HEMODIALYSIS VASCULAR ACCESS CLINICAL TRIALS CONSORTIUM

Release Date:  December 14, 1999

RFA:  DK-00-012 (Requesting competing applications from current awardees, see NOT-DK-05-010)

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date: February 29, 2000
Application Receipt Date: March 28, 2000

PURPOSE

The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of 
the National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) has a longstanding and substantial interest in research on 
the care of patients with end-stage renal disease (ESRD).  Among 
patients with ESRD, hemodialysis is the most common form of therapy. 
 In 1996, about 60% of the approximately 280,000 patients with ESRD 
were treated with hemodialysis.  Despite substantial advances in the 
care of hemodialysis patients over the past decade, the mortality and 
morbidity experienced by this patient population continues to be 
substantial.  One important aspect that is essential to permit the 
treatment of hemodialysis patients, namely the establishment and 
maintenance of access to the central circulation, has recently 
received increasing attention.  While a substantial number of 
clinical epidemiological studies have shown that arteriovenous (AV) 
fistulas are less prone to failure and complications than AV grafts, 
in 1996 only about 18 percent of ESRD patients had a functioning AV 
fistula 60 days after initiating hemodialysis.  Although our 
knowledge about the factors that precipitate failure of both fistula 
and graft AV access is incomplete, there is a positive and strong 
relationship between the percentage of stenosis observed at the 
access site and the risk of thrombosis.  Despite the substantial 
medical and economic impact of AV graft and fistula failure in the 
hemodialysis patient population there have been few randomized 
controlled clinical trials that have examined the effects of drugs 
and other therapies aimed at prolonging the survival of these types 
of vascular accesses.  In order to identify effective therapies to 
reduce the rate of AV graft and fistula failure in hemodialysis 
patients, the NIDDK invites cooperative agreement applications for 
investigators to design and implement a series of multi-center, 
randomized, controlled, clinical trials.  These cooperative 
agreements will support a collaborative network of Clinical Centers 
and a Data Coordinating Center to conduct well-designed clinical 
trials over a 5-year period.  Because over 40 percent of the new 
cases of ESRD are attributed to diabetes mellitus and both AV 
fistulas and grafts are more likely to fail in these patients, 
special emphasis will be given to recruit at least 50% diabetic 
patients to permit adequate sub-group and comparative analyses.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2000," 
a PHS-led national activity for setting priority areas.  This Request 
for Applications (RFA), Hemodialysis Vascular Access Clinical Trials 
Consortium, is related to the priority area of chronic disabling 
conditions and prevention services.  Potential applicants may obtain 
a copy of "Healthy People 2000" at 
http://odphp.osophs.dhhs.gov/pubs/hp2000.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit 
organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and Local governments, and 
eligible agencies of the Federal Government.  Foreign institutions 
are not eligible to apply. Racial/ethnic minority individuals, women, 
and persons with disabilities are encouraged to apply as principal 
investigators.

An institution may apply for both a clinical center and the data 
coordinating center; however, separate applications are required and 
a specific plan of how the independent operation (i.e., 
confidentiality of the study-wide data) of each unit will be 
maintained is required in each application.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program 
will be a cooperative agreement (U01), an "assistance" mechanism 
(rather than an "acquisition" mechanism), in which substantial NIH 
scientific and/or programmatic involvement with the awardee is 
anticipated during 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. Details of the responsibilities, relationships and 
governance of the study to be funded under cooperative agreements are 
discussed later in this document under the section "Terms and 
Conditions of Award."

The total project period for applications submitted in response to 
the present RFA may not exceed five years.  The anticipated award 
date is September 29, 2000.  This is a one time solicitation for 
applications.

The number of awards to be made and level of support to be provided 
depend on receipt of a sufficient number of applications of high 
scientific merit.  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 for this purpose.

FUNDS AVAILABLE  

It is expected that approximately $2,000,000 total cost (direct plus 
Facilities and Administrative costs) will be available for each year 
over a five year period.  It is anticipated that one award for the 
Data Coordinating Center will be made for approximately $625,000 
total cost per year, and five awards for Clinical Centers will be 
made for $275,000 per year.

