MULTICENTER CLINICAL TRIAL OF FOCAL GLOMERULOSCLEROSIS IN CHILDREN AND 
YOUNG ADULTS

Release Date:  June 28, 2001

RFA:  RFA-DK-02-013

National Institute of Diabetes and Digestive and Kidney Diseases

Applicant Information Forum Date:  October 8, 2001
Letter of Intent Receipt Date:     February 15, 2002
Application Receipt Date:          March 15, 2002

PURPOSE

The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
invites cooperative agreement (U01) applications for Regional Clinical 
Coordinating Centers and a Data Coordinating Center to conduct a randomized 
clinical trial of cyclosporin or novel immunomodulatory agents in children and 
young adults with Focal Segmental Glomerulosclerosis (FSGS).

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 Request for Applications (RFA), 
Multicenter Clinical Trial Of Focal Glomerulosclerosis In Children And Young 
Adults, is related to one or more of the priority areas.  Potential applicants 
may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit 
institutions, public and private organizations, such as universities, 
colleges, hospitals, units of State and local government; and eligible 
agencies of the Federal government.  Only institutions located in North 
America are eligible to apply.  Racial/ethnic minorities, women, and persons 
with disabilities are encouraged to apply as Principal Investigators.  

An institution may apply to serve as both a Regional Clinical Coordinating 
Center and a Data Coordinating Center.  However, separate applications are 
required for each of these components.  The same applicant may not serve as 
the Principal Investigator of a Regional Clinical Coordinating Center and the 
Data Coordinating Center, and other key staff cannot be shared by these two 
centers.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for these awards will be 
the cooperative agreement (U01).  The cooperative agreement is an assistance 
mechanism in which substantial NIDDK scientific and programmatic involvement 
is anticipated during the performance of the activity.  Under the cooperative 
agreement, the NIDDK’s purpose is to support and encourage the recipient’s 
activities by working jointly with the awardees in a partnership role, but not 
to assume direction, prime responsibility, or dominance.  Details of the 
responsibilities, relationships, and governance of a clinical trial funded 
under a cooperative agreement are described under the section entitled “Terms 
and Conditions of Award.”  The total project period for applications submitted 
in response to this RFA is five years.  The anticipated award date is 
September 2002.  At this time, the NIDDK has not determined whether or how 
this solicitation will be continued beyond the present RFA.

FUNDS AVAILABLE (ICs should modify as necessary)

The NIDDK plans to make four awards for Regional Clinical Coordinating Centers 
and one award for a Data Coordinating Center.  Approximately $1,000,000 total 
cost (direct plus facilities and administrative costs) is expected to be 
available during year one of the study.  In each subsequent year $ 2,000,000 
will be available under this RFA.  It is anticipated that the award for each 
Regional Clinical Coordinating Center will be about $200,000 total cost in 
year one and $400,000 total cost in each subsequent year.  The award for the 
Data Coordinating Center will be about $200,000 total cost in year one and 
approximately $400,000 total cost in each subsequent year of the program.  

The number of awards to be made is dependent on the receipt of a sufficient 
number of applications of high scientific merit and availability of funds. 
Although this program is provided for in the financial plans of the NIDDK, 
awards pursuant to this RFA are contingent upon the availability of funds and 
the receipt of a sufficient number of applications of outstanding scientific 
and technical merit.

RESEARCH OBJECTIVES

Background

Most children and young adults who present with nephrotic syndrome have renal 
biopsy findings consistent with the diagnosis of minimal change disease; 
typically such patients will have remission of clinical symptoms with 
treatment with a course of high dose prednisone; progression to renal failure 
in this patient group is unusual.  There is however a sub-group of nephrotic 
children and young adults for whom the long-term prognosis is substantially 
poorer; risk factors include steroid-resistant or steroid-dependent nephrotic 
syndrome and evidence of focal glomerulosclerosis on renal biopsy. No 
satisfactory treatment exists for this high-risk patient group. In the long 
term, patients with FSGS face a high risk of renal failure.  In the shorter 
term, patients encounter the symptoms and complications of nephrotic syndrome 
including edema, ascites, hyperlipidemia and thromboembolism.  The goal of 
this initiative is to develop and conduct a multi-center clinical trial that 
will address the treatment of nephrotic syndrome and reduction in residual 
proteinuria in patients with FSGS.  While the long-term goal in these patients 
has to be protection of renal function, proteinuria provides a valuable 
surrogate marker that is both a measure of the severity of the nephrotic 
syndrome and a strong correlate of the risk of progressive loss of renal 
function. 

