Subject: NIH GUIDE - RFA DK-92-10 - V20(44) 11/22/91
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Thu, 21 Nov 91 14:03 EST

Hi Paul,
   This should be the last for today.  Please post to the NIH Listserver
as:  RFADK-92-10.911122
    Thanks.
 Also, thanks for your input and support in the meeting this morning.
Have a super weekend.
                     Dottie
 ---------------------------- Text of forwarded message -----------------------
 
$$XID RFA DK9210 DK-92-10 P1O1 *****************************************
 
REDUCTION IN MORTALITY AND MORBIDITY AMONG HEMODIALYSIS PATIENTS:
PILOT STUDY
 
RFA:  DK-92-10
 
P.T. 34; K.W. 0745025, 0715075, 0710095, 0755015
 
National Institute of Diabetes and Digestive and Kidney Diseases
 
Letter of Intent Receipt Date:  February 7, 1992
Application Receipt Date:  March 13, 1992
 
PURPOSE
 
The Division of Kidney, Urologic and Hematologic Diseases of the
National Institute of diabetes and Digestive and Kidney Diseases
(NIDDK) invites cooperative agreement applications from investigators
to carry out a pilot clinical trial directed toward reducing overall
mortality and morbidity among the hemodialysis patient population.
Areas of investigation may include an evaluation of different modes of
dialysis, with respect to patient outcome.  For instance, one objective
of the clinical trial could be to assess the effect of high-flux
hemodialysis on mortality and morbidity.  The study may include the
design of a comprehensive and uniform program of high quality medical
care for control of blood pressure, lipid levels, and diabetes as well
as appropriate nutrition counseling and management of vascular access.
 
The assistance mechanism used to support the study is the cooperative
agreement, which is similar to the traditional NIH research grant.  It
differs from a research grant in the extent and nature of NIDDK staff
involvement.  A center selected as a Clinical Center also may serve as
the Data Coordinating Center and the Intervention Coordinating Center;
however, separate applications are required for each of these study
components.
 
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 RFA,
Reduction in Mortality and Morbidity among Hemodialysis Patients:
Pilot Study is related to the priority area of diabetes and chronic
disabling diseases.  Potential applicants may obtain a copy of "Healthy
People 2000" (Full Report:  Stock No. 017-001-00473-1) or "Healthy
People 2000" (Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC
20402-9325 (telephone 202-783-3238).
 
RESEARCH OBJECTIVES
 
Background
 
End-stage renal disease (ESRD) is an important medical and public
health problem in the United States (1).  The prevalence, incidence,
and cost of treated ESRD has increased significantly during the past
decade.  According to the United States Renal Data System (2), in 1989,
190,000 Americans were treated for ESRD with over 40,000 new patients
initiating treatment in that year.  In 1989, the direct medical
payments for ESRD treatment by public and private payers was nearly
$6,000,000,000.  In this country, hemodialysis is the most common
therapeutic modality for patients with ESRD; in 1989 nearly 60 percent
of ESRD patients were treated with hemodialysis (2).  Based on the
likelihood that the ESRD population will continue to increase in the
U.S. in the coming decades (3), hemodialysis will undoubtedly continue
to be the most common therapy for ESRD.  Despite numerous advances in
medical care for patients with ESRD, gross mortality of U.S. ESRD
patients in 1987/1988 was 23.4 percent.  This is significantly greater
than the mortality observed in Germany (10.0 percent), France (7.3
percent), Japan (8.8 percent), and Australia (13.5 percent) during the
same time period.  Only the rate for Canada (18.9 percent) in 1987/1988
approached that of the U.S.(4).
 
The five-year survival for ESRD patients in the U.S. from 1982 to 1987
was 42 percent.  The U.S. dialysis programs have older patients, with
more co-morbid conditions that affect mortality.  However, even after
adjusting for age and proportion of patients with diabetic nephropathy,
using the U.S. population as the standard, the five-year survival rate
from 1982 to 1987 among persons entered in the European Dialysis and
Transplantation Association registry was 48 percent; and in Japan it
was 54 percent (5).  Possible factors associated with the disparity in
mortality rates among ESRD patients in the U.S., Europe, and Japan
include differences in age, occurrence of diabetes, modalities of
treatment, co-morbid conditions in patients accepted for renal
replacement therapy (i.e., countries with high acceptance rate may be
treating patients with more serious co-morbid conditions), dialysis
prescription and compliance with hemodialysis prescription, and
possible bias in the selection of patients who entered the European
registry (5).
 
