Research (OER)
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and Human Services (HHS)
Full Text DK-94-003
KIDNEY DISEASE AND HYPERTENSION IN AFRICAN AMERICANS
NIH GUIDE, Volume 22, Number 36, October 8, 1993
RFA: DK-94-003
P.T. 34, FC
Keywords:
0715133
Hypertension
Clinical Trial
National Institute of Diabetes and Digestive and Kidney Diseases
Letter of Intent Receipt Date: December 21, 1993
Application Receipt Date: January 18, 1994
PURPOSE
The Division of Kidney, Urologic and Hematologic Diseases (DKUHD),
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), invites cooperative agreement applications from
investigators to serve as a clinical center and/or data coordinating
center for the full-scale phase of the "African American Study of
Kidney Disease and Hypertension" (AASK).
The experimental design of the full-scale trial is a multi-center,
prospective, double-masked, randomized study examining the impact of
three antihypertensive drug regimens with different initial
randomized drugs and two different levels of blood pressure (BP)
control on the rate of change of the glomerular filtration rate (GFR)
in African American subjects with hypertension and established renal
insufficiency. The study will follow a three by two factorial
design. The first factor will consist of three drug regimens, each
initiated by a different agent. The three initial drugs used in
these regimens will be a calcium channel blocker, an angiotensin
converting enzyme inhibitor, and a beta-blocker. The second factor
will be two levels of goal BP as defined by the mean arterial
pressure (MAP). One group will have a goal MAP less than or equal to
92 mm Hg and the other group will have a MAP between 102-107 mm Hg
inclusive.
Study participants in the AASK full-scale trial are restricted to
African Americans. The protocol for the ongoing AASK pilot study
provides details on inclusion and exclusion criteria and procedures
for participants. It is recommended that applicants obtain a copy of
this protocol, available upon request from DKUH staff, to assist them
in preparing their applications for this RFA.
HEALTHY PEOPLE 2000
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Health People 2000,"
a PHS-led national activity for setting priority areas. This Request
for Applications (RFA), Kidney Disease and Hypertension in African
Americans, is related to the priority areas of diabetes and chronic
disabling conditions. Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or
Summary Report: Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-783-3238).
ELIGIBILITY REQUIREMENTS
Only U.S. organizations are eligible to apply. Domestic applications
may not include international components. Applications may be
submitted by for-profit and non-profit organizations, public and
private, such as universities, colleges, hospitals, laboratories,
units of State and local governments, and eligible agencies of the
Federal government. Applications from minority and women
investigators and minority institutions are especially encouraged.
The expertise appropriate for this research program includes a
knowledge of the epidemiological and clinical aspects of kidney
disease and hypertension. Experience in carrying out renal and
hypertension clinical trials is also essential. Experience and skill
in measurement of kidney function (glomerular filtration rate),
intervention with anti-hypertensive drugs among a large number of
patients, and recruitment and follow-up of study participants,
particularly African Americans, in clinical studies are appropriate
for Clinical Centers. Skills in management of multi-center clinical
trials, establishing and maintaining a large data base, and analysis
of complex data sets 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 for each
center will be required from an institution applying for both a
Clinical Center and Data Coordinating Center.
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. If so, a letter of agreement from either the
GCRC Program Director or Principal Investigator could be included
with the application.
MECHANISM OF SUPPORT
The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01), which is an assistance
mechanism rather than an acquisition mechanism. Under the
cooperative agreement, the NIH purpose is to support and/or stimulate
the recipient's activity by involvement in and otherwise working
jointly with the award recipient in a partner role, but it is not to
assume direction, prime responsibility, or a dominant role in the
activity. Details of the responsibilities, relationships and
governance of the study to be funded under cooperative agreement(s)
are discussed later in this document under the section "Terms and
Conditions of Award."
FUNDS AVAILABLE
The estimated funds (total costs) available for the first year of
support for the entire program is approximately six million dollars.