Focal glomerulosclerosis is also called focal segmental glomerulosclerosis; it 
is a pathological entity first described by Rich in 1957 characterized by the 
presence in some glomeruli, but not all, of areas of mesangial sclerosis.  
Although it is often secondary to other disorders such as HIV nephropathy, 
heroin use, or certain malignancies, it also appears as a primary, idiopathic 
condition; it is typically diagnosed on renal biopsy in nephrotic patients 
whose nephrotic syndrome has failed to respond to steroid therapy.  Secondary 
forms are more common among older adults while the primary form is more common 
among children and young adults. FGS is also among the most common renal 
disease to recur post renal transplants, often resulting in allograft injury 
(20 to 30%) or graft loss (40-50%). The disease appears to be more prevalent 
and more severe in African-American and perhaps Hispanic-American children.  
Although steroid therapy is commonly used in the treatment of children with 
FSGS, approximately 75% of patients do not respond to therapy, relapse while 
on therapy or relapse rapidly when therapy is stopped. The overall outcome 
remains unpredictable, with some patients progressing to end-stage renal 
disease (ESRD) within a period of two years, while others reach that point 
after an average of ten years. In some children the heavy proteinuria may 
improve with steroid therapy, but at the cost of significant adverse effects. 

A number of strategies have been employed to treat FSGS. Converting enzyme 
inhibitors are one established strategy to slow the progression of certain 
forms of renal disease. However, the effects of converting enzyme inhibitors 
has not been examined in children with FGS, and in adults the number of 
patients studied has been too small to allow meaningful subgroup analyses. 
Nonetheless, because the drugs are well tolerated and frequently result in 
some reduction in proteinuria, many nephrologists consider use of a converting 
enzyme inhibitor to be standard care, at least for patients who have both 
proteinuria and hypertension.  

The other important category of agents is immunomodulatory in nature. Both 
cyclophosphamide and chlorambucil have been used for treatment of FSGS for 
several decades. These agents have been studied in several clinical trials.  A 
recent meta-anlysis summarizing experience with cyclophospahmide and 
chlorambucil (Latta K. et al. Pediatric Nephrology 16:271-282, 2001) notes an 
overall increased rate of relapse-free survival with increasing doses of 
either agent.  Overall, however, the complication rate with these agents is 
not insignificant, response rates are not satisfactory, and even among 
patients who respond a substantial portion of patients do not remain in long-
term remission.  Results with cyclosporin are viewed by at least some 
nephrologists as more promising, although the overall experience is not 
extensive, and small, randomized trials have not established an advantage over 
the cytoxic agents.

Goal

The goal of this RFA is to conduct a collaborative, multi-center randomized 
controlled clinical trial of therapy to improve the clinical course of 
children and young adults with FSGS. The primary outcome of this clinical 
trial is a clinically significant reduction or remission of proteinuria.  Each 
Regional Clinical Coordinating Center is expected to randomize at least 100 
study participants over an 18-month period.  This sample size will require 
Regional Clinical Coordinating Centers to develop cooperative arrangements 
with other institutions and practicing physicians for patient referral.   A 
Central Repository will be established by the NIDDK as a result of a separate 
solicitation to store patient samples. This is a collaborative research 
program. Investigators are required to work closely together to develop the 
design of the trial, recruit participants, and collect uniform follow–up data.  
Because the trial will involve a large number of physicians over a wide 
geographic region the trial design must be simple and the intervention readily 
acceptable by both physicians and trial participants.    