RESEARCH OBJECTIVES

Background    

End-stage renal disease is an important medical problem in the United 
States.  The number of patients who reach ESRD has been steadily 
increasing.  According to the United States Renal Data System, a 
national database including more than 95% of the treated ESRD 
patients in the United States, for the ten-year period from 1987 to 
1996, the incidence rates for ESRD were increasing between 6 and 7 
percent per year.  Currently, approximately 280,000 patients are 
treated for ESRD in the U.S. and about 70,000 new patients start ESRD 
treatment annually.  Over 60% of these patients receive in-center 
hemodialysis.  Despite improvements in the technology and approaches 
to the medical management of hemodialysis patients during the past 
decade, the mortality and morbidity experienced by these patients is 
unacceptably high.  In 1996, the adjusted one-year death rate for 
hemodialysis patients during the first year of ESRD was approximately 
25 per 100 patient years.  Of the numerous medical problems 
encountered by hemodialysis patients, the impact of failed vascular 
access has received increasing attention.  It has been estimated that 
nearly 20% of the total expenditures for hemodialysis patients (in 
excess of $1 billion annually) is related to care of vascular access. 
 The morbidity experienced by hemodialysis patients is also 
substantial; approximately 25% of all hospital stays for ESRD 
patients are related to problems with vascular access.  The two most 
common methods of gaining repetitive access to the central 
circulation are arteriovenous (AV) fistulas and AV grafts.  While the 
failure and complication rates for AV fistulas are generally 
considered to be lower than for AV grafts, less than 20 percent of 
the patients 60 days after initiating hemodialysis have a mature AV 
fistula.  A substantial number of clinical epidemiological studies, 
utilizing a variety of methods to monitor the early events associated 
with vascular access dysfunction, have been conducted.  These studies 
have shown that both AV fistula and AV graft failure is most often 
attributed to development of stenotic lesions resulting from 
neointimal hyperplasia which places the patient at high risk for 
developing access-related thrombosis. 

Despite the substantial impact of complications from vascular access 
failure, few intervention studies have been performed to evaluate 
pharmacologic therapies to improve this aspect of hemodialysis 
patient care.  Of the small number of clinical trials conducted to 
date, many were carried out over a decade ago.  This was prior to the 
introduction of other therapies for ESRD patients that may impact on 
the survival and functioning of AV grafts and fistula such as the use 
of erythropoietin and the increased use of high-flux dialysis 
membranes.  The patient population in these older clinical trials was 
also different than the current hemodialysis patient population since 
the proportion of patients with ESRD due to diabetes (and other co-
morbid medical conditions) has rapidly escalated during the past ten 
years.  Importantly, novel anti-thrombotic agents and drugs to 
inhibit cytokines that have been developed over the past several 
years have not been systematically and rigorously evaluated for their 
effect on the rate of access survival and complications in 
hemodialysis patients.  The few trials that have been performed more 
recently have suffered from numerous methodological shortcomings, 
including small sample sizes. 
 
A workshop on the Critical Issues in the Care of the Dialysis 
Patient, sponsored by the NIDDK, was held in September 1998.  Among 
the recommendations from the workshop, the initiation of randomized 
controlled clinical trials to reduce both AV graft and fistula 
complications in hemodialysis patients was rated as having the 
highest priority.  

Objectives and Scope    

The intent of this Request for Applications is to solicit 
applications from investigators proposing to serve as Clinical 
Centers or the Data Coordinating Center to conduct collaborative 
studies among hemodialysis patients.  These centers will design and 
conduct a series of multi-center, randomized, placebo-controlled 
clinical trials of drug therapies to reduce the failure and 
complication rate of AV grafts and fistulas in hemodialysis patients 
over a 5-year period.  

In order to accumulate a sufficient sample size to test the effect of 
these interventions, a collaborative effort will be required by five 
Clinical Centers and one Data Coordinating Center.  In this 
collaborative effort, participating institutions will agree to follow 
a uniform study protocol with standardized data collection 
procedures.  While applicants for a Clinical Center are requested to 
propose a single clinical trial design for either AV fistulas or 
grafts, they must be willing to conduct one or more clinical trials 
for a type of vascular access not originally proposed in their grant 
application.  Thus it is essential that applicants for Clinical 
Centers be able to recruit a sufficient number of hemodialysis 
patients to study both AV fistulas and grafts during the five-year 
period of this clinical trials consortium program.  It is estimated 
that each Clinical Center will be required to randomize at least 125 
individual hemodialysis patients for each of the trials to be carried 
out by the consortium.


The collaborative protocols will be developed by the Steering 
Committee, composed of the awardees and the NIDDK Project Scientist. 
 The protocols will be subject to peer review by an uninvolved expert 
group, the Data and Safety Monitoring Board.  The studies will 
proceed only with the concurrence of both the awardees and the NIDDK.
 
Applicants are encouraged to contact pharmaceutical manufacturers of 
agents proposed for their clinical trial to determine their interest 
in participating in protocol development and to provide both drug and 
placebo to the consortium.  For those applicants proposing to monitor 
vascular accesses by Doppler ultrasound, ultrasound dilution 
techniques, or via some other method requiring specialized equipment, 
it is recommended that applicants communicate with manufacturers of 
these devices.  Applicants are requested to determine the level of 
interest of these manufacturers in participating in the trials to be 
conducted by the consortium, including providing equipment to the 
investigators.  The results of these discussions should be clearly 
described in the grant application.  The intent of this Request for 
Applications is to provide for an infrastructure to conduct a series 
of clinical trials among hemodialysis patients.  In cases where 
applicants have an existing clinical research program within their 
hemodialysis units, the economic implementation of the proposed 
clinical trial should be documented in the application.

It is anticipated that a series of randomized, placebo-controlled 
clinical trials will be designed and completed over the 5-year period 
of this program.  While the timetable noted below indicates that four 
clinical trials are scheduled for the 5-year period, the actual 
number of protocols implemented may vary depending upon the specific 
study designs agreed upon and implemented by the Steering Committee. 

