PROSPECTIVE STUDY OF CHRONIC KIDNEY DISEASE IN CHILDREN
 
RELEASE DATE:  November 26, 2002 
 
RFA:  DK-03-012 (Reissued as RFA-DK-07-501)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov/)
National Institute of Neurological Disorders and Stroke (NINDS)  
 (http://www.ninds.nih.gov/)
National Institute of Child Health and Human Development (NICHD)  
 (http://www.nichd.nih.gov/)

LETTER OF INTENT RECEIPT DATE:  January 21, 2003

APPLICATION RECEIPT DATE:  February 21, 2003
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) 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 Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of 
the National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK), in collaboration with the National Institute of Neurological 
Disorders and Stroke (NINDS) and the National Institute of Child Health 
and Human Development (NICHD), invites cooperative agreement 
applications for two Clinical Coordinating Centers and a Data 
Coordinating Center to conduct a prospective epidemiological study of 
children with chronic kidney disease. The primary goals of this study 
are to determine the risk factors for decline in renal function; the 
incidence of, and risk factors for, impaired neurocognitive development 
and function; the prevalence of risk factors for cardiovascular 
disease; and the long-term effects of growth failure and its treatment.
 
RESEARCH OBJECTIVES
 
Background
  
The incidence of end-stage renal disease (ESRD) in patients age 0   19 
years in the United States is 15 per million population, according to 
the 2002 USRDS Annual Data Report. The primary etiologies vary with 
age, but structural anomalies predominate. Data in the most recent 
report from the Chronic Renal Insufficiency arm of the North American 
Pediatric Renal Transplant Cooperative Study (NAPRTCS) indicate about 
two thirds of the patients on the registry had some type of structural 
anomaly. Numerous metabolic derangements occur in chronic kidney 
disease (CKD)and significantly impact on the overall well-being of 
affected children. Of the negative effects of pediatric renal disease, 
growth impairment is the best documented and studied, but there is very 
little systematic information about the magnitude of other 
developmental problems. In fact, there have been no large-scale 
prospective studies of pediatric chronic kidney disease.

Short stature is one of the more commonly recognized effects of CKD, 
first recognized over a century ago. The height deficits are greatest 
for younger patients and it has been previously documented that the risk 
for growth failure is highest in patients developing CKD at birth or 
early in infancy. The degree of renal failure, and particularly a GFR < 
25 ml/min/1.73m2, has been touted as critical to poor growth. Recent 
data also link poor growth to increased morbidity and mortality. 

When CKD develops during the neonatal period or in early infancy, there 
are significant problems with neurocognitive development. Some studies 
suggest an incidence of severe neurodevelopmental delay as high as 60% 
- 85% in this subpopulation. Growth in head circumference is uniformly 
subnormal. Gross motor delay, along with global developmental 
retardation and a lack of maturation on electroencephalography are 
common. Myoclonic seizures and cerebellar dysfunction have also been 
described in infants. However, there is virtually no information on the 
impact of a decrease in renal function that develops later in 
childhood. Overall, the impact of renal disease and uremia on 
neurocognitive development has been the subject of little systematic 
evaluation. Both the nature and magnitude of impaired neurocognitive 
development in pediatric patients with renal failure is unknown. Renal 
failure, however commonly affects both the central and peripheral 
nervous systems. Chronic uremic encephalopathy is associated with 
problems in learning and memory. These symptoms are believed to result 
from altered metabolic states in the CNS with ionic changes and 
possibly impaired synaptic function. Renal failure may also be 
accompanied by neuropathy and involvement of large diameter axons. 
There is substantial uncertainty whether earlier institution of renal 
replacement therapy offers advantages for the child's development. 

