CLINICAL STUDY OF VESICOURETERAL REFLUX IN CHILDREN
 
RELEASE DATE:  July 8, 2004
 
RFA Number:  RFA-DK-04-019 

 September 16, 2009 - This RFA has been reissued as (RFA-DK-09-502).

(see amendment NOT-DK-04-010)

EXPIRATION DATE:  March 17, 2005

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

COMPONENT OF PARTICIPATING ORGANIZATION:  
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov/)
 
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.849  NIDDK  
Kidney Diseases, Urology and Hematology Research

LETTER OF INTENT RECEIPT DATE:  February 16, 2005
APPLICATION RECEIPT DATE:  March 16, 2005  
 
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 Supplementary Instructions
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) 
invites cooperative agreement applications for pediatric nephrology/urology 
clinical treatment centers (CTC) and a data coordinating center (DCC)for the 
design and conduct of treatment trials and studies in children with 
vesicoureteral reflux (VUR). The primary goals of this study are to 
determine: the relationship between renal scarring and decline in renal 
function, the risk factors for decline in renal function, the impact of 
prophylactic antibiotic use on preservation of renal function, and the role 
for surgical intervention in the preservation of renal function and 
prevention of recurrent urinary tract infections.
 
RESEARCH OBJECTIVES
 
Background

Vesicoureteral reflux (VUR), the retrograde flow of urine from the bladder to 
the upper urinary tract, is one of the most common problems for which children 
are referred to pediatric nephrologists and urologists. Clinical management 
strategies range from observation, to prophylactic antibiotic administration 
to various types of surgical intervention. There are no long-term, well 
documented studies, which demonstrate the effectiveness of these various 
clinical management strategies in preventing deterioration of renal function. 
In addition, there are many other topics related to VUR for which there is 
poorly documented data.  For example, in the scientific literature there is a 
lack of consistent correlation of VUR and renal scarring, as well as a lack of 
correlation of antibiotic use, urinary tract infection and renal scarring. 
Likewise, it is unclear whether surgical intervention improves outcome, and if 
a delay abrogates potential benefit from intervention. On May 18, 2003, the 
NIDDK sponsored a strategic planning workshop on the potential for conducting 
a randomized controlled trial in children diagnosed with VUR. A summary of the 
meeting and list of participants may be found at 
http://www.niddk.nih.gov/fund/divisions/KUH/kuhconferences.htm. As indicated 
above, the two big issues facing physicians who take care of this group of 
patients are: a) when, and what type of surgical intervention is indicated, 
and b) if and when antibiotic use is indicated. There are also difficulties in 
choosing appropriate outcome measures of clinical significance. These 
difficulties are compounded in children, since growth and development create 
the need for long-term outcome measures. 

Research Scope and Goals

The primary goals of this program are to study disease progression in a cohort 
of 600 children with mild to moderate VUR (grade I – III/IV) and to determine 
which interventions are most beneficial. 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 areas of research are:

o The relationship between the extent of scarring and renal function

o An assessment of the effect of surgical intervention on preserving renal 
function

o A comparison of the long-term outcomes of the different surgical approaches

o A comparison of the long-term efficacy of prophylactic antibiotic use in the 
different grades of VUR

o Delineation of early biomarkers for change in renal function

o The impact of dysfunctional elimination syndrome (DES)

o Family history/heritability of VUR

Applicants should propose testable hypotheses on critical issues that can be 
resolved in the context of this study.

MECHANISM OF SUPPORT
 
This RFA will use NIH U01 award mechanism.  As an applicant you will be 
solely responsible for planning, directing, and executing the proposed 
project.  This RFA is a one-time solicitation.  Future unsolicited, 
competing-continuation applications based on this project will compete with 
all investigator-initiated applications and will be reviewed according to the 
customary peer review procedures. The anticipated award date is September 
2005. Applications that are not funded in the competition described in this 
RFA may be resubmitted as NEW investigator-initiated applications using the 
standard receipt dates for NEW applications described in the instructions to 
the PHS 398 application.  

This RFA uses just-in-time concepts.  It also uses the modular budgeting as 
well as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular budget format.  Otherwise follow the instructions 
for non-modular budget research grant applications.  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm.  