Timetable 

Year I:  

o Protocol development for clinical trial #1 (first six months)

o Patient recruitment (second 6-month period in year 1)

o Protocol development for clinical trial #2 (second six-month 
period)

Year II: 

o Complete patient follow-up for protocol #1 (end of year 2)

o Begin recruitment for clinical trial #2 (beginning of year 2)

o Complete recruitment for clinical trial #2 (midpoint of year 2)

o Data analysis/reporting of results for clinical trial #1(second 
half of year 2)
                
Year III:   

o Complete follow-up for clinical trial #2 (midpoint of year 3)

o Develop protocol for clinical trial #3 (first half of year 3)

o Data analysis/reporting of results for clinical trial #2 (second 
half of year 3)

o Recruitment for clinical trial #3 (second half of year 3)
                
Year IV:   

o Data analysis/reporting of results for clinical trial #2 (first 
half of year 4)

o Develop protocol for clinical trial #4 (first half of year 4)

o Complete follow-up for clinical trial #3 (end of year 4)

o Recruitment for clinical trial #4 (second half of year 4)       
                
Year V:

o Data analysis/reporting of results for clinical trial #3 (first 
half of year 5).

o Complete follow-up for clinical trial #4 (end of year 5)

o Data analysis/reporting of final results for clinical trial #4 (end 
of year 5) 

o Close-out of Clinical Centers

SPECIAL REQUIREMENTS

A. Participation in a Collaborative Program

To promote the development of a collaborative program among the 
awardees, the applicant should present evidence of experience in 
working cooperatively with other Clinical and Data Coordinating 
Centers and of ability to follow common protocols that are 
collaboratively developed.  Clinical Centers will be expected to 
communicate with the Data Coordinating Center and the NIDDK Project 
Scientist on a regular basis.  

All Clinical Centers in the consortium must agree to implement the 
protocols and manual of operations that will be developed 
cooperatively and agree to electronically transmit all study data in 
a timely fashion to a central Data Coordinating Center for 
combination and analysis.  An explicit statement of willingness to 
cooperate in a collaborative program should be included in the 
application.  Willingness to study both AV fistulas and grafts must 
be indicated.

The Data Coordinating Center will be involved in collaborations with 
the NIDDK and the Clinical Centers during all phases of the trials.  
Thus the applicant for the Data Coordinating Center is expected to 
demonstrate experience in working cooperatively with Clinical Centers 
and sponsoring organizations in a multi-center clinical trial or 
clinical research study and overseeing the implementation of and 
adherence to a common protocol, as well as assuring quality control 
of the data collected.  An explicit statement of the willingness to 
participate in a collaborative program should be included in the 
application.  In addition to organizing and attending regular 
meetings, the Data Coordinating Center will be expected to maintain 
close communications with the NIDDK Project Scientist and the 
Clinical Centers.

B. Study Components

1) Clinical Centers.  Clinical Centers in the consortium will be 
expected to:

a) Design the study protocols and write the manual of operations for 
each of the clinical trials

b) Develop operational plans for the recruitment, treatment, and 
follow-up of patients

c) In collaboration with the Data Coordinating Center, suggest 
approaches to data analysis and participate in writing of manuscripts 
for publication in peer-reviewed scientific journals.

A Clinical Center is an institution that is actively involved in the 
recruitment, evaluation, treatment, and follow-up of study 
participants.  For these trials it will consist of a core team of 
researchers who are skilled in nephrology, delivery of hemodialysis, 
the care and management of vascular accesses, and have experience in 
collaborative clinical investigation.

An important goal of this consortium is to conduct clinical trials 
among an overall patient population that at least reflects the gender 
and racial/ethnic composition of the U.S. hemodialysis patient 
population. Thus individual Clinical Centers will be required to 
target recruitment of a sufficient number of women, African American, 
Hispanic, and Native American hemodialysis patients.  Clinical 
Centers that are able to enhance recruitment in one or more these 
populations are encourage to indicate this capability in the grant 
application.

Clinical Centers must work in concert with the Data Coordinating 
Center and must be willing to submit to data audits and other data 
quality control procedures as established by the study protocol.

2) Data Coordinating Center.  The Data Coordinating Center will have 
the primary responsibility for collecting, editing, storing, and 
analyzing data provided by the Clinical Centers.  It should be 
prepared to assume a key role in providing guidance and assistance on 
development of the design of the trials, developing the manual of 
procedures for each of the individual trials, overseeing 
implementation and adherence to the protocols, and assuring quality 
control of the data collected.  The Data Coordinating Center will be 
expected to provide appropriate biostatistical, data management, and 
coordination expertise. Expertise in nephrology with particular 
emphasis on hemodialysis and vascular access is beneficial.   
Applicants for the Data Coordinating Center must provide a detailed 
description of prior experience in multi-center studies, and should 
address the aspects of the Data Coordinating Center described below.

