PEDIATRIC HEART DISEASE CLINICAL RESEARCH NETWORK

Release Date:  May 24, 2000

RFA:  HL-00-013                                                                   

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  September 20, 2000
Application Receipt Date:       November 20, 2000

More information on this initiative can be found on the 
Pediatric Heart Disease Clinical Research Network web pages.

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites applications to 
participate in the establishment of a Pediatric Heart Disease Clinical Research 
Network (Network) of interactive pediatric clinical research centers.  This 
Network will promote the efficient evaluation of novel treatment methods and 
management strategies having potential benefit for children with structural 
congenital heart disease, inflammatory heart disease, heart muscle disease, and 
arrhythmias.  Pediatric heart disease will be understood here to refer to these 
conditions; specifically excluded for purposes of this focused RFA are 
preventive cardiology issues such as pediatric hypertension and dyslipidemias, 
and adults with congenital heart disease.  It is anticipated that one outcome of 
the Network will be to promote rapid dissemination of the findings from these 
clinical studies to the medical community.  This Request for Applications (RFA) 
will establish and maintain (1) the infrastructure required for a Network of up 
to six clinical centers to perform multiple clinical studies in the focused 
areas of pediatric heart disease, and (2) a Data Coordinating Center for the 
Network.  This is a one-time solicitation to support a Pediatric Heart Disease 
Clinical Research Network for five years.  

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, Pediatric Heart Disease Clinical 
Research Network, 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/.

ELIGIBILITY REQUIREMENTS								

Applications may be submitted by domestic or Canadian for-profit and non-profit 
organizations, public and private, such as universities, colleges, hospitals, 
laboratories, units of State and local governments, and eligible agencies of the 
Federal government.  Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal Investigators.  All current 
policies and requirements that govern the research grant programs of the 
National Institutes of Health (NIH) will apply to grants awarded under this RFA. 
 Among the disciplines and expertise that may be appropriate for this program 
are pediatrics, pediatric cardiology, pediatric cardiovascular surgery, 
pediatric critical care, pediatric anesthesiology, pediatric cardiovascular 
imaging, pharmacology, therapeutic development, clinical trials management, and 
biostatistics.


Awards for a Clinical Center and a Data Coordinating Center will not be made to 
the same Principal Investigator to ensure that data analysis is performed 
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, and must be submitted as separate 
applications.

MECHANISM OF SUPPORT

This RFA will use the cooperative agreement (U01) administrative and funding 
mechanism of support.  Under the cooperative agreement, the NIH assists, 
supports, and/or stimulates, and is substantially involved with recipients in 
conducting a study by facilitating performance of the effort in a "partner" 
role.  Details of the responsibilities, relationships, and governance of a study 
funded under a cooperative agreement are discussed later in this document under 
the section entitled SPECIAL REQUIREMENTS.  

The total project period for an application submitted in response to this RFA 
may not exceed five years.  This RFA is one-time solicitation.

The anticipated award date is August 1, 2001.  It is anticipated that the award 
for the Data Coordinating Center will be approximately $1,500,000 total costs 
per year and the maximum award for each Clinical Center will be $510,000 total 
costs per year.  The amount awarded to each Clinical Center per year will depend 
on the protocol(s) underway. 

FUNDS AVAILABLE

A maximum of six awards for Clinical Centers and one award for a Data 
Coordinating Center will be made under this RFA.  A maximum of about $22.8 
million (total costs) over a five-year period will be awarded for the Clinical 
Centers and the Data Coordinating Center.  Because the nature and scope of the 
research proposed in response to this RFA may vary, it is anticipated that the 
size of an award will also vary in all years.  Future year costs will be 
distributed based on the final, approved protocols.  

Although the financial plans of the NHLBI 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 applications of appropriate scientific and 
technical merit.  Designated funding levels are subject to change at any time 
prior to final award, due to unforeseen budgetary, administrative, or scientific 
developments.  It is not known if competing renewal applications will be 
accepted or if this RFA will be reissued.

RESEARCH OBJECTIVES

Background


Approximately 32,000 infants are born each year in the United States with 
congenital cardiovascular malformations, the most common congenital anomaly, and 
one of the leading causes of infant mortality.  The incidence of congenital 
heart disease is at least triple that of childhood cancers, and substantially 
greater than pediatric AIDS.  A significant number of additional children 
experience medical problems from inflammatory cardiac conditions, heart muscle 
disease, and arrhythmias.  Affected children experience morbidity and mortality 
that generate health and economic consequences out of proportion to their 
numbers.  In spite of recent improvement, the mortality rate for structural 
congenital malformations varies from less than 1% to as high as 50%, depending 
on the condition.  The medical, social and economic consequences of pediatric 
heart disease are profound, and include frequent medical monitoring and the need 
for invasive procedures, high medical care expenses, disruption of family life, 
the high cost of potential productive years of life lost when a child dies, and 
loss of parental productivity and wages.