The NIH U01 is a cooperative agreement award mechanism. In the cooperative 
agreement mechanism, the Principal Investigator retains the primary 
responsibility and dominant role for planning, directing, and executing the 
proposed project, with NIH staff being substantially involved as a partner 
with the Principal Investigator, as described under the section "Cooperative 
Agreement Terms and Conditions of Award.”  

FUNDS AVAILABLE 
 
The NIDDK intends to commit approximately $3 million in FY 2005 to fund five 
Clinical Treatment Center (CTC) grants and one Data Coordinating Center grant 
in response to this RFA. An applicant should request a project period of up 
to five years. It is anticipated that the award for the DCC will not exceed 
$800,000 total costs, excluding subcontract facility and administrative (F&A) 
costs (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html) . 
The amount awarded to each CTC will not exceed $440,000 total costs per year, 
excluding subcontract facility and administrative (F&A) costs 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html). 
Because the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size of each award 
will also vary. Although the financial plans of the IC(s) 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.  
 
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 institutions/organizations
o Foreign institutions are not eligible to apply as the applicant 
organization; however consortia agreements to foreign institutions are 
permitted

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.   

Each CTC must have at least one Pediatric Nephrologist and at least one 
Pediatric Urologist as investigators.  The Principal Investigator or Co-
Principal Investigator for a CTC may be either of those specialists. The 
Principal Investigator of a CTC should have demonstrated experience in 
enrolling patients in long-term, multicenter clinical trials and should be 
familiar with clinical trial design concepts.  The Principal Investigator of 
the Data Coordinating Center (DCC) should have demonstrated expertise in 
multicenter clinical trial design and in biostatistics.  It is anticipated 
that the DCC will also include experts in project management, data 
collection, quality control, and other areas related to the efficient and 
effective implementation of multicenter clinical trials.
 
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.  As preliminary evidence of that ability, each 
Clinical Treatment Center applicant must provide an accurate, verifiable, 
historical record of the number of eligible VUR patients seen per year for 
the past three years.  This record should be categorized by age, gender, race 
and the grade of VUR. It is expected that during the study each Clinical 
Coordinating Center will recruit a total of 120 eligible participants over a 
period of 24 months.  The Clinical Coordinating Centers and the Data 
Coordinating Center must also agree to participate in a collaborative and 
interactive manner with the other funded centers to develop the study 
protocols and carry out the study.

Cooperative Agreement Terms and Conditions of Award

A. Applicability. These special Terms of Award are in addition to and not in 
lieu of otherwise applicable OMB administrative guidelines, HHS grant 
administration regulations in 45 CFR part 74 and 92, and other HHS, PHS and 
NIH grant administration policy statements.

The administrative and funding instrument used to pay research projects 
involving clinical trials, prevention and control interventions, or 
epidemiological surveys in excess of $500,000 direct cost per year (at a 
single institution or in the aggregate for studies proposing multi-
institutional collaborative arrangements submitted as either subcontracts to 
a single application or as separate applications) shall be a cooperative 
agreement, an "assistance" mechanism (rather than an "acquisition" mechanism) 
in which substantial NIDDK scientific and/or programmatic involvement with 
the awardee is anticipated during performance of the activity. 

Under the cooperative agreement, the NIDDK 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 above concept, the dominant role and prime responsibility 
for the activity reside with the awardee(s) for the project as a whole, 
although specific tasks and activities in carrying out the studies will be 
shared among the awardees and the NIDDK Project Scientist or designee. 

Under the cooperative agreement, a relationship will exist between the 
recipient of these awards and the NIDDK, in which the performers of the 
activities are responsible for the requirements and conditions described 
below, and agree to accept program technical assistance, advice, and/or other 
coordination above and beyond normal program stewardship from a named NIDDK 
Project Scientist in achieving the project objectives.

Failure of an awardee to meet the performance requirements, including these 
special terms and conditions of award, or significant changes in the level of 
performance, may result in a reduction of budget, withholding of support, 
suspension and/or termination of the award. 

B. Awardee Rights and Responsibilities.

The Awardee is responsible for: 

1.  Research design and protocol development, including definition of 
objectives and approaches, planning, implementation, participant recruitment 
and follow-up, data collection, quality control, interim data and safety 
monitoring, final data analysis and interpretation, and publication of 
results. 