STUDY ORGANIZATION
 
1.  Regional Clinical Coordinating Centers
 
Because the number of patients with FSGS followed at any one medical 
institution is likely to be insufficient to meet the recruitment goal for an 
individual Regional Clinical Coordinating Center, these centers will consist 
of a central institution coordinating the recruitment, intervention, and 
follow-up of patients entered into the trial from other medical organizations 
and individual physicians.  A Regional Clinical Coordinating Center should 
consist of an interdisciplinary team of clinical investigators and appropriate 
personnel, such as a research coordinator and clerical staff. Regional 
Clinical Coordinating Center investigators will have direct responsibility for 
developing the trial protocol and standardized forms for data collection, 
identifying potentially eligible study participants, assessing their 
eligibility to participate in the clinical trial, conducting baseline and 
follow-up visits, and obtaining blood, urine, and other biological samples, as 
defined in the trial protocol.  The Regional Clinical Coordinating Centers 
must work closely with the Data Coordinating Center to implement procedures 
for uniform and timely data collection, transmittal of data, as well as data 
audits and other data quality control procedures as established by the trial 
protocol. Regional Clinical Coordinating Centers are required to obtain 
patient consent for the trial.  The protocol must also be approved their 
Institutional Review Board.

2.  Data Coordinating Center

The Data Coordinating Center will be responsible for assisting the Regional 
Clinical Coordinating Center investigators to develop the trial protocol, 
including providing sample size estimates and statistical power calculations. 
The Data Coordinating Center will also have primary responsibility for 
collecting, editing, storing, and analyzing data generated by the Regional 
Clinical Coordinating Centers, and for establishing and implementing data 
audits and quality control procedures. The Data Coordinating Center will be 
responsible for establishing any Central Laboratories and coordinating the 
shipping of samples to a Central Repository.   

3.  Steering and Planning Committee

The primary governing body of the study will be the Steering and Planning 
Committee, comprised of each of the principal investigators of the Regional 
Clinical Coordinating Centers and the principal investigator of the Data 
Coordinating Center, the Chairperson of the Steering and Planning Committee, 
and the NIDDK Project Scientists (described in detail under Terms and 
Conditions).  They will meet initially to develop the clinical trial protocol 
and subsequently to discuss the progress of the trial and to consider problems 
arising during its conduct. The Steering and Planning Committee will develop 
policies for the trial pertaining to access to patient data and specimens, 
ancillary studies, performance standards, and publications and presentations. 
The Steering and Planning Committee may establish subcommittees on such topics 
as recruitment, quality control, and publications and ancillary studies.  
Small working groups may be established to prepare manuscripts and 
presentations.

4.  Data and Safety Monitoring Board

An independent group of experts in areas such as pediatric nephrology, 
nephrology, pathology, biostatistics, clinical trials and ethics, who are not 
otherwise involved in the study, as well as lay persons, will be selected by 
the NIDDK to evaluate the protocol prior to implementation, to review 
periodically the progress of the trial (described in detail under Terms and 
Conditions), and to ensure patient safety.

5.  Project Scientists

The NIDDK will identify two Project Scientists for the trial.  The Project 
Scientists will assist the Steering and Planning Committee in carrying out the 
trial (described in detail under Terms and Conditions).

Study Phases

The clinical trial will be carried out in three phases over a five-year 
period.

Phase I (6 Months): Development of the Clinical Trial Protocol, Manual of 
Operations, Data Forms and Data Base   

Work to be performed during this phase will be the development of a single 
clinical trial protocol and a detailed Manual of Operations specifying the 
procedures to be performed.  If necessary, Central Laboratories will be 
established.  

2.  Phase II (51 months): Trial Implementation:  Recruitment, Intervention and 
Follow-up 

Patients will be recruited into the trial and followed-up.  It is anticipated 
that recruitment will be conducted over an 18 month period.

Phase III (3 months):  Final Data Analysis and Close-out of the Trial  

The last follow-up visit will be conducted at the beginning of Phase III.  In 
addition, final data analysis will be performed and manuscripts written on the 
primary and secondary outcomes of the trial.  The Regional Clinical 
Coordinating Centers, Central Laboratories (if required) and the Data 
Coordinating Center will be closed-out. 

SPECIAL REQUIREMENTS

Terms and Conditions of Award

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 
Scientists.

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.