It is anticipated that one award for the Data Coordinating Center for
not more than $750,000 (including direct and indirect costs) per year
and fourteen awards for Clinical Centers will be made. Funding for a
single Clinical Center will be approximately $375,000 in total costs.
Although this program is provided for in the financial plans of the
NIDDK, awards in response to this RFA are contingent on the
availability of funds for this purpose.
The total project period for applications submitted in response to
the present RFA will be seven years. The anticipated award date is
July 1994.
At this time, the NIDDK anticipates that there will not be a renewed
competition after seven years. If the NIDDK does not continue the
program, awardees may submit grant applications through the usual
investigator-initiated grants program.
RESEARCH OBJECTIVES
Background
End-stage renal disease (ESRD) is an important health problem among
African Americans. According to the most recent report from the
United States Renal Data System, Blacks (African Americans) make up
29 percent of the ESRD cases although only about 12 percent of the
U.S. population is Black. In 1990, the ESRD incidence rate for
Blacks is nearly four times that of whites (518 per million versus
132 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 6.2 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 18 times greater than the rate for
whites in 1988-90; 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 from 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 or not
one class of antihypertensive agents protects the kidney better than
another and to determine the optimum blood pressure level that
maximally protects the kidney.
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, which 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 loss of kidney function. However, this study reported
results from only a subset of randomized patients, lacked a control
or comparison group, and failed to achieve a difference in level of
blood pressure control.
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 African Americans, with
hypertension associated with the impaired renal function. The
benefit to renal function of control of blood pressure to levels
below those generally recommended (140/90 mm Hg) also needs to be
assessed.
AASK Pilot Study
The AASK Pilot Study, in which approximately 200 study participants
will be enrolled, is currently underway. The anti-hypertensive drugs
used in that study along with the two target goals for control of
blood pressure are noted below under, "Goal of the Activity". It is
anticipated that results from the pilot study, including renal
diagnosis made from kidney biopsy, will be available during the
summer of 1994. If the results of the Pilot Study indicate a need,
modifications will be made to the study protocol for the full-scale
trial.
At this time two changes to the design and operational aspects of the
Pilot Study protocol are anticipated and will be implemented in the
full-scale trial; double-masked administration of the randomized
anti-hypertensive drugs (ACEi, CCB, and beta-blocker) and use of a
distributed data entry system at the Clinical Centers.
Goal of the Activity
The first goal of this RFA is to initiate a collaborative full-phase
trial to test whether one of three anti-hypertensive drug treatment
arms significantly reduces the rate of GFR decline better in African
Americans with the clinical entity that is now attributed to
hypertensive renal disease. A second goal is examining whether one
of two levels of blood pressure control (less than 92 mm Hg vs.
102-107 mm Hg) better preserves renal function. The participants
will be assigned to one of three randomized regimens: angiotensin
converting enzyme inhibitor (ACEi), calcium channel blocker (CCB), or
beta-blockers. It is anticipated that treatment by the randomized
regimens will be carried out in a double-masked fashion. Subsequent
to that assignment, no other ACEis, CCBs, or beta-blockers will be
used in any of the participants to achieve blood pressure control.
If the BP goal is not reached in a given participant on maximal
tolerated doses of the drug assigned, additional anti-hypertensive
medications will be added. The Pilot Study protocol recommends that
anti-hypertensive medications will be added in the following order:
(1) diuretics (furosemide); (2) alpha-blockers (doxazosin); (3)
centrally-acting alpha-2 agonists (clonidine); (4) minoxidil or
hydralazine.
Scope of the Activity
Approximately 900 study participants, recruited by fourteen clinical
centers, will be required for the full-scale trial. Thus each
Clinical Center is expected to randomize at least 65 participants
during a two year period of recruitment.
The full-scale study will consist of three phases: (1) a 24-month
period of recruitment; (2) a 48-month period of intervention and
follow-up and (3) 12 months for data analysis, close-out of the
Clinical Centers, and reporting of results.