The Data Coordinating Center will have a central role in statistical 
aspects of the trials, including final sample size determinations, 
estimation of event rates, interim analyses for quality control, 
analyses of trial outcomes, and full statistical oversight.  The 
application should include a discussion of statistical issues and 
potential problems likely to arise in the design and conduct of these 
clinical trials.  The Data Coordinating Center will provide the 
support and guidance necessary to maintain the scientific integrity 
of the trials through Coordinating Center staff or procurement of 
consultants as necessary.

The Data Coordinating Center will have the primary responsibility for 
developing and implementing computer systems for intra-study 
communications.  The Data Coordinating Center will facilitate the 
design and refinement of all protocols, manuals of operations, and 
forms.  The Data Coordinating Center will establish a state-of-the-
art system for electronic submission of data in a standard format 
from the Clinical Centers.  They will also process all data 
transmitted, monitor the quality of the data and the performance of 
the Clinical Centers in the implementation of the protocols, and 
prepare periodic reports to Clinical Centers on recruitment, protocol 
adherence, and data quality.  The Data Coordinating Center will be 
responsible for developing plans and interim analyses for the Data 
and Safety Monitoring Board.  The Data Coordinating Center will 
perform analyses necessary for interim publications and 
presentations, and prepare appropriately detailed reports to the 
NIDDK, the Steering Committee and to the Data and Safety Monitoring 
Board.  Shortly after each trial is completed, the Data Coordinating 
Center will prepare outcome analyses of the data and will collaborate 
with the investigators of the Clinical Centers and the NIDDK to 
prepare final reports of the trial for publication.

Staff of the Data Coordinating Center will be required to travel to 
meetings during the planning phases for the development of study 
designs, protocols, manuals of operation, and forms.  The Data 
Coordinating Center will be required to manage the logistics of all 
committee and sub-committee meetings during the course of the trials 
and will be responsible for taking minutes of the various meetings, 
including the Data and Safety Monitoring Board. The Data Coordinating 
Center also will make logistical arrangements for meetings of the 
Data and Safety Monitoring Board, but the NIDDK Project Scientist 
will serve as Executive Secretary of this group.

The Data Coordinating Center will assist the NIDDK Project Scientist 
in written, telephone, and electronic communications with Clinical 
Centers and with various committees as requested.

3) Steering Committee.  The primary governing body of the study will 
be the Steering Committee, which will have responsibility for overall 
trial design and policy decisions (described in more detail under 
Terms and Conditions)

4) Executive Committee.  An Executive Committee also will be convened 
to facilitate the monitoring and conduct of the trials between 
meetings of the Steering Committee (described in more detail under 
Terms and Conditions).

5) NIDDK Project Scientist.  The NIDDK will name an NIDDK Project 
Scientist whose function will be to assist the other components as 
appropriate in those aspects of the trials described in more detail 
under Terms and Conditions. The NIDDK Project Scientist will 
administer the cooperative agreements and will be responsible for the 
fiscal management of the program at the NIH.

TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the 
award statement and provided to the Principal Investigator(s) as well 
as the institutional official at the time of award. The following 
special terms of award are in addition to, and not in lieu of, 
otherwise applicable OMB administrative guidelines, HHS grant 
administration regulations at 45 CFR Parts 74 and 92, and other HHS, 
PHS, and NIH grant administration policies.

1) Collaborative Responsibilities.  The administrative and funding 
instrument used for this program is a cooperative agreement (U01), an 
"assistance" mechanism (rather than an "acquisition" mechanism) in 
which substantial NIH scientific and/or programmatic involvement with 
the awardee is anticipated during 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 this concept, the dominant role and 
prime responsibility for the activity resides 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.

2) Awardees’ Rights and Responsibilities. 

Clinical Centers

The tasks or activities in which awardees for the Clinical Centers 
will have substantial and lead responsibilities are as follows:

1) Design the study protocols and write the manual of operations for 
each of the clinical trials
2) Develop operational plans and carry out patient recruitment, 
treatment, follow-up
3) Carry out complete and accurate data collection and timely 
transmission to the Data Coordinating Center 
4) Suggest approaches to the analyses of data and participate in 
writing manuscripts of the interim and final results of the 
trials
5) Ensure adequate representation of women and racial/ethnic 
minority groups in the trials

Willingness to adhere to a common study protocol for each of the 
trials is essential.

Data Coordinating Center

The tasks or activities in which awardees for the Data Coordinating 
Center will have substantial and lead responsibilities are as 
follows:

1) In conjunction with the Clinical Centers, develop the trial 
designs and manuals of operations
2) Collect, store, and evaluate the quality of the data transmitted 
by the Clinical Centers
3) Monitor performance of Clinical Centers in implementing the 
protocols
4) Provide interim reports on the progress of the Clinical Centers, 
including reports on recruitment and data quality
5) Provide analyses for the Steering Committee, Data and Safety 
Monitoring Board, the Executive Committee, and the National 
Institutes of Health
6) Conduct analyses of the data for publication in peer-reviewed 
scientific journals

Willingness to follow a common protocol for each of the trials is 
mandatory.