The high mortality rates have remained stable over the past decade.  In
1980, slightly greater than 75 percent of dialysis patients survived
one year.  In 1989, the survival rate was 79.2 percent.  The five-year
survival rate has also remained nearly stable, 31.8 percent in
1972-1977 and 30.1 percent in 1980-1985 (2).
Strikingly, the expected remaining lifetime for prevalent dialyzed
patients with ESRD is approximately one-fourth to one-sixth that for
the general population through age 50, while the ratio is often closer
to one-third for older patients (2).  Over one-half of the deaths among
hemodialysis patients are due to cardiac causes and septicemia.
 
There are many proposed reasons for the high mortality among
hemodialysis patients in the U.S.  Factors believed to be responsible
include malnutrition (6), shortened treatment times for dialysis (7),
an increased prevalence of patients with diabetes and other co-morbid
factors (8,9), increased age of patients accepted, and possibly
inadequate prescription and delivery of dialysis therapy (10).
Juxtaposed on all of these factors is the increased use of high-flux
dialysis and more biocompatible membranes; the long-term effects of
these therapies on mortality and morbidity of ESRD patients are not yet
known.  Based on the severity of the problem, the lack of earlier
clinical trials in this area, and the recent introduction of
hemodialysis membranes of different permeability and biocompatibility
and the use of high-flux hemodialysis, the NIDDK believes that a
randomized controlled clinical trial is necessary to define the
relative importance of each of these factors on patient survival and
health.
 
Goal of the Activity
 
The primary purpose of this RFA is to initiate a collaborative pilot
study of hemodialysis therapy to investigate the modes and practices of
hemodialysis therapy for the purpose of reducing mortality and
morbidity among patients with ESRD.  The pilot study will test the
feasibility of conducting a full-scale randomized clinical trial in an
adequately sized patient population.  Patient factors, such as elevated
blood pressure and lipid levels, diabetes, vascular access site, and
nutrition, may be managed in a uniform manner among all randomized
patients.
 
The pilot study has five objectives, each designed to develop and test
essential components of the full-scale clinical trial.  They include
the following:
 
1.  To design the pilot study protocol and write the manual of
procedures.
 
2.  To determine whether or not an adequate number of patients with
appropriate study eligibility criteria can be recruited efficiently
into the study.
 
3.  To observe any short-term adverse effects of the study.
 
4.  To implement procedures for and evaluate compliance to procedures
for management of blood pressure, diabetes, and lipid levels;
appropriate nutrition counseling, and state-of-the-art care of the
vascular access site.
 
5.  To better estimate the sample size required for the full-scale
study.
 
The collaborative protocol will be developed by the Project Steering
Committee, composed of the awardees, the Chairperson of the Steering
Committee, and NIDDK Staff.  The protocol will be subject to review by
an uninvolved expert group, the External Advisory Committee.
 
The study will move into its operational phase only with the
concurrence of the awardees, the External Advisory Committee, and the
NIDDK.
 
It is expected that the study will take place in four Clinical Centers
over a period of 30 months.  Each Clinical Center will randomize a
minimum of 50 study participants during a 12-month period of
recruitment.  The study will be in three phases:  (I) a nine-month
period of collaborative protocol development; (II) 12 months of patient
recruitment and follow-up; and (III) nine months of close-out of the
pilot phase, data analysis, and reporting of results.
 
Each applicant must propose the study design he or she believes most
appropriate for this project.  It is anticipated that the study will
involve both men and women patients with kidney disease of diverse
origins, and a proportional representation of minorities.
 
Applicants must provide a detailed justification for whatever strategy
is proposed for subject selection, an estimate of the number of
subjects in the source population and in the final examination sample,
and an estimate of the necessary time and effort needed for
recruitment.  Applicants also must address criteria and outcome
measures for the five pilot study objectives by which success of this
phase of the program will be judged for extension into the full-scale
study.
 
Applicants must propose in detail within the study design, eligibility
requirements, including patient age, for study participation.  In
addition, exclusion criteria must be specified.  The use of a baseline
or run-in period and the follow-up schedule also must be provided in
the application.  Outcome measures must be chosen that address the
efficacy and adverse effects of hemodialysis procedures and practices
in the study population.  It is anticipated that 200 participants will
be required for the pilot study.  The proposed approach to evaluate the
impact of the various hemodialysis procedures and practices on patient
survival and measures of morbidity, must be addressed.  It is
anticipated that investigators will design an intervention program to
control high blood pressure, lipid levels, diabetes and to provide
appropriate nutrition counseling and care of the vascular access site
as part of optimum care for all patients entered into the study.
 