Treatment of congenital and acquired pediatric heart disease involves medical, 
surgical, and catheter-based approaches.  Great strides have been made in 
diagnosing and treating pediatric heart disease since 1944, when the first 
operation for palliation of tetralogy of Fallot was performed, but important 
clinical questions remain unanswered.  Medical therapy is employed widely to 
treat various pediatric heart diseases including arrhythmias, heart failure, 
myocarditis, and coronary artery aneurysms arising after Kawasaki Disease.  Few 
drugs used as "standard therapy", however, have been tested in randomized 
controlled trials in pediatrics.  For example, standard pharmacological agents 
used in the treatment of adult heart failure, such as diuretics, digitalis, 
angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers, are used in 
children, but have not been studied in a systematic fashion.  Emerging adult 
therapies, such as immune modulation in heart failure, may benefit children but 
are virtually untested in pediatric populations.  In addition, pediatric heart 
failure can arise from multiple causes, including structural heart defects, 
heart muscle disease and inflammation, post-operative injury and edema, and 
poorly-controlled arrhythmias.  Standard and novel pharmacological agents may 
have different effects in specific types of heart failure.  As another example, 
immunosuppressive therapy, commonly used to treat pediatric myocarditis, has 
never been evaluated in a prospective, randomized trial.

Many structural congenital heart abnormalities are successfully corrected 
surgically.  However, the optimal timing and approach for complex congenital 
structural malformations including the several malformations that lead to single 
ventricle physiology are not known, and the risks and benefits of devices 
compared to surgical repair of certain defects have not been studied 
systematically.  In addition, the acute and chronic post-operative course can be 
complicated by conditions such as post-cardiopulmonary bypass syndrome 
(especially in infants), arrhythmias including those implicated in sudden death, 
neurodevelopmental deficits, ventricular dysfunction and heart failure, and 
coagulapthy leading to the need for reoperation.  Treatment strategies for these 
conditions are not supported by systematic prospective clinical studies.  A 
prime example is sudden cardiac death associated with repair of complex cyanotic 
congenital heart disease.  Many of these survivors are adolescents who have 
arrhythmias that may not be clinically apparent, and may require invasive 
testing to discern.  However, the correlation between results from invasive 
testing and sudden death is not clear, so it is difficult to risk-stratify 
surgical survivors for implantable defibrillator placement.  As the number of 
such survivors grows, there is increased urgency to answer this question.  Like 
heart failure, pediatric arrhythmias can occur in several settings, such as 
abnormal electrical pathways in structurally normal and abnormal hearts, 
postoperative edema and injury, inflammatory and heart muscle conditions, and 
ventricular dysfunction.  Therapeutic approaches include medical, 
interventional, and surgical strategies, which have improved the care of 
affected children.  As with other pediatric heart conditions, however, important 
treatment questions remain.


Most treatment decisions concerning these and other pediatric heart disease are 
not evidence-based.  In the past 25 years, fewer than 40 randomized clinical 
trials have been conducted, of which nearly half dealt with patent ductus 
arteriosus in preterm infants.  The major barriers to clinical studies in 
pediatric heart disease include the heterogeneity of conditions, the small 
numbers of individuals with a particular malformation or condition at any one 
center, differences in treatment approaches to particular problems, the absence 
of systematic centralized databases, and the lack of resources to provide 
national coordination of collaborative efforts.  The network approach is an 
effective, flexible way to study adequate numbers of patients with uncommon 
diseases, such as congenital cardiovascular malformations.  Efficiencies will be 
achieved through a common infrastructure for recruiting, monitoring, and 
following patients whose conditions will be characterized in a standard fashion. 
 A network also can serve as a platform to train junior investigators in 
pediatric clinical research, and as a vehicle for rapid and wide-spread 
dissemination of findings.  A collaborative effort through a clinical research 
network is the most scientifically sound and cost-effective way to overcome the 
current barriers and provide the information needed to bring evidence-based 
medicine to bear on children with heart disease.

Organization of the Pediatric Heart Disease Clinical Research Network

The Pediatric Heart Disease Clinical Research Network will be a cooperative 
network of 5-6 Clinical Centers, one Data Coordinating Center, and the Division 
of Heart and Vascular Diseases, NHLBI.  Clinical Centers will be responsible for 
proposing protocols, participating in their overall development, conducting the 
research, and disseminating research findings.  All individual Clinical Centers 
will be required to participate in a cooperative and interactive manner with one 
another and with the Data Coordinating Center in all aspects of the Pediatric 
Heart Disease Clinical Research Network.  The separate Data Coordinating Center 
will support protocol development; provide sample size calculations, statistical 
advice, common questionnaires, and data analysis; support manuscript 
preparation; and provide overall study coordination and quality assurance, 
including coordination of the activities of the Data and Safety Monitoring Board 
(DSMB), the Protocol Review Committee, the Steering Committee, and other 
standing committees.

