Subject: NIH GUIDE - RFA DK-91-06 - V20(19) 05/17/91
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Wed, 15 May 91 15:43 EST

Hi Paul,
   This is the fourth of the transmissions for the 5/l7/9l NIH Guide.
Please post this one to the listserver as:
        RFADK-91-06.910517
  Also, please let me know as soon as possible when these are posted.
     Thanks.   Dottie
 ---------------------------- Text of forwarded message -----------------------
 
KIDNEY DISEASE AND HYPERTENSION IN BLACKS:  PILOT STUDY
 
RFA:  DK-91-06
 
P.T. 34, FC; K.W. 0715115, 0755015, 0760013, 0760035, 0745070
 
National Institute of Diabetes and Digestive and Kidney Diseases
 
Letter of Intent Receipt Date:  September 5, 1991
Application Receipt Date:  October 18, 1991
 
PURPOSE
 
The Division of Kidney, Urologic and Hematologic Diseases
invites cooperative agreement applications for investigators
to design and carry out a pilot study to assess the
feasibility of conducting a full-scale multicenter
randomized clinical trial to determine whether one approach
to stepped-care therapy for lowering high blood pressure in
persons with chronic renal disease due to hypertension is
more effective than the others tested in slowing down loss
of kidney function.  Different antihypertensive drugs,
including a diuretic, a calcium channel blocker, and an
angiotensin converting enzyme inhibitor may be used as
primary therapy in a stepped-care regimen to control blood
pressure.  A second objective of the full-scale study is to
determine if lowering blood pressure to one of two levels is
more effective in reducing loss of kidney function.  One
blood pressure group may be near the currently acceptable
maximum level of 140/90 mm Hg, whereas patients in the other
group may have blood pressure maintained in a range well
below this goal.  At least 70% of the pilot study population
must be Black; however, persons of other racial origins may
participate if they have established kidney disease due to
high blood pressure and meet other study entrance criteria
established by investigators.  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 for the
overall study; however, separate applications are
required.
 
The Public Health Service is committed to achieving the
health promotion and disease prevention objectives of "Health
People 2000," a Public Health Service-led national activity
for setting priority areas.  This RFA, "Kidney Disease and
Hypertension in Blacks:  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) through the
Superintendent of Documents, Government Printing Office,
Washington, D.C. 20402-9325 (telephone 202-783-3238).
 
DISCIPLINE AND EXPERTISE
 
The expertise appropriate for this research program includes
a knowledge of the epidemiological and clinical aspects of
both kidney disease and hypertension, as well as experience
in the design and conduct of collaborative clinical
trials.  Experience and skill in measurement of kidney
function (glomerular filtration rate), intervention with
antihypertensive therapy among a large number of patients,
and recruitment and follow-up of study participants,
especially Blacks, in clinical studies are appropriate for
Clinical Centers.  Skills in data base management,
biostatistics, and development of clinical trial study
design are appropriate for the Data Coordinating Center.  An
institution may apply for both a Clinical Center and Data
Coordinating Center.  However, a specific plan on how the
independent operation (i.e., confidentiality of study-wide
data) of each unit will be maintained is required.  A
separate application will be required for an institution
applying for both a Clinical Center and Data Coordinating
Center.  Collaboration among institutions to carry out the
pilot study is encouraged.  The primary emphasis in this
collaboration should be to complement the individual
expertise and capabilities of investigators in such areas as
patient recruitment, treatment of hypertension, and
measurement of kidney function.  Institutions wishing to
collaborate and function as a single Clinical Center will be
required to submit one application.
 
ELIGIBILITY REQUIREMENTS
 
Domestic universities, medical colleges, hospitals, and
other public or 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 wish to identify the GCRC as a
resource for conducting the proposed research.  In such a
case, a letter of agreement from either the GCRC Program
Director or Principal Investigator could be included with
the application.
 