All centers must be willing to implement the selection and examination
strategies developed cooperatively by the Steering Committee during
protocol development and to supply their data to the Data Coordinating
Center for combination and analysis.
 
Study Components
 
1.  Clinical Centers -- A Clinical Center is an institution that is
actively involved in the recruitment, evaluation, and treatment of
study participants.  It should consist of not more than a minimal
number of staff including a clinical investigator, a study coordinator,
and an interventionist.  Applications for Clinical Centers must provide
evidence that the center will be capable of randomizing at least 50
participants into the study during the nine-month period of
recruitment.  Clinical Centers must describe their experience in
recruiting and studying hemodialysis patients.  There should be
evidence of strong institutional support for the Clinical Center,
including adequate space in which to conduct clinical activities and
office space for staff.  An organizational structure for the Clinical
Center must be set forth in the application delineating lines of
authority and responsibility for dealing with problems in all general
areas and a stated willingness to follow the common protocol agreed
upon in Phase I.
 
The applicant must include a succinct discussion of previous relevant
investigational efforts.  The applicant also must discuss in detail the
important design considerations for a clinical trial to investigate the
modes and practices of hemodialysis therapy and suggest solutions to
perceived problems.  Clinical Centers will be required to submit
protocol data expeditiously.  The Principal Investigator in each
Clinical Center must be skilled in hemodialysis, nephrology, and
collaborative clinical investigation.
 
2.  Central Functions -- The Data Coordinating Center will have primary
responsibility for collecting, editing, storing, and analyzing data
generated by the Clinical Centers.  It must be prepared to assume a key
role in protocol development, designing a distributed data collection
system, and quality control assurance.  The Data Coordinating Center
will be expected to provide appropriate biostatistics, data management,
and coordination expertise and to make a major contribution to the
development of the study protocol and manual of operations.  The Data
Coordinating Center also will be expected to provide appropriate
detailed reports to  the Steering Committee and to the External
Advisory Committee at regular intervals and will be responsible for
the logistics and planning of meetings of these committees and their
subcommittees.  The NIDDK Project Coordinator will serve as a liaison
between the Data Coordinating Center and these committees.  Applicants
for the Data Coordinating Center must provide a detailed description of
prior experience in multicenter studies.  The applicant also must
discuss in detail the important design considerations for a clinical
trial of procedures and practices of hemodialysis therapy as described
previously and suggest solutions to key problems.
 
3.  Intervention Coordinating Center -- The Intervention Coordinating
Center, in collaboration with the Principal Investigators of the
Clinical Centers and the Data Coordinating Center, will develop the
protocol for intervention on patient factors including high blood
pressure, elevated lipid levels, diabetes, nutrition, and care of the
vascular access site.  The Intervention Coordinating Center will also
assist in developing the manual of procedures for intervention,
training of clinical staff in this area, monitoring outcome data in
conjunction with the Data Coordinating Center, and preparing reports on
the progress of the trial related to issues of compliance.
 
4.  Steering Committee -- A Steering Committee will be comprised of
each of the Principal Investigators of the Clinical Centers, the
Principal Investigator of the Data Coordinating Center, the Principal
Investigator of the Intervention Coordinating Center, and the NIDDK
Project Coordinator.  The Steering Committee will be responsible for
making the major scientific decisions governing the conduct of the
Pilot Study.  Each member of the Steering Committee will have one vote.
A chairperson will be selected by the Steering Committee from the
members or, alternatively, from experts in the fields of clinical
trials, hemodialysis, and kidney disease not participating directly in
the study.  It is anticipated that the Steering Committee will meet on
a monthly basis during protocol development (Phase I), three times in
Phase II, and two times in Phase III.  Subcommittees of the Steering
Committee may be established as necessary.  The NIDDK Project
Coordinator will be part of these subcommittees.
 
5.  External Advisory Committee -- An External Advisory Committee
composed of experts in relevant medical, statistical, and bioethical
fields will be established to review periodically the progress of the
study, oversee participant safety, evaluate results, and provide advice
to the NIDDK regarding the status of the study.   The Chairperson of
the Steering Committee, the Principal Investigator of the Data
Coordinating Center, the Principal Investigator of the Intervention
Coordinating Center, and the NIDDK Project Coordinator may participate
as ex-officio non-voting members of this Committee. External Advisory
Committee members will be appointed by the Director, Division of
Kidney, Urologic, and Hematologic Diseases, NIDDK, in consultation with
Steering Committee members.
 