A Steering Committee will be the main governing body of the Pediatric Heart 
Disease Clinical Research Network.  At a minimum, the Steering Committee will be 
composed of the Principal Investigators of the Clinical Centers and the Data 
Coordinating Center.  The NHLBI Project Scientist will serve as an ex officio 
member.  By the end of the second meeting of the Steering committee, the NHLBI 
will name a Study Chairperson, who may not be associated with any of the 
Clinical Centers or the Data Coordinating Center and is not an NHLBI staff 
member, to oversee and guide Steering Committee activities.  Each Clinical 
Center, the Data Coordinating Center, and the Study Chair will have one vote.  
The Steering Committee may meet as often as three to six times in the first 12 
months of the study, and two to four times per year thereafter.  All major 
scientific decisions will be determined by majority vote of the Steering 
Committee.  The first meeting of the Steering Committee will be convened by the 
NHLBI Project Scientist.  The Steering Committee will have primary 
responsibility for the general organization of the Pediatric Heart Disease 
Clinical Research Network, finalizing common clinical protocols, facilitating 
the conduct and monitoring of studies, and reporting study results.  Topics for 
the protocols will be proposed and prioritized by the Steering Committee.  For 
each protocol, one Clinical Center will take the lead responsibility for 
drafting the protocol, although the Steering Committee will provide input and 
will be responsible for assuring development of a common protocol to be 
implemented by the Clinical Centers.  


Subcommittees of the Steering Committee will be established as necessary, but 
will include, at a minimum, a Publications and Presentations Subcommittee, a 
Research Subcommittee, and a Quality Control Subcommittee.  The Publications and 
Presentations Subcommittee will facilitate and supervise preparation of 
manuscripts prior to submission for publication.  The Research Subcommittee will 
recommend research ideas and develop Network research protocols for review by 
the Steering Committee.  The Quality Control Subcommittee will be responsible 
for developing standards for specific laboratory tests and other measures to be 
used in Network protocols.  All will be chaired by a Clinical Center Principal 
Investigator, and include representation from the Data Coordinating Center and 
NHLBI.  						
 
An independent Protocol Review Committee, established by the NHLBI, will provide 
peer review for each protocol.  A DSMB, also established by the NHLBI, will 
monitor patient safety and review performance of each study.  As a part of its 
monitoring responsibility, the DSMB will submit recommendations to the NHLBI 
regarding the continuation of each protocol.

As specific protocols are developed, support will depend on the availability of 
funds and will be provided on a per-patient basis.  All of the Clinical Centers 
must be willing to pursue this funding arrangement for each new protocol 
conducted.  Clinical protocols must be approved by local Institutional Review 
Boards and the Pediatric Heart Disease Clinical Research Network Protocol Review 
Committee before initiation.  The exact number and duration of protocols 
supported in the five-year program will depend on the nature and extent of the 
investigations proposed by the Network Steering Committee.

Research Scope

The objective of this RFA is to establish a Pediatric Heart Disease Clinical 
Research Network that will accelerate research in the diagnosis and management 
of congenital and acquired pediatric heart disease as defined earlier, 
standardize existing treatments, and evaluate new therapies.  The emphasis will 
be on clinical studies that help identify optimal diagnosis, monitoring, and 
therapy.  Therapeutic trials and studies may involve investigational drugs, 
drugs already approved but not currently used, and drugs currently used, as well 
as devices, interventional procedures, and surgical techniques.  All projects 
must be completed within the five-year duration of this RFA.

This Network cannot answer all scientific questions pertaining to pediatric 
heart disease.  However, the urgent clinical problems that fit within the limits 
of the proposed Network science and structure, and the time-frame of this 
program are expected to be considered.  Specific projects should be included 
based on their importance in the field, as indicated by numbers of patients 
affected, medical and economic burden, and problems with current management. 

Some examples of topic areas in which to pose research questions dealing with 
diagnostic and treatment strategies appropriate for this RFA include, but are 
not limited to, the following: 

o  The diagnosis and medical management of congenital cardiovascular 
malformations and acquired pediatric heart disease, including the role of novel 
imaging techniques (3-D echo, cardiac MRI) in determining cardiac structure and 
function; evaluation of standard and novel therapy for pediatric heart failure 
arising in the setting of structural malformations, cardiac inflammation, and 
heart muscle disease; and therapy for acquired conditions such as myocarditis or 
coronary artery aneurysms in Kawasaki Disease.

o  Surgical strategies for single-ventricle physiology, optimal timing of 
surgery for various defects, evaluations of combined surgical and interventional 
strategies for complex congenital heart disease, and optimal approach to severe 
right- and left-heart obstructions.


o  Postoperative issues, including ventricular support, myocardial preservation 
and post-cardiopulmonary bypass syndrome, neurodevelopmental outcome, post-
operative pulmonary artery hypertension and dysfunction, post-operative 
coagulopathy or clot formation leading to reoperation, and postoperative acute 
and chronic arrhythmias.

THESE ARE EXAMPLES ONLY.  APPLICANTS SHOULD NOT FEEL LIMITED TO THE TOPICS 
MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT TO THE 
OBJECTIVES OF THE RFA.  It is not the intent of this Network to provide support 
for only one or two protocols that run for the entire five years.  Multiple 
studies will be conducted, possibly two to four a year.  It is anticipated that 
in the initial year, studies will be selected from those proposed by the 
successful applicants.  However, a decision to fund a particular Clinical Center 
will not commit the Pediatric Heart Disease Clinical Research Network to develop 
that group's clinical protocol.

Each Clinical Center applicant should propose a research plan that includes two 
protocols as models that could potentially be used in the Network environment.  
The protocols should demonstrate knowledge in the field of pediatric heart 
disease.  Each protocol should involve sufficient subjects to require the use of 
a network with multi-center participation.  Applicants should indicate knowledge 
of the number of patients required for each study based on sample size 
calculations.  One protocol must be a short-term (two years or less) and one a 
long-term (more than two years, but completed within the overall five-year time 
frame of the RFA) investigation of congenital or acquired pediatric heart 
disease.  Inclusion of a registry to monitor patient outcomes within a protocol 
is acceptable, provided that the registry falls within the time constraints of 
the RFA.  