BACKGROUND
 
End-stage renal disease (ESRD) is an important health
problem among Black Americans.  According to the most recent
report from the United States Renal Data System,
28 percent of the ESRD cases are Blacks although only about 12
percent of the U.S. population is Black.  The ESRD incidence
rate for Blacks is nearly four times that of Whites; 376 per
million versus 99 per million.  The disparity between Blacks
and Whites is especially striking for hypertension-related
ESRD. The incidence rate of ESRD with a diagnosis of
hypertension, the leading cause of renal failure among
Blacks, is 6.5 times greater than in Whites.  For certain
age groups, the disease rates are particularly high.  For
example, among Blacks aged 25-44, the incidence rate of ESRD
associated with hypertension is 20 times greater than the
rate for whites; the rate for Blacks 45-64 years old is
nearly 10 times that of whites.  This disease burden
prevails despite the fact that improved control of blood
pressure has been responsible, in part, for a decrease in
incidence of and mortality from myocardial infarction and
stroke among both Black and White Americans during the
past decade.
 
The disproportionate number of cases of ESRD among Blacks
due to hypertension has been attributed to a number of
factors, including higher prevalence of and more severe
hypertension, greater susceptibility of the kidney to
elevated blood pressure, and difficulty in accessing
treatment services, among others.  Despite uncertainty about
the reason(s) for this preponderance of disease, there are
reports that control of blood pressure to 140/90 mm Hg (mean
arterial pressure or MAP of 107) or less is beneficial in
reducing the progression of kidney disease to end-stage.  It
is important to note, however, that a rigorously controlled
clinical trial has not yet been conducted in persons with
established renal impairment resulting from hypertension to
determine whether one class of antihypertensive agents
protects the kidney better than another and to what level
blood pressure should be reduced to protect the kidney
maximally.
 
Recently, several reports have highlighted the benefits of
antihypertensive therapy in preventing loss of renal
function among persons with established kidney disease.  For
example, although only a modest difference in the rate of
loss of renal function (as measured by serum creatinine) was
observed between the Stepped-Care (SC) and Referred Care
(RC) groups (21.7/1,000 in SC survivors and 24.6/1,000 in RC
survivors) in the Hypertension and Detection Follow-up
Program, a 50 percent relative difference in favor of SC among
participants with baseline serum creatinine concentration
indicating borderline hypercreatinemia (1.50 - 1.69 mg/dl)
was observed.  Of particular interest was the significantly
greater rate of developing hypercreatinemia in Blacks, men,
and older persons (>60 years of age) and among persons with
higher diastolic blood pressure at trial entry.  An
encouraging preliminary report from a single-center clinical
trial that enrolled a high percentage of Blacks and
utilized an accurate measure of kidney function, also
suggests that lowering blood pressure in patients with
hypertensive kidney disease may slow down loss of kidney
function.  However, this study suffers from a number of
methodological flaws, including reporting of results from
only a subset of randomized patients, lack of a control or
comparison group, inability to achieve a difference in level
of blood pressure control, relatively short-term follow-up,
and reliance on subgroup analysis to determine the effect of
a specific antihypertensive drug on decline of kidney
function.  In the pilot phase of the Modification of Diet in
Renal Disease (MDRD) Study, which was supported by the NIDDK
and the Health Care Financing Administration, study
participants with higher levels of blood pressure had more
rapid decline of kidney function (glomerular filtration
rate), suggesting a causal relationship.  It is important to
note, however, that this observation was not based on random
assignment of patients to a blood pressure intervention.  In
the ongoing full-scale MDRD Study, the effect of blood
pressure control at or below two target levels (MAP of 92
and 107 mm Hg) and three levels of dietary protein and
phosphorus intake on loss of kidney function is being
examined among persons with reduced renal function resulting
from a heterogeneous group of kidney diseases.  It is
expected that experience from the MDRD Study will be helpful
in designing the blood pressure intervention for the present
pilot study.
 
Since most, if not all, of the antihypertensive clinical
trials conducted to date have focused primarily on
cerebrovascular and cardiovascular events, a randomized
controlled clinical trial is necessary to define the
clinical usefulness and possible renal protective effects of
long-term therapy with the major blood pressure lowering
drugs in patients, especially Blacks, with hypertension
responsible for their impaired renal function.
 
REFERENCES
 
1. U.S. Renal Data System, USRDS 1990 Annual Data Report,
The National Institutes of Health, National Institute of
Diabetes and Digestive and Kidney Diseases, Bethesda, MD,
August 1990.
 
2. Brazy, PC, Fitzwilliam, JF.  Progressive renal disease:
role of race and antihypertensive medications.  Kidney
International 37:1113-1119, 1990.
 