Unless otherwise noted in this RFA, applicants should prepare the
applications using patient eligibility criteria set forth in the AASK
Pilot Study protocol. Major entry and exclusion criteria are briefly
described as follows. The study participants in this trial will be
exclusively African American men and women age 18-70 years who have
hypertension and reduced renal function. Hypertension is defined as
sitting blood pressure of 95 mm Hg or more. Reduced renal function
is defined as a pre-randomization 125I-iothalamate glomerular
filtration rate between 25-70 ml/min/1.73sq m. Selected exclusion
criteria include history of malignant or accelerated hypertension
within 6 months prior to study entry, known secondary causes of
hypertension, known history of diabetes mellitus type I and II, and a
ratio of urinary protein (mg/dl) to creatinine (mg/dl) exceeding 1.5
in a 24-hour urine sample.
It is anticipated that randomized drugs (ACEi, CCB, and beta-blocker)
will be administered in a double-masked fashion in the full-scale
trial. Changes to the protocol to accommodate this study design will
be considered at the first meeting of the Steering Committee. It is
also expected that a distributed data entry system will be
established during the full-scale trial. Applicants for the Data
Coordinating Center should include a plan to implement (and budget)
this system of data transmission.
Each applicant should demonstrate the ability to follow an
established study protocol and manual of operations. Applicants must
also demonstrate the ability to recruit and randomize the required
number of study participants, intervene with various anti-
hypertensive drugs, and maintain high rates of follow-up during the
course of the trial.
Study Outline
Investigators should develop their applications for the full-scale
trial based on the inclusion and exclusion criteria and the general
design of the pilot study as outlined in this RFA and the Pilot Study
Protocol. It is expected that investigators will carry out the
already developed protocol, however, modifications to this protocol
may be required based on the results of the pilot study.
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 should provide evidence
that the investigators are capable of randomizing at least 65
participants into the study during the two-year period of
recruitment. Applicants for the Clinical Centers should describe
their experience in recruiting from well-defined populations,
especially African Americans. Clinical Centers will be required to
submit protocol data expeditiously. The Principal Investigator and
Co-Investigators in each Clinical Center should be skilled in
collaborative clinical investigation, nephrology, and management of
hypertension. There should 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 should 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 stated common protocol.
The applicant should include a succinct discussion of previous
relevant investigational efforts. The applicant also should discuss
in detail the recruitment strategies to procure the expected number
of randomized participants, approaches to attain high levels of
adherence to the anti-hypertensive drug regimens, and high rates of
follow-up.
2. Central Functions
The Data Coordinating Center will have primary responsibility for
collecting, editing, storing, and analyzing data generated by the
Clinical Centers. It should be prepared to assume a key role in
overseeing implementation and adherence to the protocol, and assuring
quality control. The Data Coordinating Center will be expected to
provide appropriate biostatistical, data management, and coordination
expertise. 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 should
provide a detailed description of prior experience in multi-center
studies. The Data Coordinating Center will also be responsible for
identifying and supporting a collaborating Drug Distribution Center,
and a central laboratory for measurement of kidney function (Central
GFR Laboratory), and a Central Biochemistry Laboratory. If these
supporting units are not available at the applicant institution, the
Data Coordinating Center should include plans to subcontract these
functions.
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 GFR 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.
The Central Biochemistry Laboratory (CBL) will be responsible for
measurement of relevant laboratory tests as specified in the study
protocol and manual of operations. The CBL will coordinate shipping,
receipt and testing of samples, and reporting the results directly to
the Data Coordinating Center.
3. Steering Committee
The primary governing body of the study will be the Steering
Committee comprised of each of the Principal Investigators of the
Clinical Centers and the Data Coordinating Center, the Chairperson of
the Steering Committee, and the NIDDK Project Coordinator (described
in detail under Terms and Conditions).
4. External Advisory Committee
An independent committee supported by the NIDDK and composed of
experts in nephrology, hypertension, biostatistics, clinical trials,
and bioethics who are not otherwise involved in the study will be
established to review periodically the progress of the study
(described in detail under Terms and Conditions).