The research plan should follow the instructions in the PHS 398 application 
form, (revised 4/98; 
https://grants.nih.gov/grants/forms.htm) and should include: a one-page overview 
of the proposed two investigations that presents the key research objective of 
each investigation and a diagram depicting the initiation and duration of the 
two investigations over a 5-year period; a description (within the total page 
limits designated in the PHS 398 application form) of each of the two protocols 
that includes the rationale, research aims, outcome measures, and study design; 
a description of the patient populations with an estimate of the expected 
distribution of minority and female patients, ages, and assurances of the 
applicant=s access to the patient populations.  The Research Plan, including the 
overview and description for both protocols, should not exceed 25 pages in 
total.  

The applicant should indicate for each protocol how many patients are available 
in the applicant's center and how many will be required from the entire Network. 
 In the discussion of outcome measures, it will be important to indicate 
appropriate objective measures of primary and secondary outcome.  Applicants are 
encouraged to explore, within the context of their proposed protocols and the 
cost limitations outlined elsewhere in this RFA, new technologies to monitor 
disease progression and response to therapy.  The relevant technology should be 
available for each protocol proposed during the five years of funding.  It also 
will be important to include strategies to assure adherence to therapy as part 
of the protocol.

SPECIAL REQUIREMENTS

Terms and Conditions of Award


The cooperative agreement is an award instrument establishing an "assistance"  
relationship (in contrast to an "acquisition" relationship) between NHLBI and a 
recipient, in which substantial NHLBI scientific and/or programmatic involvement 
with the recipient is anticipated during performance of the activity.  The NHLBI 
purpose is to support and/or stimulate the recipient=s activity by involvement 
in and otherwise facilitating the activity in a "partner" role, but avoiding a 
dominant role, direction, or prime responsibility.  The terms and conditions 
below elaborate on these actions and responsibilities, and the awardee agrees to 
these collaborative actions with the NHLBI Project Scientist toward achieving 
the project objectives.  It is anticipated that these terms and conditions will 
enhance the relationship between the NHLBI staff and the Principal 
Investigator(s), and will facilitate the successful conduct and completion of 
the study.  These agreements will be in addition to, and not in lieu of, the 
relevant NIH procedures for grants administration.  The terms will be as 
follows:						

1.  The awardee(s) will have lead responsibilities in all aspects of the study, 
including any modification of study design, conduct of the study, quality 
control, data analysis and interpretation, 
preparation of publications, and collaboration with other investigators, unless 
otherwise provided for in these terms or by action of the Steering Committee.   
 

2.  The NHLBI Project Scientist will serve on the Steering  Committee; he/she or 
another NHLBI scientist may serve on other study committees, when  appropriate. 
 The NHLBI Project Scientist (and the other cited NHLBI scientists) may work 
with awardees on issues coming before the Steering Committee and, as 
appropriate, other committees, e.g.:  recruitment, intervention, 
follow-up, quality control, adherence to protocol, assessment of problems 
affecting the study and potential changes in the protocol, interim data and 
safety monitoring, final data analysis and 
interpretation, preparation of publications, and development of solutions to 
major problems such as insufficient participant enrollment.

3.  Awardee(s) agree to the governance of the study through a Steering 
Committee.  Steering Committee voting membership shall consist of the principal 
investigators (i.e., cooperative agreement awardees), the NHLBI Project 
Scientist, and the Study Chair.  Meetings of the Steering Committee will 
ordinarily be held by telephone conference call or in the metropolitan 
Washington Area.

4.  A Data and Safety Monitoring Board will be appointed by the Director, NHLBI 
to provide overall monitoring of interim data and safety issues; the Steering 
Committee will nominate members for 
this Board.  Meetings of the Data and Safety Monitoring Board will ordinarily be 
held in Bethesda.  The NHLBI Project Scientist shall serve as Executive 
Secretary to the Board.  An Independent Protocol Review Committee, established 
by the NHLBI, will provide peer review for each protocol. 

5.  Awardees will retain custody of and have primary rights to their data 
developed under these awards, subject to Government rights of access consistent 
with current HHS, PHS, and NIH policies.  The collaborative protocol and 
governance policies will call for the continued submission of data centrally to 
the coordinating center for a collaborative database; the submittal of copies of 
the collaborative datasets to each principal investigator upon completion of the 
study; procedures for data analysis, reporting and publication; and procedures 
to protect and ensure the privacy of medical and genetic data and records of 
individuals.  The NHLBI Project Scientist, on behalf of the NHLBI, will have the 
same access, privileges and responsibilities regarding the collaborative 

data as the other members of the Steering Committee (i.e., cooperative agreement 
awardees). 

6.  Support or other involvement of industry or any other third party in the 
study -- e.g., participation by the third party; involvement of study resources 
or citing the name of the study or NHLBI support; or special access to study 
results, data, findings or resources -- may be advantageous and appropriate.  
However, except for licensing of patents or copyrights, support or involvement 
of any third party will occur only following notification of and concurrence by 
NHLBI.