6.  Project Coordinator -- The NIDDK will name the Clinical Trials
Program Director within the Division of Kidney, Urologic and
Hematologic Diseases to be the Project Coordinator and to assist the
Steering Committee and External Advisory Committee in carrying out the
study.  The Project Coordinator will provide scientific support to
protocol development, quality control, interim data monitoring, final
data analysis, preparation of publications, and performance monitoring.
 
Study Phases
 
The Pilot Study is envisioned as involving four Clinical Centers, one
Data Coordinating Center, and one Intervention Coordinating Center, for
a period of 30 months.  The Pilot Study will have three phases:
 
I    Protocol Development (nine months)
II   Sample Recruitment and Data Collection (12 months)
III  Study Close-Out and Data Analysis (nine months)
 
The protocol development phase (Phase I) will be nine months long.
After the protocol is completed, it will be reviewed by an expert
group, the External Advisory Committee.  Progression to Phase II is
dependent on the favorable recommendation of the protocol by the
External Advisory Committee and the concurrence of the NIDDK.  At the
end of the nine-month period of Phase I, the Data Coordinating Center
must be ready to implement data collection and quality control systems.
 
The protocol for the Pilot Study will be implemented in Phase II.  It
is anticipated that four Clinical Centers will recruit and randomize
participants, collect the outcome data specified in the protocol, and
provide these data to the Data Coordinating Center.  The Data
Coordinating Center will receive, process, and analyze the data and
provide reports to the Steering Committee, which will be responsible
for monitoring the progress of the Pilot Study.  The Intervention
Coordinating Center will be responsible for assisting Clinical Center
staff in establishing the intervention program, and providing technical
support throughout the study for uniform medical care of patient
factors as described in the RFA.
 
It is anticipated that the long-range operational plan of the entire
study, including the Pilot Study, will consist of five sequential
phases as follows:  Phase I Development of Protocol (nine months);
Phase II Conduct of Pilot Study (12 months); Phase III Close-out and
Analysis of Pilot Study Data (nine months); Phase IV Conduct of
Full-Scale Cooperative Clinical Trial (72 months); and Phase V Data
Analysis and Reporting of Results of the Full-Scale Study (12 months).
 
Based upon meeting the goals and objectives of the Pilot Study and a
recommendation from the External Advisory Committee, the NIDDK will
issue a separate RFA for Clinical Centers to participate in the
Full-Scale Study in order to provide a sufficient recruitment base.
RFAs will also be issued for one Data Coordinating Center and one
Intervention Coordinating Center.  Centers in the Pilot Study will be
required to compete for awards if they want to participate in the
Full-Scale Study.  These applications will be reviewed by the Division
of Extramural Activities, NIDDK.  The primary review criteria for
applications in the Full- Scale Study will be the technical
capabilities in recruitment, intervention and follow-up of study
participants for clinical centers; expertise in data collection, data
base management, study coordination, and interim and final reporting of
results for the Data Coordinating Center.  For the Intervention
Coordinating Center, the primary review criteria will be technical
capabilities in supporting an intervention on patient risk factors
identified during a Pilot Study protocol development.  It is also
anticipated that the Full-Scale Study will be supported by cooperative
agreements.
 
Clinic Staffing by Study Phase
 
Applications for a Clinical Center, the Data Coordinating Center, and
the Intervention Coordinating Center, must include adequately justified
individual yearly budgets for the entire anticipated project period of
30 months.  The budgets for each budget period of the study must be
clearly delineated.  The following information is provided to assist
applicants in the preparation of budgets.  Detailed budgets will vary
according to policies of the applicant and specific needs identified in
the response to this announcement.
 
The 01 budget period of the grant will be for a nine-month period,
September 30, 1992 through June 30, 1993. This budget period will be
for protocol development (Phase I).  The second budget period will be
for 12 months, July 1, 1993 through June 30, 1994.  Activities in the
second budget period will include recruitment, randomization,
treatment, and clinical assessment of randomized study participants.
The third budget period will for nine months, July 1, 1994 through
March 31, 1995.  This budget period will be concerned with study
close-out, analysis of data, and reporting of results.
 