Awardees will retain custody of and have primary rights to their data 
developed under these awards, subject to Government policies 
regarding rights of access.

3) NIDDK Responsibilities.  The NIDDK will name the Director, 
Clinical Trials Program, Division of Kidney, Urologic, and 
Hematologic Diseases, NIDDK, to be the NIDDK Project Scientist.  The 
Project Scientist’s function will be to assist the Steering 
Committee, the Executive Committee, the Data and Safety Monitoring 
Board, and other subcommittees in carrying out the trials, including 
quality control, interim data and safety monitoring, final data 
analysis and interpretation, preparation of publications, and 
coordination and performance monitoring.  The NIDDK Project Scientist 
will have voting membership on the Steering Committee, the Executive 
Committee, and as appropriate, other subcommittees of the Steering 
Committee.  The NIDDK Project Scientist will also serve as Executive 
Secretary of the independent Data and Safety Monitoring Board.  The 
NIDDK Project Scientist will administer the cooperative agreements 
and will be responsible for the fiscal management of the program at 
the NIH.

Other NIDDK scientists may, as appropriate, serve on study committees 
and work with awardees on issues coming before the Steering Committee 
or its subcommittees.  However, in all cases, the NIDDK will have 
only a single vote on study committees, either of the whole or on 
subcommittees. 

The NIDDK reserves the right to terminate or curtail the study (or an 
individual award) in the event of (a) a major breach in the protocol 
or substantial changes in the agreed-upon protocol with which the 
Institute does not agree or (b) human subject ethical issues that may 
dictate a premature termination or (c) failure to achieve and sustain 
a clinically meaningful differences in any of the trials, or (d) 
substantial shortfall in recruitment and/or retention of subjects.

4) Governance

The Steering Committee, comprised of each of the Principal 
Investigators of the Clinical Centers the Principal Investigator of 
the Data Coordinating Center, the NIDDK Project Scientist, and the 
Study Chairperson, will have primary responsibility for developing 
common clinical protocols.  They will also facilitate the conduct and 
monitoring of the trials, and reporting the study results.  Each 
member of the Steering Committee will have one vote, and all major 
scientific decisions will be determined by majority vote of the 
Steering Committee.  A Consortium Chairperson will be chosen from 
among the Steering Committee members (but not the NIDDK Project 
Scientist or Data Coordinating Center Director), or alternatively, 
from among experts in the field of nephrology who are not 
participating directly in the study.  Subcommittees appointed by the 
Steering Committee and comprised of Principal Investigators and 
appropriate staff from the Clinical Centers and the Data Coordinating 
Center will be involved in the design of the protocols and the manual 
of operations, and in ongoing functions of the trials, such as review 
of ancillary studies and preparation of publications.  Not all 
Clinical Centers will necessarily be represented on all 
subcommittees.

An Executive Committee comprised of the Consortium Chairperson, the 
Principal Investigator of the Data Coordinating Center and the NIDDK 
Project Scientist also will be convened to effect management 
decisions required between Steering Committee meetings, as needed for 
efficient progress of the trials.  The Executive Committee will 
report its actions to the Steering Committee on a regular basis.  
Meetings of the Executive Committee will generally be held by 
conference call.

The Director, NIDDK will appoint an independent Data and Safety 
Monitoring Board, to review periodically the progress of the trials. 
 It will be comprised of experts in relevant medical, statistical, 
operational, and bioethical fields who are not otherwise involved in 
the study.  The Data and Safety Monitoring Board will oversee 
participant safety, evaluate results, monitor data quality, and 
provide operational and policy advice to the Steering Committee and 
to the NIDDK regarding the status of the study.  The Principal 
Investigator of the Data Coordinating Center, the NIDDK Project 
Scientist, and the Director, Division of Kidney, Urologic, and 
Hematologic Disease (or representative) may participate as ex-
officio, non-voting members of the Data and Safety Monitoring Board. 
 The Data and Safety Monitoring Board will review progress and report 
to the NIDDK at least once per year.

5) Arbitration.  Any disagreement that may arise in scientific-
programmatic matters between award recipients and NIDDK may be 
brought to arbitration.  An arbitration panel will be composed of 
three members - one selected by the Steering Committee (with the 
NIDDK not voting) or by the individual awardees in the event of an 
individual disagreement, a second member selected by NIDDK, and a 
third member selected by the preceding two members.  These special 
arbitration procedures in no way affect the award’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 regulations at 
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 is provided 
that inclusion is inappropriate with respect to the health of the 
subjects or the purpose of the research.  This policy results from 
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-
43).

All investigators proposing research involving human subjects should 
read the "NIH Guidelines For Inclusion of Women and Minorities as 
Subjects in Clinical Research," which have been published in the 
Federal Register of March 28, 1994 (FR 59, 14508-14513) and in the 
NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, 
available on the web at
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS

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

LETTER OF INTENT  

Prospective applicants are asked to submit, by February 29, 2000, a 
letter of intent that includes a descriptive title of the proposed 
research; name, address, and telephone number of the Principal 
Investigator; 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 subsequent applications, the information 
allows NIDDK staff to estimate the potential review workload and to 
avoid conflict of interest in the review.