3. National High Blood Pressure Education Program (NHBPEP)
Working Group Report on Hypertension and Chronic Renal
Failure.  U.S. Department of Health and Human Services.
Public Health Service. National Institutes of Health.
National Heart, Lung and Blood Institute.  NIH Publication
No. 90-3032. August 1990.
 
4. Shulman, NB, Ford, CE, Hall, WD, et al. Prognostic value
of serum creatinine and effect of treatment of hypertension
on renal function.  Results from the Hypertension Detection
and Follow-Up Program.  Hypertension 13:I80-I93, 1989.
 
5. Eliahou, HE, Cohen, D, Hellberg, B et al. Effect of the
calcium channel blocker nisoldipine on the progression of
chronic renal failure in man. American Journal of Nephrology
8:285-290, 1988.
 
6. Ruilope, LM, Miranda, B, Morales, JM et al. Converting
enzyme inhibition in chronic renal failure.  American
Journal of Kidney Diseases 13:120-126, 1989.
 
7. Brazy, PC, Stead, WW, Fitzwilliam, JF. Progression of
renal insufficiency: role of blood pressure.  Kidney
International 35:670-674, 1989.
 
8. Pettinger, WA, Lee, HC, Reisch, J et al.  Long-term
improvement in renal function after short-term strict blood
pressure control in hypertensive nephrosclerosis.
Hypertension 13:766-772, 1989.
 
9. Klahr, S. The modification of diet in renal disease
study.  New England Journal of Medicine 320:864-866, 1989.
 
10. MDRD Study Group (Prepared by S Klahr, AS Levey, AM
Sandberg and G Williams).  Major results of the feasibility
study of the Modification of Diet in Renal Disease (MDRD)
Study.  Annual Meeting of The American Society of
Nephrology. 47A (abstract), 1988.
 
GOAL OF THE ACTIVITY
 
The primary purpose of this RFA is to initiate a
collaborative pilot study of antihypertensive therapy to
control blood pressure in men and women with kidney disease
associated with hypertension.  The pilot study will test the
feasibility of conducting a full-scale randomized clinical
trial to determine whether treatment of high blood pressure
by one of three modalities of stepped-care therapy,
including a diuretic, a calcium channel blocker, and an
angiotensin converting enzyme inhibitor as initial therapy,
is more effective than the others in significantly reducing
loss of kidney function.  Investigators also may wish to
consider whether the study design should include two
different levels of blood pressure control to assess whether
management of blood pressure within a target range
considerably below the currently accepted upper level
(140/90 mm Hg) is more effective in slowing down decline of
kidney function.
 
The pilot study has seven 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 patients with the appropriate study
criteria can be recruited efficiently into the study.
 
3.  To assess adherence with the clinic visit schedule and
to the prescribed medications.
 
4.  To evaluate if target blood pressure levels can be
maintained with the proposed drug regimens.
 
5.  To assess ways in which investigators can carry out
antihypertensive drug therapy in an unbiased fashion.
 
6.  To observe any adverse effects of the study, including
those of drug therapy and kidney biopsy.
 
7.  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 Chairman
of the Steering Committee, and the NIDDK Project
Coordinator.  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 both the awardees and the Institute.
 
SCOPE OF ACTIVITY
 
It is expected that the pilot study will take place in four
clinical centers over thirty three months.  Each clinical
center will randomize a minimum of 25 study participants
during a one-year period of recruitment.  The study will be
in three phases:  I) a twelve month period of collaborative
protocol development; II) twelve months of sample
recruitment; and III) nine months of close-out of the pilot
phase, data analysis and reporting of results.
 
Each applicant should propose the study design he or she
believes most appropriate for this project.  It is
anticipated that the study would involve both men and
women, and that at least 70 percent of
the study participants at each clinical center would be
Black. It is also expected that two important entry criteria
will be elevated diastolic blood pressure when patients are
taken off therapy, and reduced renal function.  Each
applicant should propose ways by which bias during
antihypertensive drug treatment can be minimized.
 
Whatever strategy is proposed for subject selection,
applicants must provide a detailed justification for the
projected selection plan, 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.  Applicants also must address criteria and
outcome measures for the seven pilot study objectives by
which success of this phase of the program will be judged
for extension into the full-scale study.
 
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/offerors 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.
 