5. Project Coordinator
The Minority Health Program Director, Division of Kidney, Urologic
and Hematologic Diseases will be the Project Coordinator for the
full-scale trial. The Project Coordinator will assist the Steering
Committee and External Advisory Committee in carrying out the study
(described in detail under Terms and Conditions).
Study Phases
The randomized full-scale clinical trial will include fourteen
Clinical Centers and one Data Coordinating Center for a period of 84
months. It will have the following three phases:
1. Participant Recruitment: 24 months
2. Intervention and Follow-up: 48 months
3. Study Close-Out and Data Analysis: 12 months
It is expected that each Clinical Center will recruit and randomize
65 participants during a 24-month period. The anti-hypertensive drug
intervention will be carried out immediately post-randomization.
Follow-up procedures, including measurement of blood pressure and
GFR, will be carried out during a follow-up period of 48 months. A
12-month period is planned for close-out of Clinical Centers, data
analysis, and reporting of results.
It is expected that all data will be submitted centrally and that
access to data and publications will be by the mechanism(s) defined
in the protocol. The External Advisory Committee, will review
progress at least semi-annually and provide advice to the NIDDK.
Guidelines for Budget Preparation by Study Phases
Each applicant for a Clinical Center and for the Data Coordinating
Center should submit an adequately justified yearly budget for the
entire anticipated project period of 84 months. The budgets for each
budget period of the study should 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.
Budget
Period Time Period Activity
#1 7/1/94 through 6/30/95 Recruitment, Intervention &
F/U #2 7/1/95 through 6/30/96 Recruitment, Intervention
& F/U #3 7/1/96 through 6/30/97 Intervention & Follow-
Up #4 7/1/97 through 6/30/98 Intervention & Follow-Up
#5 7/1/98 through 6/30/99 Intervention & Follow-Up #6
7/1/99 through 6/30/2000 Intervention & Follow-Up #7
7/1/2000 - 6/30/2001 Clinical Center Close-Out, Data
Analysis, and Reporting of Results
For a Clinical Center, the budget should request support for the
minimum number of staff to successfully carry out the trial. A
Clinical Center could include a Principal Investigator, Co-
Investigator, GFR technician, study coordinator, and data entry
clerk. Support for travel for two key investigators to attend
quarterly meetings of the Steering Committee should also be included.
Steering Committee meetings will be held in the Washington, DC area.
Travel for centralized training of the GFR technician, study
coordinator, and data entry clerk must also be budgeted (assume
central training to be held in the Washington, DC area).
For applications for the Data Coordinating Center, the budget should
include the time and effort of key personnel needed to conduct the
trial and the required number and cost of computers to be used at the
Clinical Centers for distributed data entry. Travel to the
Washington, DC area for External Advisory Committee meetings (two per
year), Steering Committee meetings (three per year), site visits
(seven in year 1 and seven in year 2) is also to be included in the
budget. The budget should also include travel by the Chairperson of
the Steering Committee (if he/she is not a Principal Investigator in
the Study) to the External Advisory Committee meetings and the
Steering Committee meetings. If the supporting functions of the Drug
Distribution Center, the Central Biochemistry Laboratory, and the
Central Glomerular Filtration Laboratory are not available at the
applicant institution, the budget should reflect subcontracting of
these functions.
Terms and Conditions of Award
The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01), an "assistance" mechanism"
(rather than an "acquisition" mechanism), in which substantial NIH
scientific and/or programmatic involvement with the awardee is
anticipated during performance of the activity. Under the
cooperative agreement, the NIH purpose is to support and/or stimulate
the recipient's activity by involvement in and otherwise working
jointly with the award recipient in a partner role, but it is not to
assume direction, prime responsibility, or a dominant role in the
activity. Consistent with this concept, the dominant role and prime
responsibility for the activity resides with the awardee(s) for the
project as a whole, although specific tasks and activities in
carrying out the studies will be shared among the awardees and the
Institute Project Coordinator.
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 92, and other HHS,
PHS, and NIH grant administration policy statements.