2. Establishing a Steering Committee to coordinate and manage the project.  
Awardee(s) will name investigators to serve as members on a Steering 
Committee and other subcommittees, as appropriate, meeting periodically.   
Awardees will be required to accept and implement the common protocol(s) and 
procedures approved by the Steering Committee.

3. Designating Protocol Chairs. The Principal Investigators (for studies 
involving multiple coordinated awards) shall designate a single Protocol 
Chairperson (if the Principal Investigator does not assume this role) for 
each protocol within the described research plan.  The Protocol Chairperson 
shall function as the scientific coordinator for the protocol and shall 
assume responsibility for obtaining approval to implement the protocol from 
the Steering Committee and for developing and monitoring the protocol.  Any 
significant modifications to approved protocols must be submitted to the 
Steering Committee by the Protocol Chairperson. 

4. Implementing the core data collection method and strategy collectively 
decided upon by the Steering Committee. For a study involving multiple 
institutions, it is the responsibility of each awardee/site to ensure that 
data will be submitted in a timely way to the central Data Coordinating 
Center. Additionally, individual investigators/sites must demonstrate the 
ability to implement the strategy specifically designed for their individual 
study population. 

5. Establishing mechanisms for quality control and monitoring. Awardees are 
responsible for ensuring accurate and timely assessment of the progress of 
each study, including development of procedures to ensure that data 
collection and management are: (1) adequate for quality control and analysis; 
(2) for clinical trials, as simple as appropriate in order to encourage 
maximum participation of physicians and patients and to avoid unnecessary 
expense; and (3) sufficiently staffed across the participating institutions. 
For research involving multiple awards, strategies for the analyses of pooled 
data will be developed by the Steering Committee. 

6. Submitting interim progress reports, when requested, to the NIDDK Program 
Director including as a minimum, summary data on protocol performance. For 
coordinated multiple awards or a multi-site single award, the Steering 
Committee may require additional information from individual awardees/sites. 
Such reports are in addition to the annual awardee noncompeting continuation 
progress report. 

7. Establishing procedures, where applicable, for all participating 
institutions in coordinated awards to comply with FDA regulations for studies 
involving investigational agents or devices and to comply with the 
requirements of 45 CFR Part 46 for the protection of human subjects, and the 
NIH policy requirements for the inclusion of women, minorities and children. 

8. Cooperating in the reporting of the study findings. The awardee(s) will 
retain custody of and have primary rights to the data developed under these 
awards, subject to the Government rights of access consistent with current 
HHS, PHS and NIH policies.  The NIDDK will have access to and may 
periodically review all data generated under an award. Where warranted by 
appropriate participation, plans for joint publication with NIDDK of pooled 
data and conclusions, are to be developed by the Principal Investigator or 
Steering Committee, as applicable.  NIH policies governing possible co-
authorship of publications with NIDDK staff will apply in all cases.  In 
general, to warrant co-authorship, NIDDK staff must have contributed to the 
following areas: (a) design of the concepts or experiments being tested; (b) 
performance of significant portions of the activity; and (c) preparation and 
authorship of pertinent manuscripts.

9. 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 NIDDK 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 NIDDK. 

10.  Study investigators are encouraged to publish and to release publicly 
and disseminate results and other products of the study, in accordance with 
study protocols and governances.

11. The NIDDK has established Central Biosample, Genetic, and Data 
Repositories for the archival and storage of data and biosamples collected in 
large, multi-site studies funded by NIDDK.  The Data Coordinating Center 
(DCC) will work with the NIDDK Biosample Repository to coordinate procedures 
for coding, shipping, processing, receipt, and storage of study samples that 
are to be maintained in the Repository.  In addition, the DCC will coordinate 
with the NIDDK Data Repository to prepare the collected data for eventual 
archiving and distribution. All samples and data transferred to the 
Repositories will be under the custodianship of the NIDDK, although the 
study’s Steering Committee will have proprietary control of and exclusive 
access to the samples and data for an agreed-upon period of time.  
Subsequently samples and data will be available to the wider scientific 
community in accordance with the NIH policy on Data Sharing   
(http://grants.nih.gov/grants/policy/data_sharing/ and,
http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#goals, and 
http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm)
through a process that will include prioritized distribution based on review 
of the scientific merit of the proposed use.  Therefore, it is expected that 
samples and data collected will be available to the broader scientific 
community, after a proprietary period, at no charge other than the cost of 
reproduction and distribution.