7.  Awardees are encouraged to publish and to publicly release and disseminate 
results, data and other products of the study, concordant with the study 
protocol and governance, and the approved plan for making data and materials 
available to the scientific community and to the NHLBI.  However, during or 
within three years beyond the end date of the project period of NHLBI support, 
unpublished data, unpublished results, data sets not previously released, or 
other study materials or products are to be made available to any third party 
only with the approval of the Steering Committee and in accordance with 
paragraph 6.

8.  The NHLBI reserves the right to terminate or curtail the study (or an 
individual award) in the event of (a) failure to develop or implement a mutually 
agreeable collaborative protocol, 
(b) substantial shortfall in participant recruitment, follow-up, data reporting, 
quality control, or other major breach of the protocol, (c) substantive changes 
in the agreed-upon protocol with which NHLBI cannot concur, (d) reaching a major 
study endpoint substantially before schedule with persuasive statistical 
significance, or (e) human subject ethical issues that may dictate a premature 
termination.

9.  Any disagreement that may arise in scientific/programmatic matters (within 
the scope of the award), between award recipients and the NHLBI may be brought 
to arbitration.  An arbitration panel will be composed of three members--one 
selected by the Program Steering Committee (with the NHLBI member not voting) or 
by the individual awardee in the event of an individual disagreement, a second 
member selected by NHLBI, and the third member selected by the two prior 
members.  This special arbitration procedure in no way affects the awardee's 
right to appeal an adverse action that is otherwise appealable in accordance 
with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 
CFR part 16, or the rights of NHLBI under applicable statutes, regulations and 
terms of the award.

10.  These 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 part 74, and other HHS, PHS, and NIH grant administration 
policy statements.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDIES

It is the policy of the NIH that women and members of minority groups and their 
subpopulations must be included in all NIH supported biomedical and behavioral 
research projects involving human subjects, unless a clear and compelling 
rationale and justification are provided 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 research involving human subjects should follow the 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research," which have been published in the Federal Register of March 28, 1994 
(FR 59 14508-14513), and in the NIH Guide for Grants and Contracts of March 18, 
1994, Volume 23, Number 11 and are available on the web at: 
https://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH 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.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.   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 was 
published in the NIH Guide for Grants and Contracts, March 6, 1998, and is 
available at the following URL address:
https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

This Network will, by definition, include children.  Investigators also may 
obtain copies of these policies from the program staff listed under INQUIRIES.  
Program staff may also provide additional relevant information concerning the 
policy.

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. 
 Reviewers are cautioned that their anonymity may be compromised when they 
directly access an Internet site.

LETTER OF INTENT

Prospective applicants are asked to submit, by September 20, 2000, a letter of 
intent that includes a descriptive title of the proposed research, the name, 
address, and telephone number of the Principal Investigator, the identities of 
other key personnel and participating institutions, and the number and title of 
the RFA in response to which the application may be submitted.  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 
NHLBI staff to estimate the potential review workload and plan the review.

The letter of intent is to be faxed, E-mailed, or mailed to the Deputy Director, 
Division of Extramural Affairs, NHLBI, at the address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research and may be obtained from the Division of 
Extramural Outreach and Information Resources, National Institutes of Health, 
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, 
E-mail: GrantsInfo@nih.gov.  The PHS 398 application kit is also available on 
the Internet at https://grants.nih.gov/grants/forms.htm


NHLBI will operate a web site in support of this RFA that will include 
supplemental information, frequently asked questions, and other pertinent 
details.  It can be accessed through the NHLBI public web site, 
http://www.nhlbi.nih.gov.  Applicants are encouraged to check this site 
frequently as they are preparing their applications.
 
Material to Include in the Application 

Clinical Center Applicants: 

To promote development of a collaborative program among the award recipients, 
the issues discussed below need to be addressed in each application for a 
Clinical Center.  This material is in addition to the submission of a research 
plan, as described in the section entitled Research Scope.

o  Qualifications and experience.  Participation in this Network will be a 
complex and time-consuming undertaking.  Applicants for Clinical Centers must 
have experience and expertise to conduct clinical studies in congenital and 
acquired pediatric heart disease.  Prospective Clinical Centers must have an 
established research program in the area of congenital heart defects, and 
demonstrated access to a sufficient number of patients to accomplish their 
portion of the proposed protocols.  A minimum time commitment of 25% is expected 
from the physician leadership (Principal Investigator and any Co-investigators) 
at each Clinical Center.

o  Study population.  The application should include a description of the pool 
of potential study participants, including the age range, ethnic/racial and 
gender distribution, estimated distribution of patients with different types of 
congenital and acquired pediatric heart disease, and recruitment sources.  It is 
not anticipated that all eligible patients will be enrolled in research 
protocols at any one time, and it is possible that an individual patient may be 
enrolled in more than one study.  Patient access may be accomplished by 
establishing links with other groups in addition to the applicant=s institution. 
 If this is planned, there must be a well-described plan to link the individual 
Clinical Centers with other community health care providers, such as pediatric 
cardiology practices, pediatricians, and health maintenance organizations, as 
appropriate, to ensure adequate numbers of patients for clinical studies. 