1. Awardee Activities
The tasks or activities in which awardees (for both the Clinical and
Data Centers) will have substantial and lead responsibilities include
protocol revision, data collection, quality control, final data
analysis and interpretation, and preparation of publications. The
awardee agrees to follow the common protocol and manual of operations
developed for the Pilot Study and as amended based on the results of
that phase of the trial. Specific tasks for the awardees of the
Clinical Centers include patient recruitment and follow-up and
transmission of all study data to a central Data Coordinating Center
for combination and analysis.
2. NIDDK Activities
The NIDDK Project Coordinator is the Minority Health Program
Director, Division of Kidney, Urologic and Hematologic Diseases whose
function will be to assist the Steering Committee and External
Advisory Committee in carrying out the trial. The NIDDK Project
Coordinator has expertise in clinical nephrology and clinical trials.
The individual will assist in quality control, interim data analysis,
safety monitoring, and final data analysis and interpretation,
preparation of publications, and coordination and performance
monitoring.
The NIDDK Project Coordinator will have voting membership on the
Steering Committee, and as appropriate, its subcommittees.
The NIDDK reserves the right to terminate or curtail the study (or an
individual award) in the event of (a) a major breach in the protocol
or substantial changes in the agreed-upon protocol with which the
NIDDK does not agree, (b) human subject ethical issues that may
dictate a premature termination, or (c) significant alteration in the
availability of resources to support the program.
3. Cooperative Activities
A Steering Committee, composed of the principal investigators of each
Clinical Center, the principal investigator of the Data Coordinating
Center, the NIDDK Project Coordinator and the Chairperson of the
Steering Committee will be the main governing board of the study and
will have primary responsibility for facilitating the conduct of the
trial, monitoring interim measures of trial progress, and reporting
trial results. The Principal Investigators from each Clinical Center
and the Data Coordinating Center, the Chairperson, and the NIDDK
Project Coordinator will have one vote. The Chairperson, who will be
someone other than the NIDDK staff member, will be selected by the
Steering Committee from among their members, or alternatively, from
among experts in the fields of nephrology, hypertension, or clinical
trials who are not participating directly in the trial.
Subcommittees will be established by the Steering Committee, as it
deems appropriate; the NIDDK Project Coordinator will serve on
subcommittees as he/she deems appropriate.
Any changes to the collaborative protocol will be developed by the
Steering Committee. Data will be submitted centrally to the Data
Coordinating Center. Protocols will define rules regarding access to
data and publications. An independent External Advisory Committee,
to be appointed by the NIDDK, will review progress at least annually
and report to the Institute.
It is anticipated that awardees will have lead responsibilities in
all joint tasks and activities. The NIDDK Project Coordinator will
have voting membership on the Steering Committee, and as appropriate,
its subcommittees.
Awardees will be required to accept and implement the common protocol
and procedures approved by the Steering Committee.
4. Governance
The primary governing body of the study will be the Steering
Committee comprised of each of the Principal Investigators of the
Clinical Centers and the Data Coordinating Center, the Chairperson of
the Steering Committee, and the NIDDK Project Coordinator. The
Steering Committee has primary responsibility for developing common
clinical protocols, facilitating the conduct and monitoring of the
studies, and reporting the study results. Each member of the
Steering Committee will have one vote.
It is anticipated that the Steering Committee will meet on a
quarterly basis during the course of the trial, or more often if
deemed necessary. Subcommittees of the Steering Committee may be
established as necessary and will meet as necessary. The NIDDK
Project Coordinator and the Data Coordinating Center will be
represented on each subcommittee.
An independent External Advisory Committee supported by the NIDDK and
composed of experts in relevant medical, statistical and bioethical
fields who are not otherwise involved in the study will be
established to review periodically the progress of the study. The
committee will oversee participant safety, evaluate results, monitor
data quality, and provide operational and policy advice to the
Steering Committee and the NIDDK regarding the status of the study.