(1) Responsibilities of the Regional Clinical Coordinating Centers:  The 
Regional Clinical Coordinating Centers will have primary responsibility for 
developing the trial protocol, recruiting a sufficient number of study 
participants, maintaining high rates of follow-up and data collection, 
ensuring adherence to the trial protocol, obtaining high quality data, 
transmitting it accurately and expeditiously to the Data Coordinating Center, 
and interpreting, presenting, and publishing findings from the trial. A 
Regional Clinical Coordinating Center will work collaboratively with the other 
Centers, the Data Coordinating Center, and the NIH.

(2) Responsibilities of the Data Coordinating Center:  The Data Coordinating 
Center will assist the Regional Clinical Coordinating Centers in protocol 
development and will have primary responsibility for collecting, editing, 
storing and analyzing data generated by the Regional Clinical Coordinating 
Centers, and in preparation of reports and scientific publications.  The Data 
Coordinating Center has the major responsibility of creating the database and 
data collection systems.  They will also be responsible for performing 
statistical analyses of the data, including sample size and power estimates of 
the final trial design.  The Data Coordinating Center will arrange for the 
transfer of biologic samples to a repository to be established by the NIDDK.  
The repository will be supported through a mechanism separate from this RFA, 
and the samples will be available to FSG Consortium investigators and to other 
interested investigators. In addition, the Data Coordinating Center will 
supply logistical support for the meetings of the Steering and Planning 
Committee and the Data and Safety Monitoring Board.  The Data Coordinating 
Center should be prepared to assume a key role in overseeing implementation 
and adherence to the trial protocol, and assuring quality control of the data 
collected. The Data Coordinating Center will be expected to provide the NIDDK 
with a well-documented and complete data set after termination of the trial.  
The Data Coordinating Center will also be expected to generate appropriately 
detailed reports to the Steering and Planning Committee and to the Data and 
Safety Monitoring Board at regular intervals, and will be responsible for the 
logistics and planning of the meeting of these committees and their 
subcommittees.

(3) 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 
trial, final data analysis and interpretation, and preparation of 
publications.  The awardees agree to work cooperatively with the other 
Regional Clinical Coordinating Centers and agree to follow the common protocol 
developed by the Steering and Planning 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 FSG Consortium investigators and to other interested 
investigators.

(4) NIDDK Staff Responsibilities

The NIDDK will name two Project Scientists from within the Division of Kidney, 
Urologic and Hematologic Diseases whose function will be to assist the 
Steering and Planning Committee in carrying out the trial.  The Project 
Scientists 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.  One of the 
NIDDK Project Scientists will also serve as Executive Secretary of the Data 
and Safety Monitoring Board.  The NIDDK reserves the right to terminate or 
curtail the trial (or an individual award) in the event of difficulties in 
recruitment, or other shortcomings in carrying out the trial protocol, or 
human subject or ethical issues that may dictate a premature termination. 

(5) Collaborative Responsibilities  

The Steering and Planning Committee, composed of each of the Principal 
Investigators of the Regional Clinical Coordinating Centers, the Principal 
Investigator of the Data Coordinating Center, the NIDDK Project Scientists, 
and the Chairperson of the Steering and Planning Committee, 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 Data 
Coordinating Center, and reporting the trial results.  It will also be 
responsible for establishing trial policies in such areas as access to patient 
data and specimens, ancillary studies, publications and presentations, and 
performance standards. Each member of the Steering and Planning 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 and Planning Committee.  
A Chairperson will be chosen by the NIDDK from among the Steering and Planning 
Committee members (but not one of the NIDDK Project Scientists) or 
alternatively, from among experts in nephrology who are not participating 
directly in the trial.  

An independent Data Safety and Monitoring Board will be selected by the NIDDK. 
This group will include experts in pediatric nephrology, nephrology, 
biostatistics, pathology, and lay representatives, who are not otherwise 
involved in the trial. The Data Safety and Monitoring Board will review the 
trial protocol prior to implementation and evaluate interim and final results, 
monitor data quality, participant safety, and provide operational and policy 
advice to the Steering and Planning Committee and to the NIDDK.  One of the 
NIDDK Project Scientists will serve as Executive Secretary of the Board. The 
members of the Board will review progress and report to the NIDDK at least 
once each year, or more often if necessary.  Approval of the protocol by the 
Board is necessary prior to implementation.  

