POLYCYSTIC KIDNEY DISEASE: INNOVATIVE IMAGING TO ASSESS PROGRESSION

Release Date:  December 15, 1998

RFA:  DK-99-003 (Requesting competing applications from current awardees, see NOT-DK-05-005)

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  February 10, 1999
Application Receipt Date:  March 10, 1999

PURPOSE

The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites
Cooperative Agreement Applications for a Consortium of Participating Clinical
Centers (PCCs) and a Data Coordinating and Imaging Analysis Center (DCIAC) to
develop and implement studies to test whether imaging techniques can provide
accurate and reproducible markers of progression of renal disease in patients
with Polycystic Kidney Disease (PKD).  The DCIAC will propose initial study
protocol(s) for the imaging studies and will be responsible for the collection,
management and analysis of both the radiologic and clinical data.  The PCCs will
also propose initial clinical study protocol(s) to prospectively obtain uniform
clinical and imaging data from well characterized patients with PKD. The final
studies will be jointly agreed upon by the DCIAC and PCCs, will be undertaken
both individually by the PCCs and collectively by the PCCs and the DCIAC, and
will involve several cohorts of patients at the different PCCs across the
country.  The primary objectives of this investigation will be: (1) to develop
and test the accuracy and reproducibility of imaging techniques to monitor
changes in renal cyst size and parenchymal involvement in  well characterized
cohorts of patients with PKD to assess their utility as surrogate markers of
disease progression, (2) to establish and maintain a database of uniformly and
accurately collected information including renal functional parameters and other
selected markers of disease progression identified by the DCIAC and the PCCs, to 
correlate parenchymal involvement with renal functional changes in PKD patients
with various rates of progression, and (3) to maintain and make available such
data to facilitate the planning and implementation of clinically appropriate
interventions in the near future.

HEALTHY PEOPLE  2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This RFA, Polycystic Kidney Disease:
Innovative Imaging of Disease Progression, relates to the priority areas of
chronic disabling conditions and prevention services. Potential applicants may
obtain a copy of  "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

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

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) cooperative agreement
(U01) mechanism of support. The cooperative agreement is an assistance mechanism
in which substantial NIDDK scientific and programmatic involvement is anticipated
during performance of the activity.  Under the cooperative agreement, the NIDDK
purpose is to support and encourage the recipient"s activities by working jointly
with the awardees in a partnership role, but not to assume direction, primary
responsibility, or dominance.  Details of the responsibilities, relationships,
and governance of a study funded under a cooperative agreement are described in
the section entitled "Terms and Conditions of Award."

The total project period for applications submitted in response to this RFA may
not exceed five years.  The anticipated award date is September 30, 1999.

It is anticipated that the maximum award for the DCIAC and the PCCs will not
exceed $500,000 total cost per center per year.

At this time, the NIDDK has not determined whether or how this solicitation will
be continued beyond the present RFA.

FUNDS AVAILABLE

The NIDDK intends to commit approximately $1,500,000 total cost (direct plus
indirect costs) in FY 1999, to fund two or three awards for the PCCs and one
award for a DCIAC in response to this RFA. An applicant may request support for
a project period of up to five years and a budget for total costs of up to
$500,000 per year.  It is anticipated that the award for each participating unit
will not exceed $500,000 total costs for each year of the award.  Because the
nature and scope of the research proposed in response to this RFA may vary, it
is anticipated that the size of each award will also vary.

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

RESEARCH OBJECTIVES

A.  Background

Polycystic Kidney Disease is a serious and costly disease.  About 500,000 people
in the USA are estimated to have PKD, and it is the fourth leading cause of end-
stage renal failure in the nation.  The important advances in understanding the
molecular basis of adult dominant PKD (ADPKD1 and ADPKD2) have generated intense
interest and have provided investigators with important research opportunities. 
Although certain topics are already receiving careful study, timely opportunities
to discover more about the natural history of PKD and appropriate clinical
interventions to ameliorate its course need to be addressed. Such investigations
are likely to generate, in the foreseeable future, a variety of possible
strategies for clinical intervention.