Phase I activities will require phasing-in of staff within two months
prior to initiating recruitment.  Budgets must allow for approximately
two or three key persons (part-time support), including the Principal
Investigator, per center to attend Steering Committee meetings.  The
detailed budget for this phase must be estimated on the basis of
monthly two-day meeting in Bethesda, Maryland during Phase I, three
evenly spaced meetings during Phase II, and two meetings in Phase III.
 
For Data Coordinating Center applications, the estimate also must
include the time and effort of key personnel needed to participate in
the planning and development of forms, a manual of operations, and a
data entry system. Phase-in of key personnel during protocol
development also must be detailed in the application.  Data
Coordinating Center and Intervention Coordinating Center staff
necessary for conducting training should be available for approximately
a three-day training meeting to be held in Bethesda, Maryland, about
one month before protocol development is completed.  The budget
estimate also must include the time and effort of key personnel of the
Intervention Coordinating Center required to write the intervention
protocol and manual of procedures, develop intervention support
materials, and provide technical support to Clinical Center
intervention staff throughout Phase II of the study.
 
Detailed budget estimates for Phases II and III must be based on the
applicant's proposed plan.  Budgets for both Phases II and III may be
modified based on the final protocol developed during Phase I.
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be required to include
minorities and women in study populations so that research findings can
be of benefit to all persons at risk of the disease, disorder, or
condition under study; special emphasis should be placed on the need
for inclusion of minorities and women in studies of diseases,
disorders, and conditions which disproportionately  affect them.  This
policy is intended to apply to males and  females of all ages.  If
women or minorities are excluded or inadequately represented in
clinical research, particularly in proposed population-based studies,
a clear compelling rationale should be provided.
 
The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale for
its choice.  In addition, gender and racial/ethnic issues should be
addressed in developing a research design and sample size appropriate
for the scientific objectives of the study.  This information should be
included in the form PHS 398 in Section 2, A-D of the Research Plan AND
summarized in Section 2, E, Human Subjects.  Applicants are urged to
assess carefully the feasibility of including the broadest possible
representation of minority groups.  However, the NIH recognizes that it
may not be feasible or appropriate in all research projects to include
representation of the full array of United States racial/ethnic
minority populations (i.e., Native Americans (including American
Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks,
Hispanics).  The rationale for studies on single minority population
groups should be provided.
 
For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders, or conditions, including but not limited to clinical trials.
 
The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the  study broadly, and this should be addressed by the applicants.
 
If the required information is not contained within the application,
the application will be returned.
 
Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.
 
All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.
 
MECHANISM OF SUPPORT
 
It is anticipated that six awards (four Clinical Centers, one Data
Coordinating Center, and one Intervention Coordinating Center) will be
made under this RFA for a total of approximately $1 million (including
direct and indirect costs) during the first year.  The funding level
will be approximately $100,000 in total costs for each Clinical Center,
approximately $300,000 in total costs for the Data Coordinating Center,
and approximately $300,000 in total costs for the Intervention
Coordinating Center per year.  Funding is expected to begin in
September 1992; total support for the project will be for 30 months.
 
The funding mechanism will be the cooperative agreements (U01).  The
cooperative agreement is an award instrument establishing an assistance
relationship between NIH and a recipient in which substantial
programmatic involvement is anticipated between NIH and the recipient
during performance of the contemplated activity.
 
TERMS AND CONDITIONS OF AWARD
 
The tasks or activities in which awardees will have substantial and
lead responsibilities include protocol development, patient recruitment
and follow-up, data collection, quality control, final data analysis
and interpretation, preparation of publications, and collaboration with
other awardees.  The NIDDK Project Coordinator will assist in quality
control, interim data and safety monitoring, final data analysis and
interpretation, preparation of publications, and coordination and
performance monitoring.
 
The NIDDK reserves the right to terminate 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 NIDDK
does not agree or (b) human subject ethical issues that may dictate a
premature termination.
 
Any disagreement that may arise in scientific matters between award
recipients and the NIDDK may be brought to arbitration.  An arbitration
panel will be composed of three  members---one selected by the Steering
Committee (with 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 members.  This
special arbitration procedure in no way affects the awardees' 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.
 
The NIDDK may not use the Pilot Study data in any manner without
explicit approval of the awardee investigators.
 