STUDY OUTLINE
 
Applicants must propose in detail within their study
design, eligibility requirements including patient age,
level of blood pressure, and renal function level as well as
use of kidney biopsy to monitor progression of disease.  In
addition, exclusion criteria must be specified.  The use
of a baseline or run-in period and the follow-up and
intervention schedule also must be provided in the
application.  Outcome measures must be chosen so as to
address the efficacy and adverse effects of antihypertensive
therapy in the study population.  Techniques for accurate
and precise measurement of kidney function (glomerular
filtration rate; the GFR) must also be specified.  It is
anticipated that 100 participants will be required for the
pilot study.  The proposed approach to control of blood
pressure, using the main classes of antihypertensive drugs
in a stepped-care approach, and if feasible, two different
levels of blood pressure control, also must be discussed.
 
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 and necessary specimens to the Data Coordinating
Center and other central laboratories 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 an
interdisciplinary team of clinical investigators and
appropriate personnel, such as a research coordinator,
recruitment director, blood pressure interventionist, and
clerical staff.  Applications for Clinical Centers must
provide evidence that they will be capable of randomizing at
least 25 participants into the study during the one-year
period of recruitment.  Clinical Centers must describe
their experience in recruiting from well-defined
populations, especially Blacks.  Clinical Centers will be
required to submit protocol data expeditiously.  The
Principal Investigator and Co-Investigators at each Clinical
Center must be skilled in collaborative clinical
investigation, nephrology, and management of
hypertension.  There must be evidence of strong
institutional support for the Clinical Center, including
adequate space in which to conduct clinic 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 as well as 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 of antihypertensive
therapy, primarily in Blacks, and suggest solutions to
perceived problems.
 
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 ensuring
quality control.  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 antihypertensive therapy primarily
among Blacks and suggest solutions to key problems.  The
Data Coordinating Center also will be responsible for
identifying and supporting a collaborating Kidney Biopsy
Center, a Drug Distribution Center, and a central laboratory
for measurement of kidney function (Central GFR Laboratory).
 
The Kidney Biopsy Center will process and review all kidney
biopsy specimens obtained during the course of the pilot
study and report results to the Data Coordinating Center.
Prior to study entry, biopsies will be obtained from study
participants to confirm the presence of kidney disease due
to hypertension.  Once entered into study, follow-up
biopsies will be conducted on a sample of study participants
or the entire group to assess disease progress.
 
The Drug Distribution Center will acquire, store, and
distribute study medications on a timely basis to all of the
participating clinical centers.
 
The Central GFR Laboratory will be responsible for
implementing and coordinating glomerular filtration rate
testing, including sample receipt and counting, GFR
calculation, and reporting of results to the Data
Coordinating Center.  The Central GFR Laboratory also will
be responsible for training and certification of clinical
center GFR personnel.
 
It is anticipated that support of the Kidney Biopsy Center,
Drug Distribution Center, and Central GFR Laboratory will be
provided through subcontracts from the Data Coordinating
Center.  For central laboratories and distribution centers
supported by a subcontract from the Data Coordinating
Center, all NIH policies and procedures governing consortium
grants must be followed.
 
3.  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, 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 chairman will
be selected by the Steering Committee from among their
members, or alternatively, from among experts in the field
of clinical trials 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) and on a
quarterly basis thereafter.  Subcommittees of the Steering
Committee may be established as necessary.  The NIDDK
Project Coordinator also will be a member of these
subcommittees.
 
4.  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 NIDDK regarding the status of the study.
The Chairman of the Steering Committee, the Principal
Investigator of the Data 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, NIDDK in
consultation with Steering Committee members.
 
5.  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 awardees' activities including
protocol development, quality control, interim data
monitoring, final data analysis, preparation of
publications, and peformance monitoring.
 
STUDY PHASES
 
The Pilot Study is envisioned as involving four Clinical
Centers and one Data Coordinating Center for a period of
thirty three months.  The Pilot Study will have three
phases:
 
I    Protocol Development 12 months
II   Sample Recruitment and Data Collection 12 months
III  Study Close-Out and Data Analysis 9 months
 
The protocol development phase (Phase I) will be twelve
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
attainment of Pilot Study objectives, favorable
recommendation of the protocol by the External Advisory
Committee, and the concurrence of the NIDDK.  At the end of
the twelve-month period of Phase I, the Data Coordinating
Center should 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 Clinical Centers will
recruit and randomize participants, initiate treatment,
collect the outcome data specified in the protocol, and
provide these data to the Data Coordinating Center.  The
Data Coordinating Center will collect, process and analyze
the data and provide reports to the committee responsible
for monitoring the progress of the Pilot Study.  It is
anticipated that the operational plan of the entire study
will consist of five sequential phases as follows:
 