Several previous studies have established typical rates of decline of glomerular
filtration rate (GFR) in PKD patients.  Patients with PKD genotypes vary in their
rate of progressive loss of renal function.  Nevertheless, through much of the
course of PKD, GFR is maintained and detectable decreases in GFR occur relatively
late in the natural history of the disorder.  Therefore, a clinical investigation
to attempt to alter the decline of GFR can only be undertaken late in the
disease.  Furthermore, although functionally a critical parameter, GFR is
cumbersome to assess.  Therapeutic interventions are likely to be targeted to
patients at highest risk for the development of progressive deterioration of
renal function.  Methods to identify such patients and monitor markers of
progressive disease are critical to the development of early, effective
interventions.

The focus of this research initiative is investment in the groundwork that will
facilitate the development and eventual testing of clinically practical
intervention strategies. For example, current state-of-the-art methods using
magnetic resonance imaging (MRI) techniques with rapid image acquisition rates
make possible high resolution three dimensional images of the kidneys.  Semi-
automated image analysis algorithms also exist to determine renal size and the
portion of the kidney occupied by cystic structures.  Some experience has been
gained in establishing that repeat imaging of the same PKD patient, using these
techniques, yields reproducible estimates of kidney size and the proportion of
renal parenchyma occupied by cysts.  MRI may also have the advantage of
permitting simultaneous estimation of GFR.  Ultrasound has the advantage of being
more cost-effective and perhaps more acceptable to patients for repetitive
studies, but the measurements may be less accurate and reproducible. 
Nonetheless, there is very limited experience in applying these techniques to
follow progression of the renal disease. Development of improved, reproducible
imaging methods, which assess cyst growth and provide markers of disease
progression could markedly improve the feasibility of clinical trials.

B. Research Goals and Scope

It is the intent of this solicitation to invite applications from investigators
with diverse scientific interests who wish to apply their expertise into the
development and testing of accurate and reproducible imaging techniques to
monitor progression of both dominant (ADPKD) and recessive (ARPKD) PKD.  It is
the overall goal of this solicitation to develop methods that would facilitate
shortening the observation period necessary to determine efficacy of treatment
interventions in PKD patients.  The specific goals of this solicitation are to
be able to (1) quantify cyst growth and ascertain severity of renal parenchymal
involvement by sequential measurement of total kidney volume and the ratio of
intact parenchyma to renal parenchyma occupied by cysts over time,  (2) establish
useful clinical correlations of imaging data with other markers of disease
progression, (3) identify and test other potential markers or indices of disease
progression, e.g., assessment of loss of heterozygosity of renal cells shed in
the urine, or other markers, in cohorts of patients with PKD, and (4) gain
information about the cost-effectiveness, patient acceptability,  and advantages
and disadvantages of different imaging techniques used serially in patients with
PKD.

It is anticipated that the study will take place in two to three PCCs over a
period of five years.  It is envisioned that the PCCs will need to study a total
of approximately 100-200 well-characterized participants, depending on the power
analysis calculations arrived at during the Planning Phase of the study.

The data collection activities of the PCCs will be supported by a single DCIAC.

C.  Study Design

It is anticipated that over the five-year period several cohorts of patients, at
different stages of disease, and with varying rates of disease progression, will
be studied in interrelated investigations. The individual PCCs and the DCIAC
participating in the cooperative study should conduct mutually agreed upon
protocols.

The design of the final research protocols for implementation, including the
eligibility criteria for the final study populations and the studies to be
undertaken, will be effected by the Steering and Planning Committee, based on
protocols submitted by the PCCs and the DCIAC, and approved by the Initial Review
Group during the review process.

Study Components

1.  Participating Clinical Centers (PCCs)

A PCC is an institution that is actively involved in the recruitment, evaluation,
and follow-up of PKD patients as appropriate study subjects.  It should consist
of an interdisciplinary team of clinical investigators and appropriate personnel,
such as a research coordinator and clerical staff.

2. Data Coordinating and Imaging Analysis Center (DCIAC)

The DCIAC will have primary responsibility for proposing the development of the
initial study protocols for the imaging studies, and will be responsible for the
collection and analysis of the clinical and imaging data. The DCIAC will also
have primary responsibility for establishing standardization of the imaging data,
for collecting, editing, storing, and analyzing data generated by the PCCs, and
for establishing and implementing data auditing and quality control procedures
for each aspect of the study. The DCIAC should establish a core facility for
clinical specimen handling and analyses. The DCIAC will provide realistic
estimates of the power of the imaging studies to predict progression.  Sub-
contracting of various aspects of the DCIAC to other institutions with special
expertise, i.e., expertise in imaging techniques and software development to be
applied to the study, may be included in the application.  The DCIAC should be
prepared to assume a key role in overseeing implementation and adherence to the
study protocol, and assuring quality control of the data collected.  The DCIAC
will be expected to provide appropriate biostatistical expertise, as well as data
management and coordination expertise.  The DCIAC also will be expected to
generate appropriately detailed reports to the Steering and Planning Committee
and to the External Advisory Committee at regular intervals, and will be
responsible for the logistics and planning of the meeting of these committees and
their subcommittees.