The incidence of hypertension in children with CKD is reported at 38-
78%. As a general rule, hypertension is infrequent in congenital renal 
disease, but is almost universal in primary glomerular disease and 
renal injury caused by systemic disease. In addition, uremic 
cardiomyopathy can be seen in pediatric patients with advanced CKD or 
ESRD, and may be associated with congestive heart failure. A recent 
report indicates that hyperhomocysteinemia is found in children with 
CRF, but it is unclear whether treatment of hyperhomocysteinemia in 
children decreases the risk for future atherosclerosis. 
Hyperhomocysteinemia has been identified as a risk factor for 
development of atherosclerosis in adults with CRF. Cardiovascular 
disease is a major problem in the adult nephrology patient population, 
but the incidence and types of cardiovascular disease present in 
children is unknown. For patients who have kidney failure starting in 
childhood, the incidence of risk factors for cardiovascular disease 
needs to be clearly delineated.

Research Scope and Goals

The primary goals of this program are to recruit a cohort of 600 
children with mild to moderately impaired kidney function and to follow 
these children in a prospective fashion for five years in order to 
define factors that impact on their well-being. Examples that illustrate 
possible areas of research are presented below. They are intended only 
to provide a broad direction for research and should be considered 
illustrative and not restrictive. Some potential goals are:

o Determination of the risk factors for accelerated decline in renal 
function. 

o Determination of the incidence of, and risk factors for, impaired 
neurocognitive development and function. 

o Determination of the nature (sensory, motor, visual and temporal 
processing; learning and memory; attention; social cognition and affect) 
and magnitude of neurocognitive impairment in pediatric CRF

o To establish brain structure/function correlates of neurocognitive 
impairment in pediatric CRF (imaging, behavioral and psychophysiological 
methodologies)

o Examination of genetic contributions to disease.

o Determination of the implications of growth failure and its treatment 
on morbidity and mortality.

o Determination of the prevalence of risk factors for cardiovascular 
disease.

The information obtained from this prospective cohort study of chronic 
kidney disease will establish natural history and outcome measures for 
intervention/prevention trials. Applicants should develop testable 
hypotheses on critical issues that can be resolved in the context of 
this study. The total sample size for the cohort study is projected to 
be approximately 600. It is anticipated that this number of 
participants will permit subcohort studies of neurocognitive impairment 
and cardiovascular disease.

STUDY ORGANIZATION
 
This prospective epidemiological study will be a cooperative 
arrangement of two Clinical Coordinating Centers, one Data Coordinating 
Center, and the Division of Kidney, Urologic and Hematologic Diseases.  
Clinical Coordinating Centers are responsible for protocol development, 
conducting the study, and disseminating research findings.  The 
Clinical Coordinating Centers are required to participate in a 
cooperative and interactive manner with each other and with the Data 
Coordinating Center.  The Data Coordinating Center will support 
protocol development and provide sample size calculations, statistical 
advice, data analysis, data management and quality control, and 
coordinate the activities of the Steering Committee, and overall study 
coordination and quality assurance.  

A Steering Committee composed of the principal investigators of the 
Clinical Coordinating Centers and the Data Coordinating Center and the 
NIDDK Project Scientist will be the main governing body of the study. A 
representative from both NINDS and NICHD will also participate at all 
steering committee meetings for input regarding research interests and 
topics specific to these participating Institutes.  Each Clinical 
Coordinating Center, the Data Coordinating Center, and the NIDDK will 
have one vote of the Steering Committee.  The Steering Committee will 
have primary responsibility for the general organization of the study, 
finalizing common protocols, facilitating the conduct and monitoring of 
the studies, and reporting study results.

Subcommittees of the Steering Committee will be established as 
necessary; for example, it is envisioned that committees will be 
established for study design, forms development, ancillary and sub-
studies, recruitment, publications and presentations, and others as 
necessary.