The primary governing body of the study will be the Steering Committee,
composed of the Principal Investigators of the Clinical Centers, the
Data Coordinating Center, the Intervention Coordinating Center, and
NIDDK Project Coordinator.  Subcommittees will be formed on such topics
as study design and execution, quality control, recruitment and
publications. The NIDDK Project Coordinator will be a member of these
subcommittees.  The first meeting of the Steering Committee will be
convened by the NIDDK Project Coordinator.  All major scientific
decisions will be determined by vote of the Steering Committee.  The
Steering Committee will have primary responsibility for the development
of the study protocol, facilitation of the conduct of the study, and
reporting of study results.
 
It is expected that data will be submitted centrally and that the
protocol will define rules regarding access to data and publications.
An External Advisory Committee, to be appointed by the NIDDK, will
review progress at least semi-annually and provide advice to the
Institute.
 
These special terms of award are in addition to and not in lieu of
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR part 74, and other HHS, PHS, and
NIH grant administration policy statements.
 
DISCIPLINE AND EXPERTISE
 
The expertise appropriate for this research program includes a
knowledge of the clinical and epidemiological aspects of both kidney
disease and hemodialysis and experience in the design and conduct of
collaborative clinical trials.  Experience in recruitment and follow-up
of a large number of patients for clinical trials and clinical
experience with a large number of hemodialysis patients, is especially
useful.  Skills in data base management, biostatistics, and development
of clinical trial study design are appropriate for the Data
Coordinating Center.  For the Intervention Coordinating Center,
experience in design and technical support of an intervention for a
clinical trial is helpful.  An institution may apply to be a Clinical
Center, the Data Coordinating Center, and the Intervention Coordinating
Center.  However, a specific plan is required with the applications for
how the independent operation (i.e., confidentiality of study-wide
data) of each unit will be maintained.  Separate applications will be
required for the Clinical Center, the Data Coordinating Center, and the
Intervention Coordinating Center.  Collaboration among institutions to
carry out the study is encouraged. Institutions wanting to collaborate
and function as a single Clinical Center are required to submit one
application.
 
ELIGIBILITY REQUIREMENTS
 
Domestic universities, medical colleges, hospitals, and other public
and private research institutions, including State and local government
units, are eligible.  Applications from minority investigators and
women are encouraged.  Applications from foreign institutions will not
be considered since only a small number of centers will be selected to
participate in this program.
 
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research Resources
may want to identify the GCRC as a resource for conducting the proposed
research.  If so, a letter of agreement from either the GCRC Program
Director or Principal Investigator must be included with the
application.
 
REVIEW PROCEDURES AND CRITERIA
 
General Procedures
 
Upon receipt, applications will be reviewed by NIDDK staff for
responsiveness to the objectives of this RFA. If an application is
judged unresponsive, the applicant will be contacted and given the
opportunity to withdraw the application or to have it considered for
the investigator-initiated research grant program.
 
If the number of applications is large compared to the number of awards
to be made, the NIDDK will conduct a preliminary scientific peer review
and withdraw applications from further competition if judged not to be
competitive for award.  The NIDDK will notify the applicant and
institutional official of this action.  Those applications judged to
both responsive and competitive will be evaluated further according to
the review criteria stated below for scientific and technical merit by
an appropriate peer review group convened by the Division of Extramural
Activities, NIDDK.  Subsequent review will be by the National Diabetes
and Digestive and Kidney Diseases Advisory Council.
 
If the application submitted in response to this RFA is substantially
similar to a grant application already submitted to the NIH for review,
but has not yet been reviewed, the applicant will be asked to withdraw
either the pending application or the new one.  Simultaneous submission
of identical applications will not be allowed, nor will essentially
identical applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this RFA
that is essentially identical to one that has already been 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 Criteria
 
The evaluation of applications for Clinical Centers, the Data
Coordinating Center and the Intervention Coordinating Center, will be
based primarily on the scientific merit of the proposed study.  If an
institution wants to apply as a Clinical Center, the Data Coordinating
Center, and the Intervention Coordinating Center, separate applications
must be prepared.  Specific criteria for review of applications will be
as follows.
 
For Clinical Centers:
 
1.  The scientific merit of the proposed study design to address the
problem outlined in the RFA.
 
2.  Documentation of the specific competence and previous experience of
professional, technical, and administrative staff pertinent to the
operation of a Clinical Center in the proposed study.  Evaluation will
include the following:  familiarity with and experience in recruiting
participants in a randomized trial or other epidemiological studies; in
collaborating with other investigators under a common protocol; and in
meticulous and expeditious handling of study data.  Specific experience
in treatment of patients by hemodialysis will be emphasized.
 
3.  Documentation of access to a target population of hemodialysis
patients from which trial participants can be recruited in sufficient
numbers to meet or exceed the goals specified above.
 