3.  Steering and Planning Committee

The primary governing body of the study will be the Steering and Planning
Committee, which will be comprised of each of the Principal Investigators of the
PCCs and the DCIAC, the Chairperson of the Steering and Planning Committee, and
the NIDDK Project Coordinator (described in detail under Terms and Conditions). 
Each of the members will have one vote.

4.  External Advisory Committee

An independent committee supported by the NIDDK and composed of experts in
nephrology, biostatistics, radiology, 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).  This
Committee will also be responsible for reviewing the acceptability of initial
data-quality monitoring plans established by the Steering and Planning Committee
and the subsequent monitoring of data quality by means of reports prepared by the
DCIAC.

5.  Project Coordinator

The NIDDK will appoint a Project Coordinator, within the Division of Kidney,
Urologic and Hematologic Diseases, to assist the Steering and Planning Committee
and External Advisory Committee in carrying out the study (described in detail
under Terms and Conditions).  The Project Coordinator will provide scientific
support to awardees" activities, including protocol development, quality control,
interim data monitoring, final data analysis and interpretation, preparation of
publications, and overall performance monitoring.

6.  Study Phases

It is anticipated that the studies comprising the work of this RFA will be
implemented in three phases over a five-year period.  There may be some overlap
in functions within each of the proposed phases, and the time estimates are only
approximations.  The purpose of the phases is to provide broad guidelines of the
total scope of work to be accomplished for this RFA.

Phase I: Development of the study infrastructure, completion of the study
protocol(s), and development of the Manual of Operations.  This phase should take
approximately 6 (six) months.

The first six months of the study will be devoted to finalizing the study
protocol, establishing the clinical studies infrastructure and committees"
structure. Goals for the Steering and Planning Committee will be to finalize the
study protocol, including to determine patient eligibility criteria and define
outcome criteria, train staff in procedures, help set up data acquisition and
consent forms, define terms and outcome measures, and develop a manual of
operations, questionnaires, and procedures for quality control.

The DCIAC will play a key role in the logistics for the planning and development
stage. It is anticipated that in the application, criteria for standardization
of the instrumentation and data collection for the radiologic and clinical
studies to be performed will be outlined.  In addition to assisting the PCCs in
finalizing the study protocols, the DCIAC will establish the data acquisition,
transfer, and management system, develop procedures for quality control,
training, and certification, develop and produce a Manual of Operations, and take
the lead in insuring the orderly collection and transmission of data for the
clinical and imaging studies.

Phase II: Patient recruitment, protocol implementation and further protocol
refinement.  This phase should take approximately 48 (forty-eight) months.  An
interim analysis of the statistical power of the study should be prepared by the
end of the second year.

In Phase II, the DCIAC will have full responsibility for data management, storing
of data, providing interim analyses as needed, for implementing training of
pertinent PCC staff, and for implementing data auditing and quality control
procedures.  The DCIAC will also support the PCCs with the central processing and
analysis of imaging, laboratory and clinical data.  The DCIAC will assist with
randomization procedures and formulation of strategies to enhance patient
recruitment, and it will assist with the overall protocol implementation and
refinement, as necessary. The PCCs will have full responsibility for identifying,
recruiting and enrolling the necessary number of study participants to meet the
study goals and bring the study to completion.  The PCCs will collect and
transmit imaging and clinical data, pursuing study participant follow-up
schedules and procedures as delineated in the Manual of Operation.

Phase III: Data analysis and reporting of study findings.  This phase should take
approximately six months.