C. NIDDK Staff Responsibilities 

An NIDDK Project Scientist will have substantial involvement in the project 
above and beyond normal stewardship and monitoring of the award, as described 
below.  

1.  Being the contact point for all facets of the scientific interaction with 
the awardee (s).  As required for the coordination of activities and to 
expedite progress, NIDDK may designate additional NIDDK staff to provide 
advice to the awardee on specific scientific and/or analytic issues.  Such 
staff may include another Project Scientist or Analyst, who will provide 
direct technical assistance to the awardees to optimize the conduct and/or 
analysis of the study; or who may assist in the coordination of activities 
across multiple sites. 

2. For multi-institutional protocols, convening the first meeting of and 
subsequent participation in the Steering Committee that oversees study 
conduct. The NIDDK Project Scientist or designee will be a full participant 
and voting member of the Steering Committee and, if applicable, 
subcommittees. 

3. Serving as a resource with respect to other ongoing NIDDK activities that 
may be relevant to the protocol to facilitate compatibility and avoid 
unnecessary duplication of effort. 

4. Substantial involvement assisting in the design and coordination of 
research activities for awardees as elaborated below: 

a. Assisting by providing advice in the management and technical performance 
of the investigations, coordinating clearances for investigational agents 
held by NIDDK. The NIDDK may reserve the right to cross file or independently 
file an Investigational New Drug Application form with the FDA. 

b. For multi-institutional protocols, through participation in the Steering 
Committee and with the agreement of the Principal Investigator(s) of any 
coordinating center and data management centers, the NDDK Project Scientist 
or designee may coordinate activities among awardees by assisting in the 
design, development, and coordination of a common research or clinical 
protocol and statistical evaluations of data; in the preparation of 
questionnaires and other data recording forms; and in the publication of 
results. 

c. Reviewing and approving advice regarding the establishment of mechanisms 
for quality control and study monitoring.

An NIDDK Program Director identified in the Notice of Grant Award will be 
responsible for the normal stewardship and monitoring of the award.   The 
Program Director may also serve as the Project Scientist. 
The NIDDK Program Director responsibilities include:

1. Retaining overall programmatic responsibility for the award, and will 
clearly specify to the awardee the name(s) and role (s) of any additional 
individuals with substantial involvement in the project and the lines of 
reporting authority.  

2. Interacting with the principal investigator(s) on a regular basis to 
monitor study progress. Monitoring may include: regular communications with 
the principal investigator and staff, periodic site visits for discussions 
with awardee research teams, observation of field data collection and 
management techniques, quality control, fiscal review, and other relevant 
matters; as well as attendance at Steering Committee, data safety and 
monitoring board, and related meetings. The NIDDK retains, as an option, 
periodic external review of progress. 

3. Reviewing and approving protocols to insure they are within the scope of 
peer review and for safety considerations, as required by Federal 
regulations. The NIDDK Program Director will monitor protocol progress, and 
may request that a protocol study be closed to accrual for reasons including: 
(a) accrual rate insufficient to complete study in a timely fashion; (b) 
accrual goals met early; (c) poor protocol performance; (d) patient safety 
and regulatory concerns; (e) study results that are already conclusive; and 
(f) emergence of new information that diminishes the scientific importance of 
the study question. The NIDDK will not permit further expenditures of NIDDK 
funds for a study after requesting closure (except for patients already on-
study).

4. Making recommendations for continued funding based on: a) overall study 
progress, including sufficient patient and/or data accrual; b) cooperation in 
carrying out the research (e.g., attendance at Steering Committee meetings, 
implementation of group decisions, compliance with the terms of award and 
reporting requirements); and/or c) maintenance of a high quality of research, 
which will allow pooling of data and comparisons across multiple cooperative 
agreement awards for common data elements. 

D. Joint Responsibilities 

In addition to the interactions defined above, NIDDK Staff and Awardees shall 
share responsibility for the following activities: 

1. Steering Committee. 
         
A Steering Committee organized by the Principal Investigator (or P.I. of the 
Coordinating Center in the case of multiple coordinated awards) will be the 
main oversight body of the study. 
         