The Letter of Intent is to be sent to:

Ann A. Hagan, Ph.D.
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, Maryland 20892-6600
Telephone (301) 594-8885
FAX: (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these awards. These forms are available at most 
institutional offices of sponsored research; from the GrantsInfo, 
Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, Suite 6095, Bethesda, MD 
20892-7910, telephone 301-435-0714, email: GrantsInfo@nih.gov.

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.  
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 2a of the face page of the application form and the YES box must 
be marked.  The RFA number must be typed on the label as well.

The sample RFA label is 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

Applicants who wish to use express mail or courier service should 
change the zip code to 20817.

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

Ann A. Hagan, Ph.D.
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, Maryland 20892-6600

Applications must be received by March 28, 2000.  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 announcement 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 a substantial 
revision of an application already reviewed, but such an application 
must follow the guidance in the PHS Form 398 application instructions 
for the preparation of revised applications, including an 
introduction addressing the previous critique.

Special Instructions for Preparing Applications

Within the narrative portions of the applications for the Clinical 
Center, the following issues should be covered:

o Applicants should propose primary and secondary outcomes for 
randomized clinical trials of drug therapy to improve vascular access 
survival and reduce complications. It is anticipated that clinical 
trials will be conducted among patients with both AV fistulas and AV 
grafts with individual trials focused on one or other type.  
Applicants should propose a single study design although a series of 
trials will be conducted over the course of this program.  Solutions 
should be suggested for potential problems related to the design of 
conduct of such trials.  The applicant’s study design should propose 
the type of vascular access to be investigated, eligibility 
requirements for study participation, including patient age, gender, 
racial/ethnic background, duration of hemodialysis treatment, the use 
of placebo, and cause of ESRD.  In addition, exclusion criteria 
should be specified, along with a rationale for the major criteria 
proposed.  Applicants should provide a justification for the subject 
selection criteria, including discussion of statistical 
considerations, an estimate of the number of subjects (and power 
calculations) required for the proposed trial, and the projected time 
necessary for recruitment.  Applicants must propose primary and 
secondary outcomes.  A rationale for selection of a specific drug for 
the proposed trial must also be provided.  Because of the substantial 
burden of complications among hemodialysis patients with diabetes as 
a cause of their renal failure, Clinical Centers must be able to 
recruit at least 50% diabetic patients for each of the trials.  
According to the National Kidney Foundation’s Dialysis Outcomes 
Quality Initiative, several different techniques are useful in 
monitoring hemodialysis AV grafts and fistulas for stenosis, 
including dynamic venous pressures, static venous pressures, intra-
access flow, among others.  A uniform method to monitor hemodialysis 
AV grafts and AV fistulas for stenosis will be adopted by all of the 
participating Clinical Centers.  The rationale for selecting one 
technique over another for adoption trial-wide should also be 
described.  However, there may be the opportunity to prospectively 
evaluate different methods of monitoring in order to compare their 
ability to predict access failure and complications.    

o Clinical Center applicants should describe their experience in 
recruiting and studying hemodialysis patients, and in minimizing 
losses of patients to follow-up during clinical trials.  Particular 
emphasis will be placed on documenting the ability to recruit women 
and racial/ethnic minorities for the trials to be conducted by the 
consortium.  The capability to randomize at least 125 individual 
participants for each of the clinical trials is required.  Clinical 
Centers also should document prior involvement in multi-center 
clinical trials, success in recruiting minority and women 
participants, and the ability to recruit a high proportion (at least 
50%) of patients whose cause of ESRD is attributed to diabetes 
mellitus.  It is planned that both AV grafts and fistulas will be 
studied in separate clinical trials over the five-year period of this 
research program.  However, it is not known at this time in what 
order the trials for these types of vascular accesses will be 
performed.  Thus applicants for Clinical Centers must document a 
sufficient number of hemodialysis patients having AV fistulas and AV 
grafts that could be readily recruited and are likely to be eligible 
to participate in a clinical trial of drug therapy.

An organizational structure for the Clinical Center should be 
provided in the application, delineating lines of authority and 
responsibility for dealing with problems in all general areas.  There 
should be evidence of strong institutional support for the Clinical 
Center, including documentation of adequate space in which to conduct 
clinic activities and office space for staff.

Applicants should submit adequately justified budgets for each 12-
month period of the trials.  These budgets must reflect the major 
changes in proposed activities that occur as the first protocol is 
developed, patients recruited and followed-up, development and 
implementation of subsequent protocols, and final data analyses for 
each of the trials.  See the timetable above for a detailed listing 
of the proposed activities over the five-year period of this program. 
 Applicants are to assume that all meetings of the Steering Committee 
(budget for three meetings per year for each year of the program) 
will be held in the Washington, D.C. area. 