o  Applicants from institutions that have a General Clinical Research Center 
(GCRC) funded by the NIH National Center for Research Resources may wish to 
identify the GCRC as a resource for conducting the proposed research.  In such a 
case, a letter of agreement from either the GCRC Program Director or Principal 
Investigator should be included with the application.
o  Willingness to participate in the Pediatric Heart Disease Clinical Research 
Network.  Applicants should state their general support of collaborative 
research and interaction with other Clinical Centers, the NHLBI, and the Data 
Coordinating Center through this Network concept.  Applicants should discuss 
their willingness, and that of the institutions involved, to pursue a per-
patient basis (capitation) of operational costs for each protocol.  Clinical 
Center applicants must be able to interact with the Data Coordinating Center to 
transmit and edit data and should discuss their capability to participate in a 
distributed data entry system.

Data Coordinating Center Applicants

o  Qualifications and experience.  Applicants for a Data Coordinating Center 
must demonstrate experience in the area of pediatrics and/or cardiovascular 
medicine and in coordinating multi-center clinical studies in all phases: 
protocol and manual of operations development, data collection and management, 
data safety and confidentiality, quality assurance, data analysis, distributed 
data entry, electronic communications, administrative management and 
coordination.  A minimum time commitment of 25% is expected from the Principal 
Investigator of the Data Coordinating Center.

o  Study design and management.  Data Coordinating Center applicants should 
discuss various aspects of study design that would be important in developing 
clinical protocols, for example: eligibility criteria; baseline and outcome 
measures; methods of randomization; important considerations for making sample 
size and power calculations; methods and frequency of data collection and entry; 
monitoring accuracy of data collection; quality control procedures including 
training and certification for multiple protocols, some of which may occur 
simultaneously; managing labeling and handling of blood samples (see below); and 
plans for statistical analysis.  Applicants also should describe their 
experience with pediatrics or pediatric cardiology and their ability to provide 
leadership in pediatric cardiology to support the clinical studies envisioned 
under this RFA.  In addition, they should describe their plans for 
administrative management of the DSMB, the Protocol Review Committee, the 
Steering Committee, and associated subcommittees.  The proposed Data 
Coordinating Center budgets should stipulate and justify the amount included for 
managing the DSMB and other Committees.  Travel expenses to attend the Steering 
Committee will be included in the budgets prepared by the Clinical Centers.

o  The Data Coordinating Center should describe how laboratory specimens (e.g., 
blood or tissue samples) will be handled.  Laboratories responsible to the Data 
Coordinating Center will manage specimens and laboratory studies as required by 
the Steering Committee.  The costs of performing specific laboratory tests that 
are not clinically indicated (i.e., will not be reimbursed through third-party 
payers as part of routine clinical care) will be budgeted as a part of the per-
patient costs of each Clinical Center.  The costs of specimen shipment as well 
as laboratory data acquisition and management will be a part of the budget of 
the Data Coordinating Center.  Estimated shipping and handling expenses for 
specimens should be justified and included in the budget of the Data 
Coordinating Center.  For the purposes of planning, the Data Coordinating Center 
should assume 2,000 patients over the course of the 5-year study period.

o  The Data Coordinating Center will be responsible for one or more central labs 
that will analyze data from clinical testing, such as echocardiograms, 
electrocardiograms, Holter monitor tracings, electrophysiology studies, and 
angiograms.  It is understood that the specific central lab(s) needed will 
depend on the protocols ultimately selected.  However, for purposes of the 
application, Data Coordinating Center applicants should describe in detail how 
they will identify and secure the necessary central lab(s) once specific 
protocols are approved.  In addition, because most, if not all protocols will 
include pediatric echocardiography, Data Coordinating Center applicants should 
describe the development and maintenance of a central lab for echocardiography 
(including fetal, transthoracic, and transesophageal components).  The costs of 
performing specific tests (i.e., tests that are not eligible for third-party 
reimbursement) will be budgeted as a part of the per-patient costs of each 
Clinical Center.  The format of transfer of data to the Data Coordinating Center 
should be specified.  For example, will the central echocardiography lab review 
tapes or digitally-archived information?  The expense of transferring the data 
on the clinical studies to the central lab(s), training technicians to obtain 
the data in a uniform manner, and instituting quality control measures (e.g., 
provision for re-reading a proportion of the studies to determine accuracy of 
interpretation) will be included in the Data Coordinating Center budget. 

BUDGET AND RELATED ISSUES

Applicants should complete the budget information as directed in the PHS 398 
application form. 

Clinical Center Applicants:
 
Clinical Center applicants should consider the following additional issues 
regarding budgets.  The underlying concept of the Pediatric Heart Disease 
Clinical Research Network is that a core effort is essential to maintain the 
infrastructure required to perform multiple clinical trials.  Based on this 
approach, it is estimated that the individual Clinical Centers will require a 
minimum level of effort to sustain the organizational aspects of the Pediatric 
Heart Disease Clinical Research Network.  Therefore, individual Clinical Centers 
should submit requests for a CORE BUDGET not to exceed $175,000 total costs per 
year.  It is anticipated that this core budget will cover a minimum of 25% 
effort for the combined physician leadership (Principal Investigator and any Co-
investigators), and appropriate percentages of effort for other key personnel 
(e.g., clinical coordinator, data entry clerk), and travel costs for 
approximately eight trips each year to attend Steering Committee meetings in 
Bethesda, MD, and other travel related to Network operations.  These costs 
should include appropriate justification.  Total costs for the core budget can 
be escalated at three percent annually for future years.  It should be noted 
that funds will not be provided for the purchase of expensive equipment such as 
echocardiographic or magnetic resonance imaging systems.

