAL CONSIDERATIONS 

BUDGET:  The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  July 12, 2004
Application Receipt Date:  August 9, 2004
Peer Review Date:  October/November 2004 
Council Review:  January 2005
Earliest Anticipated Start Date:  April 01, 2005

AWARD CRITERIA

Criteria that will be used to make award decisions include: 

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities

REQUIRED FEDERAL CITATIONS

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained 
(http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

DATA AND SAFETY MONITORING PLAN:  Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II); efficacy, 
effectiveness and comparative trials (phase III).  The establishment of data 
and safety monitoring boards (DSMBs) is required for multi-site clinical 
trials involving interventions that entail potential risk to the participants 
(NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and 
Contracts, June 12, 1998: 
https://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the 
research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines is available at 
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that:  a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; and 
b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them.  

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 
https://grants.nih.gov/grants/funding/children/children.htm.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy 
requires education on the protection of human subject participants for all 
investigators submitting NIH proposals for research involving human subjects.  
You will find this policy announcement in the NIH Guide for Grants and 
Contracts Announcement, dated June 5, 2000, at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:  The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA.  
It is important for applicants to understand the basic scope of this 
amendment.  NIH has provided guidance at 
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the application.  
In addition, applicants should think about how to structure informed consent 
statements and other human subjects procedures given the potential for wider 
use of data collected under this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to 
the "Standards for Privacy of Individually Identifiable Health Information", 
the "Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). 

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on "Am I a covered 
entity?"  Information on the impact of the HIPAA Privacy Rule on NIH processes 
involving the review, funding, and progress monitoring of grants, cooperative 
agreements, and research contracts can be found at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES:  All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.  Furthermore, we 
caution reviewers that their anonymity may be compromised when they directly 
access an Internet site.

HEALTHY PEOPLE 2010:  The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas.  This 
RFA is related to one or more of the priority areas.  Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  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 52 and 45 CFR Parts 74 and 92.  All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
https://grants.nih.gov/grants/policy/policy.htm.  

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, Public 
Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain 
facilities (or in some cases, any portion of a facility) in which regular or 
routine education, library, day care, health care, or early childhood 
development services are provided to children.  This is consistent with the 
PHS mission to protect and advance the physical and mental health of the 
American people.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

Department of Health and Human Services

National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892