An independent External Advisory Committee (EAC) will be established by 
the NIDDK, NINDS and NICHD from among experts in areas such as pediatric 
nephrology, pediatric neurology, pediatric neuropsychology, pediatric 
cardiology, pediatric endocrinology, nephrology, pathology, 
biostatistics, epidemiology and ethics, who are not otherwise involved 
in the study, as well as lay persons.  The EAC will review the protocol 
prior to implementation and monitor protocol performance and participant 
safety at least annually.

Study Phases

The timetable for this cohort study may be subdivided into four phases 
over a five-year period.

Phase I (Months 1-6): Development of the Study Protocol. Work to be 
performed during this phase includes the development of the study 
protocol by the Steering Committee, including forms for data collection. 
If necessary, Central Laboratories, including a Central GFR Laboratory, 
will be established. If the Central NIDDK Biosample Repository is 
available, it will be used as the study repository for genetic and other 
material. If the Central NIDDK Biosample Repository is not available or 
is not chosen as the sample repository at the time the study is in the 
protocol development phase, an alternative repository for central 
storage and distribution of samples will need to be established. The DCC 
will begin computer programming to establish the database for the study.  
Prior to implementation of the cohort study, the protocol will be 
reviewed and must be approved by the External Advisory Committee.  

Phase II (Months 7-30): Recruitment of Cohort Study Participants / 
Initiate Follow-up. Over this period of 24 months potentially eligible 
participants will be identified, and will undergo baseline assessment. 
Those found eligible will be invited to enter into the cohort study. A 
subcohort of participants will undergo specific neurocognitive, growth 
or cardiac assessments. Concurrent with recruitment, follow-up of all 
study participants will be conducted in a standardized fashion over 
regular intervals.  

Phase III (Months 31-54):  Follow-up. The major activity during this 
period will be follow-up clinic visits.  Renal function will be 
measured, and additional studies as defined by the final protocol, will 
be performed in all cohort study participants. A subcohort of 
participants will undergo specific neurocognitive assessments, 
cardiovascular studies, or growth assessments.  The last follow-up visit 
of cohort study participants will be scheduled during the final four 
months of this phase.  

Phase IV (Months 55-60): Final Data Analysis and Close-out of the Study. 
During the final six months of the program, the activities include final 
data analysis and preparation of manuscripts on the findings from the 
cohort study.  The Clinical Coordinating Centers, Data Coordinating 
Center and all central facilities (excluding the Central Repository) 
will be closed-out in the last two months of this phase of the study.  
It is anticipated that the NIDDK will maintain the Central Repository 
for genetic and other material beyond the five years of this program.
 
MECHANISM OF SUPPORT
 
This RFA will use NIH U01 award mechanism. The NIH (U01) 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". The anticipated award date is September 
30, 2003. 

FUNDS AVAILABLE 
 
The NIDDK, NINDS and NICHD plan to commit approximately $2,000,000 in FY 
2003 to fund two Clinical Coordinating Centers and one Data 
Coordinating Center. An applicant should request a project period of 
five years. It is anticipated that the award for the DCC will be 
approximately $600,000 direct costs (no more than $800,000 total costs) 
per year. The amount awarded to each CC will vary between $400,000 to 
$500,000 direct costs (no more than $600,000 total costs) per year. 
Although the financial plans of the NIDDK, NINDS and 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(s) 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 
 
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 their 
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.   

SPECIAL REQUIREMENTS 

The ability to recruit and retain a sufficient number of participants 
into this study is the most important requirement for a successful 
Clinical Coordinating Center.  It is expected that each Clinical 
Coordinating Center will recruit a total of 300 participants over a 
period of 24 months.  The Clinical Coordinating Centers and the Data 
Coordinating Center must also participate in a collaborative and 
interactive manner to develop the study protocol and carry out the 
study.

Cooperative Agreement Terms and Conditions of Award

The following terms and conditions will be incorporated into the award 
statement and provided to each Principal Investigator as well as to the 
institutional officials at the time of the award.  These terms are in 
addition to, not in lieu of, otherwise applicable Office of Management 
and Budget (OMB) administrative guidelines, HHS Grant Administration 
Regulations at 45 CFR Part 74 and 92, and other HHS and NIH Grants 
Administration policy statements.