4.  Understanding and awareness of the scientific, ethical, and
practical issues underlying the proposed trial and appropriateness of
plans to deal with them.
 
5.  Appropriateness of the budget for the work proposed.
 
6.  Adequacy of the proposed facility and space.
 
7.  Evidence of the degree of institutional commitment and support for
the proposed program, including the relative position of the proposed
project staff within the administrative structure of the institution.
 
8.  Evidence of willingness to work cooperatively with other centers in
the manner summarized in the RFA.
 
For the Data Coordinating Center:
 
1.  The scientific merit of the proposed approach to study design, data
collection and management, and intervention as outlined in the RFA.
 
2.  Documentation of the specific competence and previous experience of
professional, technical, and administrative staff pertinent to the
operation of a Data Coordinating Center for a collaborative clinical
trial, as well as available, on-site medical consultation in
hemodialysis and kinetic modeling of hemodialysis and time these
professionals will devote to the project.  Prior experience in the
collection of data from multiple clinical sites and experience in
monitoring the quality and timeliness of such data, must be
demonstrated.
 
3.  The approach to and likelihood of soliciting cooperation from the
participating clinical centers and exercising appropriate leadership in
matters of study design, data acquisition, data management, and data
analysis.
 
4.  Suitability of the proposed data management and data analysis
plans.
 
5.  Appropriateness of the budget for the work proposed.
 
6.  The adequacy of the proposed facility, technical hardware, and
space.
 
7.  The organizational and administrative structure of the proposed
program.
 
8.  Evidence of the degree of commitment and support of the
organization/institution for the proposed program, including the
relative position of the proposed project staff within the
administrative structure of the organization.
 
For the Intervention Coordinating Center:
 
1. The scientific merit of the proposed approach to study design,
especially intervention, as outlined in the RFA.
 
2.  Experience in design, coordination, and support of interventions
for clinical trials or other epidemiological studies.
 
3.  Evidence of ability to work collaboratively with Principal
Investigators of the Clinical Centers and the Data Coordinating Center
to develop a protocol for intervention on patient factors as outlined
in the RFA.
 
3.  Experience in training and certification of staff to carry out the
intervention.
 
4.  Experience in assessing and reporting results of compliance to
intervention within a clinical trial setting.
 
METHOD OF APPLYING
 
Letter of Intent
 
Prospective applicants are asked but not required to submit a letter of
intent to apply to the RFA as a Clinical Center, the Data Coordinating
Center, or the Intervention Coordinating Center.  This letter is to
include the name, telephone number, and mailing address of the
Principal Investigator, the names of other key personnel, the name of
the applicant institution and other collaborating entities, and the
number and title of this RFA.  A letter of intent is not binding and it
will not enter into the review of any application subsequently
submitted, nor is it a necessary requirement for application.  Letters
of intent are requested solely for planning purposes.  Thus, the NIDDK
Staff will not acknowledge such letters.  Letters of intent are to be
received no later than February 7, 1992, and are to be addressed to:
 
Dr. Robert D. Hammond
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Westwood Building, Room 603
Bethesda, MD  20892
 
Format for Application
 
Submit applications on form PHS 398 (revised 10/88, reprinted 9/89),
the application form for the traditional NIH research project grant.
Copies of this form are available in the applicant institution's Office
of Sponsored Research, and may be obtained from the Office of Grant
Inquiries, Division of Research Grants, National Institutes of Health,
Westwood Building, Room 449, Bethesda, MD  20892, telephone 301/496-
7447.
 
Use the conventional format for research project grant applications and
ensure that the points identified in the section above on "Review
Procedures and Criteria" are fulfilled.  To identify the application as
a response to this RFA, CHECK "YES" on item 2 of page 1 of the
application and enter the title "Reduction in Mortality and Morbidity
Among Hemodialysis Patients:  Pilot Study" and enter the RFA number
"DK-92-10" in the space provided.  Groups of investigators wishing to
apply as a Clinical Center, and/or the Data Coordinating Center, and/or
the Intervention Coordinating Center must submit separate applications.
 
THE RFA LABEL FOUND IN THE FORM PHS-398 (REVISED 10/88, REPRINTED 9/89)
APPLICATION KIT MUST BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE
ORIGINAL COMPLETED APPLICATION FORM.  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.
 