The Steering Committee has primary responsibility to design research 
activities, establish priorities, develop common protocols and manuals, 
questionnaires and other data recording forms, establish and maintain quality 
control among awardees, review progress, monitor patient accrual, coordinate 
and standardize data management, and cooperate on the publication of  
results. Major scientific decisions regarding the core data will be 
determined by the Steering Committee. The Steering Committee will document 
progress in written reports to the NIDDK Program Director, and will provide 
periodic supplementary reports upon request. 

The Steering Committee will be composed of all Principal Investigator(s), 
(including those of data coordinating /statistical centers, if any) and co-
investigators as deemed necessary, and the NIDDK Project Scientist or 
designee. An initial meeting of the Steering Committee will be convened early 
after award by the NIDDK Project Scientist or designee. The final structure 
of the Steering Committee will be established at the first meeting. The NIDDK 
Project Scientist or designee will have voting membership on the Steering 
Committee, and as appropriate, its subcommittees. Such a committee usually 
will meet at least twice yearly. 
         
A Chairperson, other than the NIDDK representative, will be selected by a 
vote of the members. The Chairperson is responsible for coordinating the 
Committee activities, for preparing meeting agendas, and for scheduling and 
chairing meetings. 
         
2. Data Safety and Monitoring Board. 
         
An independent Data and Safety Monitoring Board will be established by the 
NIDDK for Phase III clinical trials. The Data and Safety Monitoring Board 
will review interim results periodically and report to the Steering Committee 
and NIDDK.  In all other studies where warranted, the NIDDK Program Director 
will facilitate and the awardee shall allow for interim data and safety 
monitoring through the establishment of an independent (external) Data and 
Safety Monitoring Board.
         
E. Arbitration 
         
Any disagreement that may arise on scientific/programmatic matters (within 
the scope of the award), between award recipients and the NIDDK may be 
brought to arbitration. An arbitration panel will be composed of three 
members --one selected by the awardee (or the Steering Committee, with the 
NIDDK member not voting), a second member selected by NIDDK, and the third 
member elected by the two prior selected members. These special arbitration 
procedures in no way affect the awardee's right to appeal an adverse action 
that is otherwise appealable in accordance with PHS regulations at 42 CFR 
Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. 

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 Blvd., Room 639
Bethesda, Maryland 20892-5458
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  mm726k@nih.gov

Leroy M. Nyberg, M.D., Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 627
Bethesda, MD  20892-5458
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
E-mail:  ln10f@nih.gov

Stuart Howards, M.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 627
Bethesda, MD  20892-5458
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
E-mail:  sh359d@nih.gov

o Direct your questions about peer review issues to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes, Digestive, and Kidney Diseases
6707 Democracy Boulevard, Room 752
Bethesda, Maryland 20892-5452 
Telephone: (301) 594-8897
Fax:   (301) 480-3505
Email:  fc15y@nih.gov

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

Carolyn Kofa
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 727
Bethesda, Maryland 20892-5452
Telephone:  (301) 594-7687
FAX:  (301) 480-3504
Email:  ck104i@nih.gov
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes 
the following information:

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

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows IC staff to estimate the potential review workload and plan 
the review.
 
The letter of intent is to be sent by the date listed at the beginning of 
this document.  The letter of intent should be sent to:

Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a DUN and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/. The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 
398 document is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.
 
SUPPLEMENTARY INSTRUCTIONS: 

BUDGET: Clinical Centers should prepare a budget for each year of the program 
not to exceed $440,000 total costs (direct and facilities and administrative 
costs) per year. The funds for the DCC should not exceed $800,000 total costs 
per year. The first 8 months of year 1 will be a period of intensive protocol 
development with meetings of the steering committee to be held every other 
month, generally in the Washington DC area. The total percent effort of the 
Principal Investigator and co-investigator during this time should be 
reflected on the budget page. It is anticipated that recruitment for the 
clinical trial will begin in year 2.  Applicants should budget for key 
personnel for study coordination and data entry.  Beginning in year 2 and for 
the duration of the program applicants should budget for travel to three 
meetings of the Steering Committee each year.  These will generally be held 
in the Washington DC, area. The DCC should budget for all key personnel, 
describe % effort and description of responsibilities. 

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/labels.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application and all 
copies of the appendix material must be sent to:

Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD 20817)
 
APPLICATION PROCESSING: Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the applicant 
without review. 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.
 
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is, the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes from the 
previous unfunded version of the application.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK. Incomplete and/or nonresponsive applications 
will not be reviewed. 