The administrative and funding instrument used for this program is the 
cooperative agreement (U01), an "assistance" mechanism (rather than an 
"acquisition" mechanism), in which substantial NIH scientific and/or 
programmatic involvement with awardees is anticipated during the 
performance of the activity.  Under the cooperative agreement, the NIH 
purpose is to support and/or stimulate the recipient's activity by 
involvement in and otherwise working jointly with the award recipient in 
a partner role, but it is not to assume direction, prime responsibility, 
or a dominant role in the activity.  Consistent with the cooperative 
agreement concept, the dominant role and prime responsibility for the 
planned activity reside with the awardees for the project as a whole, 
although specific tasks and activities in carrying out the activity will 
be shared among the awardees and NIDDK Project Scientist.

Awardees' Rights and Responsibilities: Awardees will have substantial 
and lead responsibilities in all tasks and activities.  These include 
protocol development, enrollment of study participants, data collection, 
quality control of the data, management of the study, final data 
analysis and interpretation, and preparation of publications.  The 
awardees agree to work cooperatively with the other Clinical 
Coordinating Centers and the Data Coordinating Center and agree to 
follow the common protocol developed by the Steering Committee.  The 
awardees agree also to transmit the trial data in a timely manner.  
Awardees will retain custody of and have primary rights to their data 
developed under these awards for the duration of the awards, subject to 
Government (e.g., NIDDK, NIH, or PHS) rights or access consistent with 
current HHS and NIH policies.  Patient samples will be stored and 
retained in the Central Repository, and the samples will be available to 
study investigators and to other interested investigators.

NIDDK Staff Responsibilities: The NIDDK will name a Project Scientist 
whose function will be to assist the Steering Committee in carrying out 
the trial.  The Project Scientist will have substantial scientific-
programmatic involvement in assisting protocol development, quality 
control, interim data analysis, final data analysis and interpretation, 
preparation of publications, and will provide assistance in coordination 
and performance monitoring.  The NIDDK Project Scientist will also serve 
as Executive Secretary of the External Advisory Committee.  The NIDDK 
program director assigned to administer the award will also serve as the 
Project Scientist, with substantial involvement above and beyond the 
normal program stewardship. The NIDDK reserves the right to terminate or 
curtail the study in the event of difficulties in recruitment, or other 
shortcomings in carrying out the study protocol, or human subject or 
ethical issues that may dictate a premature termination. 

Collaborative Responsibilities: The Steering Committee, composed of the 
Principal Investigators of the Clinical Centers, and the principal 
investigator of the Data Coordinating Center, the Chairperson of the 
Steering Committee, experts in the fields of pediatric neurology, 
endocrinology and cardiology and the NIDDK Project Scientist, will be 
the main governing board of the study.  This committee will have the 
primary responsibility for developing the study protocol, facilitating 
the conduct of participant follow-up and testing, monitoring 
completeness of data collection adherence to the protocol, timely 
transmission of the data to the DCC, and reporting the study results.  
It will also be responsible for establishing study policies in such 
areas as access to patient data and specimens, ancillary studies, 
publications and presentations, and performance standards. Each member 
of the Steering Committee will have one vote (NIDDK will have one vote), 
and all major scientific decisions will be determined by a majority vote 
of the Steering Committee.  A Chairperson will be chosen by the NIDDK 
from among the Steering Committee members (but not the NIH Project 
Scientist) or alternatively, from among experts in pediatric nephrology 
who are not participating directly in the trial.  