(6) Arbitration

Any disagreement that may arise on scientific/programmatic matters (within the 
scope of the award) between recipients and the NIDDK may be brought to 
arbitration.  An arbitration panel will be composed of three members, one 
selected by the Steering and Planning 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.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are 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 research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to 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) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS

All investigators proposing research involving human subjects should read the 
policy that was published in the NIH Guide for Grants an Contracts, June 5, 
2000 (Revised August 25, 2000), and is available at the following URL address 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

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.

INFORMATION FOR PROSPECTIVE APPLICANTS

Open Forum

A one-day open information forum will be held for prospective applicants on 
October 8, 2001 from 1 p.m. to 4 p.m. (E.S.T.) in Conference Room 701A, 6707 
Democracy Boulevard (Two Democracy Plaza), Bethesda, Maryland.  At this forum 
NIDDK program staff will answer any questions that prospective applicants 
might have regarding the clinical/scientific concepts of the RFA.  Attendance 
is not required and is not a pre-condition for submission of an application.  
Applicants planning to attend this meeting should submit their questions in 
writing (electronic mail is acceptable) to John W. Kusek, Ph.D. at the address 
listed under INQUIRIES at least two weeks in advance of the forum.  Applicants 
may also contact Dr. Kusek to obtain a summary of the forum. 

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent by February 15, 
2002 that includes a descriptive title of the proposed research, the name, 
address, and telephone number of the Principal Investigator, the identities of 
other key personnel and participating institutions, and the number and title 
of the RFA in response to which the application may be submitted.  Although a 
letter of intent is not required, is not binding, and does not enter into the 
review of a subsequent application, the information that it contains allows 
NIDDK staff to estimate the potential review workload and plan the review.

The letter of intent is to 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: 	fc15y@nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research and from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, 
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
GrantsInfo@nih.gov.

Applicants for Regional Clinical Coordinating Centers should describe their 
plans for participating in a multi-center clinical trial to address the goals 
as stated in the RFA. The design for a single clinical trial must be included 
in the application.  The design should include primary and secondary outcomes, 
entry and exclusion criteria, a comparison or “usual care” group-specifying 
treatment regimens for that group, a proposed follow-up visit schedule, and 
tests to be performed. Sample size estimates and power calculations are not 
required.  Applicants should provide detailed information regarding the size 
of the potential pool of FSGS patients who will be willing to come to the 
Regional Clinical Coordinating Center to participate for 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 clinical trial as outlined in this RFA.  A detailed description of 
the patient database from which patients targeted for this intervention will 
be selected, as well as a comprehensive plan to recruit patients, must be 
provided.  Realistic rates of study drop-outs, out-migration, and intervention 
non-adherence should be proposed.  Efforts to maintain follow-up of study 
participants and to collect data from participants recruited from distant 
locations should be specified.  

Applications for the Data Coordinating Center must also include a design for a 
single clinical trial, specifying primary and secondary outcomes, possible 
entry and exclusion criteria, use of a comparison or control group, a follow-
up visit schedule and test measurements.  Power calculations using clinically 
significant reduction of proteinuria or remission of proteinuria as the 
primary outcome should be provided. The application should also include plans 
for data collection, and overall quality control of the trial. An 
administrative plan to coordinate the activities of the Central Laboratories 
(if required), including quality control and data transmission to the Data 
Coordinating Center should be included in the application. The experience of 
the Data Coordinating Center in developing and maintaining web-based data 
collection systems for multi-center studies, including clinical trials should 
be documented.  Plans for transferring biologic samples to a repository to be 
established by the NIDDK should be outlined.  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, including adequate space in which to conduct 
participant follow-up (Regional Clinical Coordinating Centers) and data 
analysis/management (Data Coordinating Center) activities. An organizational 
structure for the trial 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 clinical trials, 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 (Regional 
Clinical Coordinating Centers only).  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 Regional Clinical Coordinating Centers, expertise in 
pediatric nephrology, 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 Regional 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.  Personnel for the Data Coordinating Center 
must have training and experience in biostatistics, data management, computer 
programming and database development.  Experience in the use of web-based data 
collection systems in a multi-center study setting is also necessary.  

Budget Preparation by Year

Applicants for the Regional Clinical Coordinating Centers and the Data 
Coordinating Center 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.  