The Principal Investigator of the Data Coordinating Center, the NIDDK
Project Coordinator, and the Director of the Division of Kidney,
Urologic and Hematologic Diseases may participate as ex-officio, non-
voting members of this Committee. Committee members will be
appointed by the NIDDK in consultation with members of the Steering
Committee. The NIDDK named Project Coordinator will serve as
executive secretary of the External Advisory Committee.
5. Arbitration
Any disagreement that may arise in scientific-programmatic matters
between award recipients and NIDDK may be brought to arbitration. An
arbitration panel will be composed of three members: one selected by
the Steering Committee (with NIDDK member not voting) or by the
individual awardees 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 special terms of award (1-5) described above are in addition to
and not in lieu of otherwise applicable OMB administrative
guidelines, HHS Grant Administration Regulations at 45 CFR parts 74
and 92, and other HHS, PHS, and NIH granting policy statements.
STUDY POPULATIONS
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING
IMPLEMENTATION OF NIH POLICIES CONCERNING
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS
NIH policy is that applicants for NIH 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 is to 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 is to be provided. In the present study,
however, only African Americans are to be enrolled and studied, as
explained under "Research Objectives."
Gender must be addressed in developing a research design and sample
size appropriate for the scientific objectives of the study. This
information must be included in the form PHS 398 (rev. 9/91) in Item
4 (Research Design and Methods) of the Research Plan AND summarized
in Item 5, Human Subjects.
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.
If the required information is not contained within the application,
the application will be returned without review.
Peer reviewers will address specifically whether the research plan in
the application conforms to these policies. If the representation of
women 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.
LETTER OF INTENT
Prospective applicants are asked, but not required, to submit a
letter of intent. This letter is to include the name, telephone
number, and mailing address of the Principal Investigator, the names
of key personnel, the name of the applicant institution, 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 requirement for application. Letters of intent
are requested solely for planning purposes. The information
contained in these letters is helpful in planning for review of
applications. It allows NIDDK staff to estimate the potential review
workload and to avoid possible conflicts of interest in the review.
The NIDDK staff will not provide responses to such letters.
Letters of intent are to be received no later than December 21, 1993
and are to be addressed to:
Dr. Robert D. Hammond
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 406
Bethesda, MD 20892
APPLICATION PROCEDURES
The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these awards. These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/594-7250; and from the NIH program administrators named
below.
Use the conventional format for research project grant applications
and ensure that the points identified in the Review Criteria section
below are fulfilled. To identify the application as a response to
the RFA, Check "YES" on item 2a of page 1 of the application and
enter the title "Kidney Disease and Hypertension in African
Americans" and enter the RFA number DK-94-003 in the space provided.
The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page of the original
completed application form. Failure to use the label could result in
delayed processing of the application such that it may not reach the
review committee in time for review.
Send or deliver the completed, signed application and three complete
photocopies to the following office, making sure that the original
application with the RFA label attached is on top to:
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 three 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 January 18, 1994. An application
not received by this date will be returned to the applicant.
REVIEW CONSIDERATIONS
Upon receipt, the Division of Research Grants (DRG) will review the
application for completeness. Applications will be reviewed by NIDDK
staff for responsiveness to the objectives of this RFA. If an
application is judged to be incomplete or unresponsive, it will be
returned to the applicant.
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 will withdraw from further competition those
applications that are not competitive for award. The NIDDK will
notify the applicant and institutional official of this action.
Those applications judged to be 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.
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 institution wishes to apply both as a
Clinical Center and Data Coordinating Center, separate applications
must be prepared.
The IRG evaluates the merit of each grant application on the meeting
agenda according to specific criteria. The principal criteria for
the initial review of research project grant applications, as
required in the PHS Scientific Peer Review Regulations include:
o scientific, technical, or medical significance and originality of
the proposed research;
o appropriateness and adequacy of the experimental approach and
methodology to be used;
o qualifications of the Principal Investigator and staff in the area
of the research;
o the Principal Investigator's experience and record in previous
research activity;
o reasonable availability of resources;
o reasonableness and adequacy of justification for the proposed
budget and duration of support; and
o adequacy of the proposed means for protecting against adverse
effects upon humans, vertebrate animals, or the environment.