External Advisory Committee: An independent External Advisory Committee 
will be selected by the NIDDK, NINDS and NICHD. This group will include 
experts in pediatric nephrology, pediatric neurology, pediatric 
neuropsychology, pediatric cardiology, pediatric endocrinology, 
nephrology, biostatistics, epidemiology, and lay representatives, who 
are not otherwise involved in the trial. The External Advisory Committee 
will review the study protocol prior to implementation and evaluate 
interim and final results, monitor data quality, participant safety, and 
provide operational and policy advice to the Steering Committee and to 
the NIDDK.  The NIDDK Project Scientist will serve as Executive 
Secretary of the Committee. The members of the Committee will review 
progress and report to the NIDDK at least once each year, or more often 
if necessary.  Approval of the protocol by the Committee is necessary 
prior to implementation.  

Arbitration: Any disagreement that may arise on scientific/programmatic 
matters (within the scope of the award) between the recipient and the 
NIDDK may be brought to arbitration.  An arbitration panel will be 
composed of three members, one selected by the Steering Committee (with 
the NIDDK member not voting) or by the individual awardee in the event 
of an individual disagreement, a second member selected by NIDDK, and 
the third member selected by the two prior selected 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 45 
CFR Part 16, or the rights of the NIDDK under applicable statutes, 
regulations, and terms of award.
 
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:

Marva M. Moxey-Mims, M.D.,
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard
Room 639, MSC 5458
Bethesda, Maryland 20892-5458 (for express or courier service use 20817)
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  [email protected]

Emmeline Edwards, Ph.D.
Systems and Cognitive Neuroscience
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd.  Rm. 2109
Rockville, MD 20892-9527
Telephone:  (301) 496-9964
FAX:   (301) 402-2060
Email:  [email protected]

Lynne Haverkos, M.D., M.P.H.
Child Development and Behavior Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard 
Room 4B05, MSC 7510
Bethesda, MD 20892-7510
Telephone:  (301) 435-6881
FAX:  (301) 480-0230
Email:  [email protected]

o Direct your questions about peer review issues to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes, Digestive, and Kidney Diseases
6707 Democracy Boulevard
Room 752, MSC 5452
Bethesda, Maryland 20892-5452 
Bethesda, Maryland 20827 (for courier service)
Telephone: (301) 594-8897
Fax:   (301) 480-3505
Email:  [email protected]

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

Teresa Farris Marquette
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Room 728MSC 5452
6707 Democracy Boulevard
Bethesda, Maryland 20892-5452 (for express/courier service use 20817)
Telephone:  (301) 594-7682
FAX:  (301) 480-3504
Email:  [email protected]

Rita Sisco
Grants Management Officer
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd.  Rm. 3265
Rockville, MD 20892
Telephone: (301) 496-7488
FAX: (301) 402-0219
Email: [email protected]

Christopher Myers
Grants Management Officer
National Institute of Child Health and Human Development
Building 6100E/Room 8A17
6100 Executive Blvd MSC 7510
Bethesda, MD 20892-7510
Email: [email protected]
 
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:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes, Digestive, and Kidney Diseases
6707 Democracy Boulevard
Room 752, MSC 5452
Bethesda, Maryland 20892-5452 
Bethesda, Maryland 20827 (for courier service)
Telephone: (301) 594-8897
Fax:   (301) 480-3505
Email:  [email protected]

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: [email protected].
 
SUPPLEMENTAL INSTRUCTIONS: 

Clinical Coordinating Centers

Applicants should describe their plans for participating in a multi-
center epidemiological study to address the goals as stated in the RFA. 
Applicants should clearly state the level of GFR to be used as the 
definition of CKD for different age groups in the pediatric population. 
The design should include testable hypotheses for the study to address, 
entry and exclusion criteria, a proposed follow-up visit schedule, and 
tests to be performed. Sample size estimates and power calculations for 
each hypothesis should be included.  Applicants should provide detailed 
information regarding the size of the potential pool of chronic kidney 
disease patients who will be willing to come to participate in screening 
visits to assess study eligibility, and a reasonable projection of the 
proportion of patients screened and found eligible that would be willing 
to participate in a long-term follow-up as outlined in this RFA.  
Realistic rates of study drop-outs and out-migration should be proposed.  
Efforts to maintain follow-up of study participants and to collect data 
from participants recruited from distant locations should be specified.  
The application should also include plans for data collection, and 
overall quality control of the study. 