Phase I   Development of Protocol (12 months)
Phase II  Conduct of Pilot Study (12 months)
Phase III Close-out and Analysis of Pilot Study Data (9
months)
Phase IV  Full-Scale Cooperative Clinical Trial (72 months)
Phase V   Data Analysis and Reporting (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 Request for
Applications for Clinical Centers to participate in the
Full-Scale Study in order to provide a sufficient
recruitment base.  An RFA will also be issued for one Data
Coordinating Center.  Existing Centers in the Pilot Study
also will have to re-compete if they wish 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 for the Full-Scale
Study will be the technical capabilities in recruitment,
intervention and follow-up of study participants for
clinical centers and expertise in data collection, data base
management, study coordination, and interim and final
reporting of results for the data coordinating center.  It
is anticipated that the Full-Scale Study also will be
supported by cooperative agreements.
 
MECHANISM OF AWARD
 
It is anticipated that five awards (four Clinical Centers
and one Data Coordinating Center) will be made under this
RFA for a total of approximately 1.0 million dollars
(including direct and indirect costs) during the first
year.  The funding level for the Clinical Centers will be
approximately $150,000 in total cost for each Clinical
Center and approximately $400,000 in total costs for the
Data Coordinating Center per year.  Funding is expected to
begin in July 1992; total support for the project will be
for thirty three months.
 
The administrative and funding mechanism to be used to
undertake this program will be cooperative agreements (UO1).  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.  NIH assists and is involved
substantially with recipients in conducting projects similar
in program intent to those for grants, facilitating
performance of the effort in a "partner" role.
 
STUDY RESPONSIBILITIES, GOVERNANCE, AND FUNDING
 
The primary governing body of the study will be the Steering
Committee, composed of the Principal Investigators of the
study centers, 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 also 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 Committee will have primary
responsibility for the development of the study protocol,
facilitating 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 Institute, will review progress at least
semi-annually and provide advice to the Institute.
 
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 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.
 
Any disagreement that may arise in scientific 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 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.
 
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.
 
REVIEW PROCEDURES AND CRITERIA
 
General Procedures
 
Upon receipt, applications will be reviewed by NIDDK staff
for their 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 regular NIH
grant program.
 
In cases where 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 they are not competitive for
award.  The NIDDK will notify the applicant and
institutional official of this action.
 
Those applications judged to to both competitive and
responsive 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.  Subsequently, they will be
reviewed by the National Diabetes and Digestive and Kidney
Diseases Advisory Council.
 
If an application submitted in response to this RFA is
substantially similar to a research grant or cooperative
agreement application already submitted to the NIH for
review, the applicant will be asked to withdraw the pending
application before the new one is accepted.
If the application submitted in response to this RFA is
substantially similar to a research 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 both Clinical Centers and
the Data Coordinating Center will be based primarily on the
scientific merit of the proposed study.  If an insitution
wishes to apply both as a Clinical Center and Data
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 Pilot Study.  Evaluation will include the
following:  familiarity with and experience in recruiting
participants in a randomized trial; providing counseling on
antihypertensive drugs; handling laboratory specimens;
working in collaboration with other investigators under a
common protocol; and meticulous and expeditious handling of
study data.  Specific experience in the recruitment and
antihypertensive drug treatment of Blacks will be
emphasized.
 
3. Documentation of access to a Black target population 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
applicant's organizational structure.
 
8. 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 central
facilities 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, and time these
professionals will devote to the project.  Prior experience
in similar studies in the collection of data and patient
specimens from multiple clinical sites, as well as
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 and
direction, data acquisition, management, and 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 applicant's organizational structure.
 
9. Suitability of the organizational and administrative
arrangements for a Biopsy Center, Central GFR Laboratory,
and Drug Distribution Center.
 
For the Kidney Biopsy Center:
 
1. Ability to provide accurate histological interpretation
of biopsy specimens in a rapid manner and to report results
to the Data Coordinating Center.
 
2. Willingness to work collaboratively with Clinical Centers
to ensure that appropriate specimen collection techniques
are followed.
 