In addition to the core budget, each Clinical Center will be provided funds for 
implementation of protocols.  This support will be provided for each protocol on 
a per-successfully-enrolled-patient basis.  The precise number of protocols 
conducted over the five years will be determined by the Pediatric Heart Disease 
Clinical Research Network Steering Committee and will depend on a number of 
factors including availability of funds, length of the protocols, and ease of 
recruitment.  It is anticipated that after the first year, two to four protocols 
may be active each year.  Clinical Centers should request protocol enrollment 
funds as PATIENT CARE costs not to exceed $335,000 per year. This amount should 
be placed in the patient care category.  Patient care costs can be escalated at 
three percent annually for future years.  Maximum allowable total costs for each 
clinical center (core costs, costs per patient to conduct the protocols, and 
facilities and administrative costs) will be $510,000 a year.

Applicants for the Clinical Centers should present the following information:

o  For each year, the Clinical Centers should include the core budget costs (not 
to exceed $175,000 total costs) and patient care costs (not to exceed $335,000 
total costs). Estimated protocol implementation costs for Year 1 should be based 
on the two proposals presented in the applicant=s research plan.  A table should 
be included showing estimated costs per patient for conducting each protocol.


o  The budget for each clinical protocol in the PATIENT CARE category should be 
developed on a cost-per-patient-basis and include all direct costs and the 
associated protocol facilities and administrative costs at a rate not to exceed 
28%.  Costs of drugs or laboratory tests that are not clinically indicated 
(i.e., are not eligible for third-party reimbursement as part of routine 
clinical care) should be part of the per-patient cost of conducting a protocol. 
 Applications should identify the potential source(s) for any drugs or 
substances that are being considered for clinical protocols that are currently 
unavailable commercially.  If either of the protocols proposed by a Clinical 
Center applicant includes obtaining blood or tissue samples, the applicant 
should delineate how such specimens will be handled and analyzed.  In the event 
that a central laboratory is required to analyze specimens, the Clinical Centers 
will be responsible for obtaining the sample(s) and the cost of obtaining them 
will be part of the Clinical Center=s per-patient expense.  The cost of 
shipping, analyzing, and storing them, as well as training of personnel and 
quality control will be the responsibility of the Data Coordinating Center.   

o  Investigators should prepare budgets only for their own Clinical Center to 
conduct the proposed trial, and not for the entire Pediatric Heart Disease 
Clinical Research Network.  The applicant should state the total number of 
patients required by the entire Network to complete each proposed trial.  The 
yearly budget for the applicant's Center should include the number of patients 
available for the proposed protocol at the applicants center. A budget based on 
the costs per patient for recruiting and maintaining the specified number of 
subjects at the applicant's Center should be included for each protocol. 

Note that ongoing annual budgets for protocols will be based on the protocols 
approved by the Protocol Review Committee and the Pediatric Heart Disease 
Clinical Research Network Steering Committee.  The individual Clinical Centers 
will be expected to project patient enrollment for a specific protocol during a 
specified time frame; continuation and level of funding for each Clinical Center 
will be based on actual recruitment and overall performance. 

Awards will be subject to administrative review annually.

Data Coordinating Center applicants:

Applicants for the Data Coordinating Center should prepare budgets for five 12-
month periods that roughly correspond with the standard coordinating center 
responsibilities outlined elsewhere in this RFA.  For budget purposes, Data 
Coordinating Center applicants should assume that in the first year, all 
administrative aspects of the Pediatric Heart Disease Clinical Research Network 
will be organized and at least one protocol will be developed and started.  For 
subsequent years, applicants may assume that two to four protocols a year will 
be active; i.e., either in the protocol development, implementation, or analysis 
and writing phase.  Data Coordinating Center applicants should include costs for 
managing the DSMB, the Protocol Review Committee, and the Steering Committee 
including the cost of DSMB meetings two times per year in Bethesda, the cost of 
Protocol Review Committee conference calls and meetings, and the administrative 
expenses of Steering Committee conference calls and meetings.  Travel of 
Steering Committee members will be budgeted by Clinical Centers.  The Data 
Coordinating Center also should include costs for site visits of each of the 
Clinical Centers over the five-year study period, assuming six Clinical Centers 
throughout the U.S., and a five-member site visit team, for purposes of budget 
preparation.  

The award will be subject to administrative review annually.  It is expected 
that all protocols will be performed in a manner consistent with United States 
Food and Drug Administration guidelines.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.

The RFA label available in the PHS 398 (rev. 4/98) 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 types on line 2 of te 
face page of the application form and the YES box must be marked.


The sample RFA label available at:
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change.  Please note this is in pdf format.

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 must be sent 
to the Deputy Director, Division of Extramural Affairs, NHLBI, at the address 
listed under INQUIRIES.