Within the narrative portions of the applications for the Data 
Coordinating Center, the following issues should be covered:

o Applicants must propose a single design for a clinical trial of 
drug therapy for vascular access addressing the essential study 
elements as described above for a Clinical Center, including a plan 
for methods to monitor the functioning of the access.  Applicants 
must also address the potential requirements of the trial by 
providing a description of projected tasks likely to be performed by 
the Data Coordinating Center.  The application should be structured 
around the requirements of a projected study design that addresses 
the proposed primary and secondary outcomes.  Detailed information on 
the sample size and power calculations must also be provided.  A 
rationale for proposed primary and secondary outcomes must be 
included in the application.  A discussion about promoting adherence 
to the recommended intervention should be included. Plans for 
collection and handling of data consistent with the projected needs 
of the trial should be discussed.  Approaches to interim and final 
data analysis must also be proposed. Special emphasis should be given 
to sub-group and comparative analyses of outcomes in diabetic 
patients.

o Applicants should submit adequately justified budgets for each 12-
month period of the trials.  These budgets must reflect the major 
changes in proposed activities that occur as the first protocol is 
developed, patients recruited and followed-up, development and 
implementation of subsequent protocols, and final data analyses for 
each of the trials.  See the timetable above for a detailed listing 
of the proposed activities over the five-year period of this program. 
 Applicants are to assume that all meetings of the Steering Committee 
(budget for three meetings per year for each year of the program) 
will be held in the Washington, D.C. area.  In addition, meetings of 
the Data and Safety Monitoring Board (budget for one meeting per year 
for each year of the program) will be held in the Washington, D.C. 
area.

REVIEW CONSIDERATIONS

Applications will be judged on the basis of the scientific merit of 
the proposed project and the documented ability of the investigators 
to meet the RESEARCH OBJECTIVES of the RFA.  Although the technical 
merit of the proposed protocol is important, it will not be the sole 
criterion for evaluation of a study.  Other considerations, such as 
the importance and timeliness of the proposed clinical trial, access 
to patients, and experience in multi-center collaborative studies, 
will be part of the evaluation criteria.

Review Method

Upon receipt, applications will be reviewed for completeness by the 
CSR and responsiveness by the NIDDK. Incomplete 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 will be discussed, assigned a priority score, and receive a 
second level review by the National Diabetes and Digestive and Kidney 
Diseases Advisory Council.

Review Criteria

Applicants are encouraged to submit and describe their own ideas 
about how best to meet the goals of the cooperative study and their 
specific protocols, and are expected to address issues identified 
under SPECIAL REQUIREMENTS of the RFA.

Review Criteria for Clinical Centers

The review group will assess the scientific merit of the protocols 
and related factors, including:

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? Demonstrable knowledge of the problems 
associated with the conduct of randomized clinical trials of vascular 
access and possible solutions is necessary.
 
The final design for the first clinical trial will be developed 
collaboratively by the Steering Committee. Thus, the peer review 
group will focus on evidence that the applicant has carefully thought 
about the issues involved and possesses the knowledge necessary to 
contribute meaningfully to the final designs, including understanding 
of the scientific, ethical, and practical issues underlying the 
proposed clinical trial. Plans for monitoring the performance of AV 
grafts or AV fistulas will also be evaluated. 

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

Investigators:  Are 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)? Evidence of prior experience in working 
collaboratively to carry out a developed study protocol is 
necessary.  Willingness to work cooperatively in this study is 
required.  For the vascular access clinical trials consortium 
described in this RFA, this criterion will focus on the documented 
evidence of the training, experience, and specific competence of the 
investigators and staff relevant to the operation of a Clinical 
Center.

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?

Review of applications for Clinical Center awards also will focus on 
the following specific criteria:

Recruitment Capability: Evidence of prior experience in the 
recruitment of hemodialysis patients to clinical trials is 
necessary.  In addition, realistic plans for the recruitment of 
patients, including women and minority participants for the vascular 
access clinical trials consortium must be included in the grant 
application.  Major emphasis will be placed on the ability of a 
Clinical Center to recruit at least 50% diabetic patients.  The 
recruitment of at least 125 individual hemodialysis patients for 
each of the trials to be conducted by the consortium must be 
documented although a clinical trial design requiring fewer patients 
may be proposed.  The recruitment plans must include the number of 
hemodialysis units proposed for the trials.  In addition, the number 
of patients available, the number and type of grafts, fistulas and 
other vascular accesses prevalent in the target patient population, 
and an estimate of the percent of patients willing to participate in 
the proposed trial must be provided. If the hemodialysis units from 
which patients are to be recruited are not under the direct medical 
management of the Principal Investigator, then assurance that 
patients can be recruited from these sites must be made available.

Retention Capabilities: Plans and/or experience in achieving high 
rates of follow-up of trial participants and promoting high levels 
of adherence to the protocol are essential.

Data Management and Transmission: Adequacy of plans to ensure 
complete, reliable, and timely transmission of the study data.

Collaboration between Centers: For those applications proposing 
collaborative efforts between two applicants from different 
institutions to form a single Clinical Center additional factors to 
be considered would include the advantages of collaboration in terms 
of cost and recruitment capabilities. The 
organizational/administrative plan for such arrangements needs to be 
clearly delineated.