A major effort will be placed on identifying risk factors for incident 
cases neurocognitive impairment and worsening with disease progression. 
To that end, a number of neurophysiological, neuropsychological and 
neuroanatomical assessment tools may be considered in the design of the 
cohort study protocol: electroencephalograms (EEG), 
magnetoencephalograms (MEG) sensory evoked potentials, and cognitive 
event related potentials (ERPs), functional magnetic resonance imaging 
(fMRI), neuropsychological assessment including measures of vigilance 
(attention), visual-spatial tasks, short- and intermediate-term memory, 
intelligence rating tests. Other measurements that assess more subtle 
impairment in higher brain function (executive functions) may also be 
proposed for implementation of the entire cohort or in defined 
subgroups.   However, these recommendations must be supported by 
published literature and their utility and practicality in a multi-
center study as described in this RFA must be considered.

Data Coordinating Center
Applicants for the DCC component are not required to be a Clinical 
Coordinating Center within the study, although applicants for the 
Clinical Coordinating Center sites may also submit a separate 
application to be the DCC.

An administrative plan to coordinate the activities of the Central 
Laboratories (if required), including quality control and data 
transmission to the DCC should be included in the application. The 
experience of the DCC in developing and maintaining web-based data 
collection systems for multi-center studies should be documented.  The 
proposal should include a Sharing Plan that outlines how specimens and 
data collected will be shared with the wider scientific community, 
through eventual transfer of these materials to the NIDDK Central 
Repository or through another mechanism determined by NIDDK. A 
description of anticipated problems in carrying out this study and their 
proposed solutions must be included in the application.

Institutional Support:  There should be evidence of strong institutional 
support for the study. An organizational structure for the study should 
be set forth in the application, delineating lines of authority and 
responsibility for dealing with anticipated problems in all general 
areas as well as stated willingness to follow the commonly agreed-upon 
protocol.

Previous Experience:  The applicant should include a succinct discussion 
of previous relevant research efforts in multi-center studies and 
epidemiological studies, and any relevant experience/success in working 
collaboratively with investigators outside their own research 
institution.  Experience in the recruitment and retention of 
participants for long-term studies should be described. Previous 
participation in studies of racial and ethnic minority populations 
should be included.

Suggested Personnel Requirements:  The application must describe the 
expertise of key scientific, technical and administrative personnel and 
include a mechanism for replacing key professional or technical 
personnel should the need arise.  For the Clinical Coordinating Centers, 
expertise in pediatric nephrology, pediatric neurology, clinical 
research study management, and clinical trials is required.  Personnel 
may be full-time or part-time and may serve in more than one capacity. A 
suggested Clinical Coordinating Center study team might include, besides 
a Principal Investigator, a co-investigator (M.D. or Ph.D.), study 
coordinators, appointment-scheduler or administrative assistant and data 
entry clerk.  For the Data Coordinating Center, personnel with training 
and experience in biostatistics, data management, computer programming 
and database development are required.  Experience in the use of web-
based data collection systems in a multi-center study setting is also 
necessary.  

Budget Preparation by Year

Applicants must include an adequately justified year-by-year budget, 
reflecting the major changes in proposed activities as the study 
progress through its various phases.  Note that budgets are not to be 
prepared in modules.  The total budget should not exceed $600,000 per 
year for each Clinical Coordinating Center, or $800,000 per year for 
the Data Coordinating Center. NIDDK is also adopting a new approach 
regarding funding of Participating Clinical Centers during the patient 
recruitment phase.  Funds provided to the Clinical Centers after the 
study is initiated will be allocated for infrastructure costs and for 
reimbursement for recruitment on a per participant recruited basis.  
Infrastructure costs normally may include support for items such as 
personnel, travel, and supplies.