Application procedure
 
Send or deliver the completed, signed application and four complete
photocopies of it to the following, making sure that the original
application with the RFA label attached is on top:
 
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892 **
 
SEND TWO ADDITIONAL COPIES OF THE APPLICATION TO DR. HAMMOND AT THE
ADDRESS LISTED UNDER "LETTER OF INTENT." IT IS IMPORTANT TO SEND THESE
TWO COPIES AT THE SAME TIME AS THE ORIGINAL AND FOUR COPIES ARE SENT TO
THE DIVISION OF RESEARCH GRANTS; OTHERWISE THE NIDDK CANNOT GUARANTEE
THAT THE APPLICATION WILL BE REVIEWED IN COMPETITION FOR THE RFA.
 
Applications must be received by March 13, 1992.  An application not
received by this date will be returned to the applicant.
 
SCHEDULE
 
Letter of intent (optional):                  February 7, 1992
Application receipt date:                     March 13, 1992
Initial Review:                               June 1992
Review by the National Diabetes & Digestive
 & Kidney Diseases Advisory Council:         September 1992
Anticipated award date:                      September 1992
 
INQUIRIES
 
Inquiries regarding this announcement may be directed to:
 
John W. Kusek, Ph.D.
Clinical Trials Program Director
Division of Kidney, Urologic and Hematologic Diseases,
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3AO4C
5333 Westbard Avenue
Bethesda, MD  20892
Telephone:  (301) 496-7133
FAX:  (301) 496-9721
 
and
 
Lawrence Y. Agodoa, M.D.
Director, Clinical Affairs
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A11
5333 Westbard Avenue
Bethesda, MD  20892
Telephone:  (301) 496-7572
 
For fiscal and administrative matters, contact:
 
Nancy C. Dixon
Supervisory Grants Management Specialist
Grants Management Branch, DEA
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649B
Bethesda, MD  20892
Telephone:  (301) 496-7467
 
AUTHORITY AND REGULATIONS
 
These programs are described in the Catalog of Federal Domestic
Assistance No. 93.849 Kidney, Urologic and Hematologic Diseases
Research.  Awards will be made under the authority of the Public Health
Service Act, Title III,  Section 301 (Public Law 78-4110, as amended:
42 USC 241) and administered under PHS Grants Policies and Federal
Regulations 42 CFR Part 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental requirements of Executive Order 12372
or Health Systems Agency review.
 
REFERENCES
 
1. Rettig RA and Levinsky NG (editors).  Kidney Failure and the Federal
Government.  Institute of Medicine. National Academy Press. Washington,
D.C. 1991.
 
2. U.S. Renal Data System, USRDS 1991 Annual Data Report, The National
Institutes of Health, National Institute of Diabetes and Digestive and
Kidney Diseases, Bethesda, MD, August 1991.
 
3. Eggers PW. 1989.  Projections for the end-stage renal disease
population to the year 2000.  Proceedings of the 1989 Public Health
Conference on Records and Statistics. U.S. Department of Health and
Human Services.  DHHS Publ. No. PHS90-1214. November, pp. 121-126.
 
4. Hull AR and Parker T.  Introduction and Summary. Proceedings from
the Morbidity, Mortality and Prescription of Dialysis Symposium,
Dallas, TX, September 15 to 17, 1989.  American Journal of Kidney
Diseases XV:375-383, 1990.
 
5. Held PJ, Brunner F, Odaka M, et al. Five-year survival for end-stage
renal disease patients in the United States, Europe, and Japan, 1982 to
1987.  American Journal of Kidney Diseases XV:451-457, 1990.
 
6. Lowrie EG and Lew NL.  Death risk in hemodialysis patients:  the
predictive value of commonly measured variables and an evaluation of
death rate differences between facilities.  American Journal of Kidney
Diseases XV:458-482, 1990.
 
7. Held PJ, Levin NW, Bovbjerg RR et al.  Mortality and duration of
hemodialysis treatment.  Journal of the American Medical Association
265:871-875, 1991.
 
8. Eggers PW.  Mortality rates among dialysis patients in Medicare's
end-stage renal disease program.  American Journal of Kidney Diseases
XV:414-421.
 
9. Collins AJ, Hanson G, Umen A et al.  Changing risk factor
demographics in end-stage renal disease patients entering hemodialysis
and the impact on long-term mortality.  American Journal of Kidney
Diseases XV:422- 432, 1990.
 
10. Gotch FA, Yarian S, and Keen, M.  A kinetic survey of US
hemodialysis prescriptions.  American Journal of Kidney Diseases
XV:511-515, 1990.