Special criteria for review of applications will be as follows:
For Clinical Centers:
1. Documentation of access to an African American target population,
and women, from which a substantial number of trial participants can
be recruited in sufficient numbers to meet the goals specified in the
RFA.
2. Understanding and awareness of the scientific, ethical, and
practical issues underlying the proposed trial and appropriateness of
plans to deal with them.
3. 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 Clinical Trial.
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 African Americans will be emphasized.
4. Responsible budgeting, staffing, and distribution of available
resources appropriate for the work proposed.
5. Adequacy of the proposed facility and space.
6. 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.
7. Willingness to work cooperatively with other centers in the
manner summarized in the RFA.
For the Data Coordinating Center:
1. 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 the
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.
2. Suitability of proposed data management and data analysis plans.
3. Ability to design, implement and maintain a distributed data
entry system for the Clinical Centers.
4. The approach to and likelihood of soliciting cooperation from the
participating clinical centers and exercising appropriate leadership
in matters of study design and protocol revision, and data
acquisition, management, and analysis.
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 procuring the services of (or subcontracting for) a Central
Biochemistry Laboratory, Central GFR Laboratory, and Drug
Distribution Center.
For the Glomerular Filtration Rate Testing Laboratory:
1. Experience in carrying out GFR assessment with 125I-iothalamate.
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 investigators 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 from the relevant
pharmaceutical companies, and other medications that may be necessary
for the study.
2. Ability to store and maintain study drugs according to state,
local, and federal regulations.
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.
For the Central Biochemistry Lab:
1. Experience in carrying out relevant routine testing of a large
number of samples comprised primarily of body fluids, including urine
and blood, as specified in the study protocol and manual of
operations.
2. Ability and capability 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 investigators to
ensure correct collection and shipping of specimens.
5. Ability to carry out centralized training of clinic staff for
proper collection and shipment of specimens to the CBL.
AWARD CRITERIA
Applications recommended by the National Diabetes and Digestive and
Kidney Diseases Advisory Council will be considered for award based
upon (a) scientific and technical merit; (b) program balance,
including in this instance, sufficient compatibility of features to
make a successful collaborative program a reasonable likelihood; and
(c) availability of funds.
INQUIRIES
Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome. Applicants are encouraged to request a copy
of the pilot study protocol.
Inquiries regarding programmatic issues may be directed to:
Lawrence Y. Agodoa, M.D.
Division of Kidney, Urologic and Hematologic Diseases,
National Institute of Diabetes and Digestive and Kidney Diseases Room
3A11, Westwood Building
Bethesda, MD 20892
Telephone: (301) 594-7553
FAX: (301) 594-7501
Inquiries regarding fiscal matters may be directed to:
Nancy C. Dixon
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649B
Bethesda, MD 20892
Telephone: (301) 594-7543
FAX: (301) 594-7594
Schedule
The timetable for receipt, peer review, and funding of this RFA is as
follows:
Letter of Intent Receipt Date: December 21, 1993 Application
Receipt Date: January 18, 1994 Initial Review:
February/March 1994 Review by the NIDDK Advisory Council:
May/June 1994
Anticipated Award Date: July 1, 1994
AUTHORITY AND REGULATIONS
This program is described in the catalog of Federal Domestic
Assistance No. 93.849-Kidney, Urologic and Hematologic Diseases
Research. Awards are made under the authority of the Public Health
Service Act, Title IV Part A (Public Law 78-410, as amended by Public
Law 99-158, 42 USC 241 and 285) and administered under PHS grants
policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 and 92.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
review.
References
1. U.S. Renal Data System, USRDS 1993 Annual Data Report, The
National Institutes of Health, National Institute of Diabetes and
Digestive and Kidney Diseases, Bethesda, MD, April 1993.
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. Am J of Nephrol 8:285-290, 1988.
6. Ruilope, LM, Miranda, B, Morales, JM et al. Converting enzyme
inhibition in chronic renal failure. Am J of Kidney Dis 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.
.
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