Phase I (First 6 months). The budget will be for development of the 
trial protocol by the Clinical Coordinating Centers in collaboration 
with the Data Coordinating Center. The Data Coordinating Center will 
establish the database necessary to accommodate the data transmitted by 
the Clinical Coordinating Centers.  A web-based technology for data 
transmission will be established in Phase I that will be efficient, and 
will protect study participant privacy.  The DCC will identify and 
establish subcontracts with Central Laboratories (if required by the 
study protocol) and other support centers as necessitated by the 
protocol. It is expected that the DCC will purchase all the necessary 
hardware and software for data transmission.  The budget for this period 
should include only those personnel actively involved in protocol 
development.  The travel budget for Phase I should be estimated based on 
travel for two key investigators to attend two-day, monthly meetings of 
the Steering Committee in the Washington, D. C. area.  

Phase II (Months 7 - 30).  The budget for the Clinical Coordinating 
Centers should reflect the level of effort necessary to recruit the 
entire study cohort and perform baseline and follow-up studies. Costs 
should be included for specialized studies of renal function, 
neurocognitive function, growth and cardiovascular studies. The Data 
Coordinating Center will receive and store the data transmitted by the 
Clinical Coordinating Centers, assess its completeness, provide feedback 
to the Clinical Coordinating Centers regarding data quality, and prepare 
progress reports for the Steering Committee and the group of external 
advisors on the progress of the cohort study.  The budget should include 
costs associated with a Central Biochemistry Laboratory and a Central 
GFR Laboratory.  In addition, the budget should include costs associated 
with a central study repository for samples, whether or not the Central 
NIDDK Repository is selected to carry out that function.  However, the 
Data Coordinating Center should budget staff to coordinate the 
activities of the Central Repository as it pertains to quality control.  
This phase of the program will require meeting approximately every four 
months in the Washington, D.C. area.  The travel budget for Phase II 
should be estimated based on travel for the Principal Investigator and 
the Study Coordinator as well as any other key personnel for both the 
Clinical Centers and the Data Coordinating Center.  Budgets for the Data 
Coordinating Center should include travel for any consultants.  Travel 
for key staff at the Clinical Centers and the Data Coordinating Center 
should be budgeted each year for central training.

Phase III (Months 31-54).  The major activities in this phase are 
follow-up and assessment of cohort study participants.  Renal function 
measurements and other specialized studies will continue during follow-
up.  A Central Biochemistry Laboratory and Central GFR Laboratory will 
continue to operate to handle follow-up data.  The Central Repository 
will receive, process, and store specimens from cohort study 
participants.  In-clinic visit follow-up of the cohort study 
participants will be terminated during the last several months of Phase 
III.  

Three meetings of the investigators should be budgeted for each year of 
this phase of the study.  Central training will occur annually and key 
staff should be budgeted to travel to the Washington, D. C. area.

For a Clinical Coordinating Center, the budget should request support 
for the minimum number of full and/or part-time staff to successfully 
carry out the proposed cohort study.  A Clinical Coordinating Center 
personnel list could include a principal investigator, co-investigator, 
study coordinators, appointment scheduler / administrative assistant, 
and data entry clerk.

For applications for the Data Coordinating Center, the budget should 
include the time and effort of key personnel for database management, 
programming, data analysis, and administrative functions to support the 
collaborative group.  The budget should also include subcontracts for a 
Central GFR Laboratory and Central Biochemistry Laboratory.  As noted 
previously, funding for the Central Repository will be directly from the 
NIDDK.  Travel by Data Coordinating Center staff to Washington, D.C. for 
a meeting with the group of external advisors should be planned and 
budgeted for annually.