Phase I (First 6 months). The budget will be for development of the trial 
protocol.  The Data Coordinating Center will establish the database necessary 
to accommodate the data transmitted by the Regional 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 Data Coordinating Center will identify and establish subcontracts with 
Central Laboratories (if required by the trial protocol) and other support 
centers as necessitated by the protocol. It is expected that the Data 
Coordinating Center 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 and Planning Committee in the 
Washington, D. C. area.  

Phase II (Months 7 through 57).  The budget for the Regional Clinical 
Coordinating Centers should include the full complement of personnel required 
to recruit the study participants, implement the intervention(s), and perform 
baseline and follow-up measurements and data collection.  Regional Clinical 
Coordinating Center personnel could include a principal investigator, co-
investigator, study coordinator, appointment scheduler/administrative 
assistant, and data entry clerk.

The budget for the Data Coordinating Center should also include the full 
complement of personnel for trial implementation. 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 include costs associated with necessary Central 
Laboratories. 

This phase of the program will require meeting approximately every four months 
in the Washington, D.C. area.  The travel budget should be estimated based on 
travel for the Principal Investigator and the Study Coordinator as well as any 
other key personnel for both the Regional Recruiting Centers and the Data 
Coordinating Center.  Budgets for the Data Coordinating Center should include 
travel for any consultants.  Travel for key staff at the Regional Clinical 
Coordinating Centers and the Data Coordinating Center should be budgeted each 
year for centralized training and re-certification of Regional Clinical 
Coordinating Center staff. Travel by Data Coordinating Center staff to 
Washington, D.C. for a meeting with the Data Safety and Monitoring Board 
should be planned and budgeted for annually.

Phase III (3 months).  Final data analysis and close-out of the Regional 
Clinical Coordinating Centers, the Data Coordinating Center, and Central 
Laboratories (if required) will take place over a three-month period.  The 
major activity during this phase will include final data analysis and 
conducting close-out visits of the study participants.  Manuscripts describing 
the primary and secondary results will be prepared and submitted to peer-
reviewed scientific journals for publication.  The Regional Clinical 
Coordinating Centers, the Data Coordinating Center and the Central 
Laboratories (if required) will be closed-out.  One meeting of the Steering 
and Planning Committee and one meeting of the Data and Safety Monitoring Board 
will be held.

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked.

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

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must be 
sent to:

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)

Applications must be received by March 15, 2002.  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.

REVIEW CONSIDERATIONS

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 receive a written critique and 
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, assigned a priority score, and receive a second level 
review by the NIDDK National Advisory Council or Board.

Review Criteria

Applicants are encouraged to submit and describe their own ideas about how 
best to meet the goals of the cooperative study as outlined in this RFA, and 
are expected to address issues identified under INFORMATION TO BE INCLUDED IN 
APPLICATIONS.  In the written comments, reviewers will be asked to discuss the 
following aspects of the application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 
goals.  Each of these criteria will be addressed and considered in assigning 
the overall score, weighting them as appropriate for each application.  Note 
that the application does not need to be strong in all categories to be judged 
likely to have major scientific impact and thus deserve a high priority score.

Review Criteria for Regional Clinical Coordinating Centers

Recruitment:  The ability to access a large number of potentially eligible 
patients with FSGS is a critical element of the application. Realistic 
estimates must be made regarding the number of patients who may prove eligible 
for the trial and are willing to be randomized and followed-up.

Significance:  The proposed trial protocol must appropriately address the 
issue of improving the clinical course of patients with FSGS as described in 
this RFA.  

Trial Design: Does the applicant propose a reasonable trial design and methods 
to achieve the aims of the RFA? Are entrance and exclusion criteria clearly 
defined and reasonable to permit recruitment of a sufficient number of 
patients?  Is the proposed comparison or control group feasible and ethically 
acceptable?  Are clinically meaningful primary and secondary endpoints 
described?  Will the intervention(s) proposed likely to be accepted by 
practicing physicians and patients alike?  Are plans presented to ensure 
patients’ follow-up and adherence to the study protocol?  