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

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate the application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals. The scientific review group 
will address and consider each of the following criteria in assigning the 
application’s overall score, weighting them as appropriate for each 
application. 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
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.

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

APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project? Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

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

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

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

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

1) Qualifications of Principal Investigator for CTC:  The applicant must have 
demonstrated experience in enrolling patients in long-term clinical trials.  

2) Qualifications for Clinical Investigators for each CTC: Each CTC must have 
at least on Pediatric Nephrologist and one Pediatric Urologist as 
investigators. 

3) Recruitment and Retention Capabilities: The application should discuss the 
number of participants the Clinical Center anticipates will be recruited for 
clinical trials.  The application should provide evidence that the 
investigators are capable of enrolling 5-7 participants per month for two 
years. Applicants should describe the target population from which they 
expect to recruit the required number of subjects as study participants.  
They must also discuss plans for recruitment of minorities.  The applicant 
should include a brief discussion of previous relevant research efforts.  The 
applicant should discuss in detail the recruitment strategies which will be 
utilized to procure the expected number of study participants.  Specific 
plans and previous experience in retaining randomized study participants for 
the duration of clinical trial should also be discussed. Each Clinical 
Treatment Center applicant must provide an accurate, verifiable, historical 
record of the number of eligible VUR patients seen per year for the past 
three years.  This record should be categorized by age, gender, race and the 
grade of VUR.

4) Proposed Clinical Trial Concept:  The general concept draft for a single 
randomized controlled clinical trial to be considered by the Steering 
Committee of the Cooperative Treatment Group should be included in the 
application.  The general concept draft should not exceed two pages, and it 
must be consistent with the scientific focus of this RFA.  Concept issues to 
be considered are identification of the intervention(s) and rationale, 
primary and secondary outcome measures, sample size estimates and proposed 
subgroup analyses. 

5) Evidence of Institutional Support:  There should be evidence of strong 
institutional support for the Clinical Treatment Center, including adequate 
space in which to conduct clinical activities and office space for staff. 

6) Collaborative relationship between Pediatric Nephrology and Pediatric 
Urology.  The applicant should describe any already existing collaborative 
clinical relationships between pediatric nephrology and pediatric urology.

7) The Data Coordinating Center should provide evidence of experience in 
developing and conducting other multicenter clinical trials.  They should 
also submit a Clinical Trial Concept, as describer in item 4 above.  Also, 
methods for data collection, quality assurance, forms generation, meeting 
planning, etc., should be discussed and delineated in the proposal.  

8) Organizational Structure of Centers: Each applicant should include an 
organizational structure of their CTC or DCC, delineating lines of authority 
and responsibility.

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated. (See Inclusion Criteria in the sections on Federal Citations, 
below).

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

ADDITIONAL REVIEW CONSIDERATIONS

SHARING RESEARCH DATA: Applicants must describe their willingness to submit 
data generated through this project to relevant publicly available databases 
(http://grants.nih.gov/grants/policy/data_sharing/).  The reasonableness of the 
data sharing plan or the rationale for not sharing research data will be 
assessed in all proposals by the reviewers. However, reviewers will not factor 
the proposed data sharing plan into the determination of scientific merit or 
priority score. 
 
BUDGET: The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:          February 16, 2005
Application Receipt Date:               March 16, 2005
Peer Review Date:                       June 2005
Council Review:                         September 2005
Earliest Anticipated Start Date:        October 2005

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.
 
REQUIRED FEDERAL CITATIONS 

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities 
involving live, vertebrate animals must comply with PHS Policy on Humane Care 
and Use of Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as 
mandated by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA 
Animal Welfare Regulations 
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.

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

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

SHARING RESEARCH DATA:  Investigators submitting an NIH application seeking 
$500,000 or more in direct costs in any single year are expected to include a 
plan for data sharing or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing  Investigators should seek 
guidance from their institutions, on issues related to institutional 
policies, local IRB rules, as well as local, state and Federal laws and 
regulations, including the Privacy Rule. Reviewers will consider the data 
sharing plan but will not factor the plan into the determination of the 
scientific merit or the priority score.

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

All investigators proposing clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 
(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. 

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

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

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

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

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

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm 

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


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


H H S Department of Health
and Human Services

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