Phase IV (Months 55-60). Final Data Analysis and Close-out of the 
Clinical Coordinating Centers, the Data Coordinating Center, Central 
Biochemistry Laboratory and the Central GFR Laboratory.  The major 
activities include final data analysis of the cohort study.  Manuscripts 
describing these findings will be prepared and submitted to peer-
reviewed scientific journals for publication.  The Clinical Centers, the 
Data Coordinating Center and the Central Laboratories will be closed-out 
during the last two months of this phase of the program.  Two meetings 
of the Steering Committee and one meeting of the group of external 
advisors will be held in Phase IV.
 
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: 
http://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 
must be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes, Digestive, and Kidney Diseases
6707 Democracy Boulevard
Room 752 MSC 5452
Bethesda, Maryland 20892-5452 
Bethesda, Maryland 20817 (for express/courier service)
 
APPLICATION PROCESSING: Applications must be received by 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.
 
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 applications already 
reviewed, but such applications must include an Introduction addressing 
the previous critique.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIDDK.  

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 NIDDK in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

o Receive a written critique
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 second level review by the NIDDK National Advisory Council 
 
REVIEW CRITERIA

Criteria for Clinical Coordinating Centers and Data Coordinating 
Center:

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 your 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 your application's overall score, weighting them 
as appropriate for each application.  Your 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, 
you may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  What will be the effect of these studies on the concepts or 
methods that drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and 
analyses adequately developed, well integrated, and appropriate to the 
aims of the project?  Do you acknowledge potential problem areas and 
consider alternative tactics?

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

(4) INVESTIGATOR: Are you appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to your 
experience level as the principal investigator and to that of other 
researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  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.

o INCLUSION:  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.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, below)

o DATA SHARING:  The adequacy of the proposed plan to share data. 

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

o OTHER REVIEW CRITERIA:  

Applicants are expected to address issues identified under the 
following sections in this RFA:  SPECIAL REQUIREMENTS, SUBMITTING AN 
APPLICATION/SUPPLEMENTAL INSTRUCTIONS as well as the OBJECTIVES OF THE 
RESEARCH PROGRAM.  All applications will be reviewed according to the 
criteria listed below. 

Clinical Coordinating Centers:

o Patient access and study population:  The ability to access a large 
number of potentially eligible pediatric patients with chronic kidney 
disease is a critical element of the application. Realistic estimates 
must be made regarding the number of patients who may prove eligible for 
the study.

o Willingness to participate in a collaborative study:  
The Clinical Coordinating Centers and the Data Coordinating Center
must participate in a collaborative and interactive manner to develop 
the study protocol and carry out the study. There should be evidence of 
prior experience in working collaboratively in carrying out a developed 
protocol.

   Data Coordinating Center:

o Understanding of the scientific, statistical, logistical, and 
technical issues underlying multicenter studies.

o Evaluation of the comprehensiveness, stability, adaptability and 
accessibility of the database.

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 the collaborative effort.

o The administrative, supervisory, and collaborative arrangements for 
achieving the goals of the program, including willingness to cooperate 
with the principal investigators of the Clinical Coordinating Centers 
and the NIDDK.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: January 21, 2003
Application Receipt Date: February 21, 2003
Peer Review Date: July 2003
Council Review: September 2003
Earliest Anticipated Start Date: October 1, 2003

AWARD CRITERIA

Award 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.
o Geographic Distribution (Clinical Coordinating Centers only)
 
REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research 
components involving Phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
http://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 AMENDMENT 
"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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a 
complete copy of the updated Guidelines are available at 
http://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. 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 is available at 
http://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 
http://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 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA 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.

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 No. 93.849, 93.864, 93.853 and 93.865 and 
is not subject to the intergovernmental review requirements of 
Executive Order 12372 or Health Systems Agency review.  Awards are made 
under authorization of Sections 301 and 405 of the Public Health 
Service Act as amended (42 USC 241 and 284)and administered under NIH 
grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

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.

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