3. Willingness and experience in providing necessary
training and certification regarding specimen collection,
preparation, and shipping by Clinical Center investigators.
 
For the Glomerular Filtration Rate Testing Laboratory:
 
1. Experience in carrying out GFR assessment with accurate
and state-of-the-art measurement techniques.
 
2. Experience in handling and testing a large number of
urine and blood samples for GFR measurement and in reporting
results in a timely fashion to the Data Coordinating Center.
 
3. Maintenance of internal quality control procedures.
 
4. Willingness to collaborate with other study participants
to ensure correct collection and shipping of specimens.
 
5. Ability to train and certify Clinical Center staff for
GFR testing.
 
For the Drug Distribution Center:
 
1. Experience in procuring antihypertensive drugs and other
medications that may be necessary for the study.
 
2. Ability to store and maintain inventory control of study
drugs.
 
3. Design and implementation of a distribution system for
the drugs.
 
4. Maintaining adequate records to fulfill requirements of
Federal and State regulatory agencies and requirements of
the study.
 
5. Providing information to clinical center pharmacists and
other team members about pharmacy-related issues pertaining
to the study.
 
Clinic Staffing by Study Phase
 
Each applicant for a Clinical Center and for the Data
Coordinating Center must submit an adequately justified
yearly budget for the entire anticipated project period of
thirty three 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 twelve month
period, July 1, 1992 through June 30, 1993; this is the
period of protocol development.  The 02 budget period will
also be for twelve months, corresponding to Phase II
(recruitment, randomization, and the beginning of treatment
and clincal assessment for randomized study participants).
The 02 budget period will be from July 1, 1993 through June
30, 1994.  For phase III, the 03 budget period, will be from
July 1, 1994 through March 31, 1994 and will be for 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 should
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 should be estimated on the basis of monthly
two-day meeting in Bethesda, Maryland during Phase I, three
such 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 staff
necessary for conducting training should be available for a
training meeting to be held in Bethesda about one month
before protocol development is completed, for approximately
three days.
The budget for the Data Coordinating Center must also include
time and effort of personnel, supplies, and equipment
necessary for the Kidney Biopsy Center, Drug Distribution
Center, and Central GFT Laboratory.
 
Detailed budget estimates for Phases II and III should be
based on the applicant's proposed plan.
 
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
or a Data Coordinating Center.  This letter should 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.  Such 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.
 
The NIDDK Staff will not provide responses to such
letters.  Letters of intent to apply to this RFA, are to be
received no later than September 5, 1991 and 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 406
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 following:
 
Office of Grant Inquiries
Division of Research Grants
Westwood Building, Room 449
National Institutes of Health
Bethesda, MD  20892
 
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 the
RFA, CHECK "YES" on item 2 of page 1 of the application and
enter the title "Kidney Disease and Hypertension in
Blacks:  Pilot Study" and enter the RFA number DK-91-06 in
the space provided.  Groups of investigators wishing to
apply both as a Clinical Center and a Data 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 PHS 398.  FAILURE TO USE THIS LABEL COULD
RESULT IN DELAYED PROCESSING OF YOUR 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
(4) 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
Westwood Building, Room 240
National Institutes of Health
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 October 18, 1991.  An
application not received by this date will be considered
ineligible and returned to the applicant.
 
Timetable
Letter of intent:                September 5, 1991
Application receipt date:        October 18, 1991
Initial Review:                  February/March 1992
Review by the National Diabetes and Digestive and Kidney
Diseases Advisory Council:         May 1992
Anticipated award date:            July 1, 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
NIDDK
Westwood Building, Room 621
5333 Westbard Avenue
Bethesda, MD  20892
Telephone:  (301) 496-7133
FAX:  (301) 496-9721
 
or
 
Lawrence Y. Agodoa, M.D.
Director, Clinical Affairs
Division of Kidney, Urologic and Hematologic Diseases
NIDDK
Westwood Building, Room 621
5333 Westbard Avenue
Bethesda, MD  20892
Telephone:  (301) 496-7572
 
For fiscal and administrative matters, contact:
 
Nancy C. Dixon
Grants Management Office , DEA, NIDDK
Westwood Building, Room 649B
Bethesda, MD  20892
Telephone:  (301) 496-7467
 
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 Grant 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.