Applications must be received by November 20, 2000.  If an application is 
received after this date it will be returned to the applicant without review.

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.  The CSR 
will not accept any application that is essentially the same as one already 
reviewed.  This does not preclude the submission of substantial revisions of an 
application already reviewed, but such applications must include an introduction 
addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and for 
responsiveness by NHLBI.  Incomplete and/or nonresponsive 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 Division of Extramural Affairs, NHLBI, in accordance with the review 
criteria stated below.  The roster of the initial review group will be posted on 
the NHLBI home page approximately two weeks prior to the review.  As part of the 
initial merit review, all applications will receive a written critique and 
undergo a review in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, will 
be discussed, assigned a priority score, and receive a second-level review by 
the National Heart, Lung, and Blood Advisory Council.

Review Criteria

Clinical Centers:


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.  Each of these criteria 
will be addressed and considered in assigning the overall score, weighting them 
as appropriate for each application.  Note that 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.

o  Significance:  Do the proposed studies address important problems?  If the 
aims of the application are achieved, how will scientific knowledge and care of 
the child with congenital or acquired pediatric cardiovascular disease be 
advanced?  What will be the effect of these studies on the concepts or methods 
that drive this field?

o  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?

o  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?

o  Investigator:  Is the Principal 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?

o  Environment:  Does the scientific environment in which the work will be done 
contribute to the probability of success?  Do the proposed studies take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements?  Is there evidence of a strong tradition of 
pediatric cardiovascular research and clinical care and ability to recruit the 
required number of patients?  Is there evidence of institutional support for the 
proposal?

o  Clinical Center Issues:  Does the application demonstrate access to patients 
and a willingness to work as part of the Pediatric Heart Disease Clinical 
Research Network and with the NHLBI Project Scientist(s)?
In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following: 

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the research. 
 Plans for the recruitment and retention of subjects will also be evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals, or the 
environment, to the extent they may be adversely affected by the project 
proposed in the application.
Data Coordinating Center:

Considerations for the review of Data Coordinating Center Applicants include the 
following issues:

o  Understanding of the scientific, statistical, logistical, and technical 
issues underlying multi-center studies, including issues relating to treatment 
and management of pediatrics and pediatric cardiovascular conditions, and taking 
a leadership role in the area of study design, statistics, logistics, data 
acquisition and management, patient confidentiality, handling of laboratory 
specimens, quality control, data analysis, and Network coordination.


o  Adequacy of the proposed plans for acquisition, transfer, management, and 
analysis of data, quality control of data collection and monitoring, and overall 
coordination of Pediatric Heart Disease Clinical Research Network activities.

o  The expertise, training, and experience of the investigators and staff, 
including the administrative abilities of the Principal Investigator, 
co-investigator, and the time they plan to devote to the program for the 
effective coordination of the Pediatric Heart Disease Clinical Research Network.

o  The administrative, supervisory, and collaborative arrangements for achieving 
the goals of the program, including willingness to cooperate with the 
participating Clinical Centers and the NHLBI.

o  Facilities, equipment, and organizational structure to coordinate Clinical 
Research Network activities effectively, and to assist Clinical Centers in 
implementing the Pediatric Heart Disease Clinical Research Network protocols, 
providing for specialized laboratory testing, and collecting data.

o  Appropriateness of the budget for the work proposed.

Schedule

Letter of Intent Receipt Date:  September 20, 2000
Application Receipt Date:       November 20, 2000
Peer Review Date:               March, 2001
Council Review:                 June 14-15, 2001
Anticipated Award Date:         August 1, 2001

AWARD CRITERIA

Factors that will be considered in making awards include: a) the scientific 
merit of the proposed program as determined by peer review, the multi-
disciplinary nature of the proposed studies, and the quality of the response to 
the special requirements stated in this RFA; b) relevance to the overall 
programmatic balance and priorities of the NHLBI and sufficient compatibility of 
features proposed in the research plan and qualifications of the investigators 
to make a collaborative program within the Pediatric Heart Disease Clinical 
Research Network a reasonable likelihood; and c) the availability of funds.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Gail D. Pearson, M.D., Sc.D.
Division of Heart and Vascular Diseases 
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 9044, MSC 7940
Bethesda, MD  20892-7940
Bethesda, MD 20817 (for express/courier service)
Telephone:  (301) 435-0524						
FAX:  (301) 480-1335
Email: gp62n@nih.gov

Direct inquiries regarding review issues to:

James Scheirer, Ph.D.

Deputy Director, Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7216, MSC 7924
Bethesda, MD  20892-7924
Bethesda, MD 20817 (for express/courier service)
Telephone:  (301) 435-0266
FAX:  (301) 480-3541					
Email:  js110j@nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Kevin Keating
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Suite 7136, MSC 7926
Bethesda, MD 20892-7926
Bethesda, MD 20817 (for express/courier service)
Telephone:  (301) 435-0177
FAX:  (301) 480-0422
Email: kk29g@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance, No. 
93.837.  Awards are made under authorization of Sections 310 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered under 
NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 
92.  This program is not subject to the intergovernmental review requirements of 
Executive Order 12372 or a Health Systems Agency Review.

The PHS strongly encourages all grant and contract recipients to provide a 
smoke-free workplace and promote the non-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.

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