Investigators: Is the Principal Investigator appropriately trained and well 
suited to carry out the work? Is the work proposed appropriate to the 
experience level of the Principal Investigator and other key personnel?  Are 
the Principal Investigator and her/his co-investigators experienced in 
collaborating with other investigators in a multi-center study?  Are the 
investigators willing to participate in establishing and conducting a common 
protocol?  Does the Principal Investigator and the proposed study team, 
possess experience in recruiting participants to long-term clinical trials?  

Necessary Expertise:  Documented experience in pediatric nephrology is 
required.

Staff Qualifications:  Documented specific competence and relevant experience 
of professional, technical, and administrative staff pertinent to the 
operation of a Regional Clinical Coordinating Center are required.

Environment:  Does the scientific environment in which the work will be done 
contribute to the probability of success?  Documented adequacy of the proposed 
facility and space is necessary.  Is there evidence of institutional support 
and commitment for the proposed program? 

Recruitment of Minority Participants:  Has the applicant described in detail 
the distribution of minority participants to be recruited?  

Review Criteria for a Data Coordinating Center:

Significance:  Will the trial design answer the important clinical issues of 
patients with FSGS?  Is the trial design feasible and practical, with 
appropriately justified primary and secondary outcomes?
 
Approach to Conduct of the Trial:  Does the applicant acknowledge potential 
problem areas and consider alternative tactics in the implementation and 
performance of a clinical trial necessary to achieve the goals of this RFA?  
What is the approach to handle missing follow-up data and patient non-
adherence? Experience in developing protocols, developing web-based technology 
for data collection, establishing and maintaining large databases for data 
from the Regional Clinical Coordinating Centers, plans for analysis of the 
combined data, and efforts to ensure high quality data collection, and 
ensuring study participant adherence and confidentiality will be evaluated. 

Investigators:  Is the Principal Investigator appropriately trained and well 
suited to carry out this work?  Is the work proposed appropriate to the 
experience level of the Principal Investigator and other researchers?  Are the 
Principal Investigator and her/his co-investigators experienced in 
collaborating with other investigators in a multi-center study?  Experience in 
database development, data management, and statistical analysis is required.  
The ability to exercise appropriate leadership in matters of trial design, the 
acquisition, management and quality of the data, data analysis, and 
administration and coordination of Steering and Planning Committee meetings 
are important elements of the application.

Environment:  Does the scientific environment in which the work will be done 
contribute to the probability of success?  Documented adequacy of the proposed 
facility and space is necessary.  Is there evidence of institutional support 
and commitment for the proposed program? 

In addition to the above criteria, in accordance with NIH policy, all 
applications will be reviewed with respect to the following:

The reasonableness of the proposed budget for each year of the program.

The adequacy of the proposed protection for humans and the environment, to the 
extent they may be adversely affected by the studies described in this RFA.  
The scientific review group will also examine the safety of the research 
environment.

Schedule

Applicant Information Forum Date:  October 8, 2001
Letter of Intent Receipt Date:     February 15, 2002
Application Receipt Date:          March 15, 2002
Special Review Committee:          June/July 2002
NDDK Advisory Council:             September 18-19, 2002
Anticipated Award Date:            September 30, 2002

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit as determined by peer review
o Ability to achieve the recruitment goals, including racial and ethnic 
minority participants
o Geographic distribution (Regional Clinical Coordinating Centers only)
o Cost

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Gladys H. Hirschman, M.D., or 
John W. Kusek, Ph.D.
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Room 630 (Dr. Hirschman) MSC 5458
Room 617 (Dr. Kusek)MSC 5458
6707 Democracy Boulevard
Bethesda, Maryland 20892-5458 (for express or courier service use 20817)
Telephone:  (301) 594-7717 (Dr. Hirschman)
(301) 594-7735 (Dr. Kusek) 
FAX:  (301) 480-3510 (for both Drs. Hirschman and Kusek)
Email:  Dr. Hirschman:  gh24q@nih.gov
Dr. Kusek:  jk61x@nih.gov

Direct inquiries regarding 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: 	fc15y@nih.gov

Direct inquiries regarding fiscal matters to:

Teresa Farris
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Room 728MSC 5456
6707 Democracy Boulevard
Bethesda, Maryland 20892-5456 (for express/courier service use 20817)
Telephone:  (301) 594-7682
FAX:  (301) 480-3504
Email:  tf102y@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.849.  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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

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

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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