Review of applications for the Data Coordinating Center will be based 
on the following specific criteria:

Significance:  Does the proposed clinical trial 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: Does the grant application clearly delineate the proposed 
design, including sample size and power calculations, for a 
randomized controlled clinical trial of drug treatment to improve 
survival of either AV fistulas or grafts? Demonstrable knowledge of 
the problems associated with the conduct of randomized clinical 
trials of vascular access and possible solutions is necessary.  The 
final design for the first clinical trial will be developed 
collaboratively by the Steering Committee. Thus, the peer review 
group will focus on evidence that the applicant has carefully thought 
about the issues involved and possesses the knowledge necessary to 
contribute meaningfully to the final designs, including understanding 
of the scientific, ethical, and practical issues underlying the 
proposed study.  

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

Investigators:  Are 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)? Evidence of prior experience in working 
collaboratively to carry out a developed study protocol is necessary. 
 Willingness to work cooperatively in this study is required. 
Documented specific competence and relevant experience of 
professional, technical, and administrative staff pertinent to the 
operation of a Data Coordinating Center for a series of randomized 
clinical trials of drug therapy to improve performance of 
hemodialysis vascular accesses.  Prior experience collecting data 
from multiple clinical sites, monitoring the data quality and 
developing and utilizing statistical methods to analysis of data 
should be demonstrated. Experience in developing remote entry, web-
based data transmission systems for the Clinical Centers is required. 
Experience of Data Coordinating Center personnel in utilizing 
procedures to insure the safety and confidentiality of all records 
should be documented.

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?

Data Management: Adequacy of the proposed plans and experience 
relating to data collection, management, editing, processing, quality 
control, analysis, and reporting.

Resources:  Adequacy of the proposed facility, technical hardware, 
and space.  Appropriateness of the organizational and administrative 
structure of the proposed Data Coordinating Center is necessary.  
Evidence of institutional support and commitment for the proposed 
program should be provided.  

Knowledge of Problems: Demonstrable knowledge of the potential 
problems associated with the conduct of clinical trials of drug 
therapy to improve survival and decrease the complication rate of 
both AV grafts and fistulas and approaches to their solution.

Experience in working with drug packaging and distribution centers: 
It is anticipated that a central distribution center will be 
established to furnish both drug and placebo in a timely fashion to 
the Clinical Centers.  The experience in establishing and working 
cooperatively with a Drug Distribution Center in cooperative studies 
should be clearly documented.

Cooperative Experience and Approach: Adequacy of the approach to 
developing a cooperative relationship among the participating 
Clinical Centers and exercising appropriate leadership in matters of 
study design, data acquisition, data management, data quality, and 
data analysis.  Evidence of experience in and willingness to 
participate appropriately in a collaborative study as described in 
this RFA.

In addition to the above criteria, in accordance with NIH policy, all 
applications for Clinical Centers and the Data Coordinating Center 
will also be reviewed with respect to the following:

The reasonableness of the proposed budget.

The adequacy of the proposed protection for human subjects and the 
environment, to the extent they may be adversely affected by the 
project proposed in the application. 

AWARD CRITERIA

It is anticipated that awards will by made on September 30, 2000.  
Applications recommended by the National Institute of Diabetes and 
Digestive and Kidney Diseases Advisory Council will be considered for 
award based upon (a) scientific and technical merit; (b) program 
balance, including in this instance, sufficient compatibility of 
features to make a successful collaborative program a reasonable 
likelihood; (c) geographic location of the applicant, (d) recruitment 
of racial and ethnic minorities and diabetic patients, (e) cost, and 
(f) availability of funds.

Schedule

Letter of Intent:	February 29, 2000
Application Receipt Date: March 28, 2000
Review by NIDDK Advisory Council: September 20-21, 2000
Anticipated Award Date: September 29, 2000

INQUIRIES

Written, including electronic mail, and telephone inquiries 
concerning this RFA are encouraged.  The opportunity to clarify any 
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

John W. Kusek, Ph.D.
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room Number 6AS13J, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7735
FAX (301) 480-3510
Electronic mail:  kusekj@ep.niddk.nih.gov

Direct inquiries regarding fiscal matters to:

Helen Ling
Grants Management Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Room 6AN-44F
Bethesda, Maryland 20892-6600
Telephone:  (301) 594-8857
FAX:  (301) 480-3504
Email:  LingH@extra.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic 
Assistance Nos. 93.849 and 93.864.  Awards are made under 
authorization of the Public Health Service Act, Title IV, Part A 
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 
285) 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 NIH strongly encourages all grant and contract recipients to 
provide a smoke-free workplace and promote the non-use of all tobacco 
products.  In addition, Public Law 103-227, the Pro-Children Act of 
1994, prohibits smoking in certain facilities (or in some cases, any 
portion of a facility) in which regular or routine education, 
library, day care, health care or early childhood development 
services are provided to children. This is consistent with the NIH 
mission to protect and advance the physical and mental health of the 
American people.


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