After the last patients in the studies have completed the follow-up measurements,
the PCCs will review the data and assist the DCIAC in the close-out of the study.
The DCIAC will continue with its activities in data management, editing, and data
analysis. The DCIAC jointly with the PCCs will also generate a special report
with realistic estimates of the power of the imaging studies and other identified
indices to predict progression of renal dysfunction, on which the feasibility of
planning intervention studies will be based.  It will support manuscript
preparation through data analysis, statistical consultation, editorial tasks, and
coordination of meetings.

SPECIAL REQUIREMENTS

Terms and Conditions of Award

The following terms and conditions will be incorporated into the award statement
and provided to each Principal Investigator as well as to the institutional
officials at the time of the award.  These terms are in addition to, not in lieu
of, otherwise applicable Office of Management and Budget (OMB) administrative
guidelines, HHS Grant Administration Regulations at 45 CFR Part 74 and 92, and
other DHHS, and NIH Grants Administration policy statements.

The administrative and funding instrument used for this program is the
cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH scientific and/or programmatic
involvement with the grantee is anticipated during the performance of the
activity.  Under the cooperative agreement, the NIH purpose is to support and/or
stimulate the recipient"s activity by involvement in and otherwise working
jointly with the award recipient in a partner role, but it is not to assume
direction, prime responsibility, or a dominant role in the activity.  Consistent
with the cooperative agreement concept, the dominant role and prime
responsibility for the planned activity resides with the awardees for the project
as a whole, although specific tasks and activities in carrying out the activity
will be shared among the awardees and the NIDDK Project Coordinator.

A.  Awardee Rights and Responsibilities

Awardees will have substantial and lead responsibilities in all tasks and
activities.  These include protocol development, patient recruitment and follow-
up, data collection, quality control, final data analysis and interpretation, and
preparation of reports and publications. The awardee will comply with the terms
of the agreement, will work cooperatively with the other PCCs and the DCIAC and
agrees to follow the common protocol and Manual of Operations developed and
finally approved by the Steering Committee.  The awardee will also agree to
transmit all study data to a central DCIAC for combination and analysis. Awardees
will retain custody of and have primary rights to their data developed under
these awards, subject to Government (e.g., NIDDK, NIH) rights or access
consistent with current HHS and NIH policies.

B.  NIDDK Staff Responsibilities

The NIDDK will name a Project Coordinator from within the Division of Kidney,
Urologic and Hematologic Diseases whose function will be to assist the Steering
and Planning Committee and External Advisory Committee in carrying out the study. 
The Project Coordinator will be a voting member of all key study group
subcommittees and will serve as Ex Officio Executive Secretary of the External
Advisory Committee.  The Project Coordinator will have substantial scientific
programmatic involvement in the overall management of the study, in protocol
development, quality control, interim data analysis, safety monitoring, and final
data analysis and interpretation, preparation of publications, and coordination
and performance monitoring.  The dominant role and prime responsibility for these
activities resides with the awardees for the project as a whole, although
specific tasks and activities in carrying out the studies will be shared among
the awardees and the NIDDK Project Coordinator.

The NIDDK Project Coordinator will have voting membership on the Steering and
Planning Committee.

The NIDDK reserves the right to terminate or curtail the study (or an individual
award) in the event of substantial shortfall in participant recruitment, follow-
up, data reporting, quality control, or other major breach of the protocol, if
a major study endpoint is reached substantially before schedule with persuasive
statistical significance or if human subject ethical issues dictate a premature
termination.

C. Collaborative Responsibilities

A Steering and Planning Committee, composed of the Principal Investigators of
each PCC, the Principal Investigator of the DCIAC, and the NIDDK Project
Coordinator will be the main governing board of the study and will have primary
responsibility for developing final common study designs, protocols, and manuals,
facilitating the conduct and monitoring of studies, and reporting study results. 
Each Principal Investigator from a PCC and the DCIAC as well as the NIDDK Project
Coordinator, will have one vote.  The Chairperson, who will be someone other than
an NIDDK staff member, will be selected by the Steering and Planning Committee.

Subcommittees will be established by the Steering and Planning Committee, as it
deems appropriate, the Project Coordinator will serve on subcommittees as he/she
deems appropriate.

The collaborative protocols will be developed by the Steering and Planning
Committee.  Data and laboratory specimens, as determined, will be submitted to
the central DCIAC.  Protocols will be determined to define 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 NIDDK.

Awardees will be required to accept and implement the common protocol(s) and
procedures approved by the Steering and Planning Committee.

D.  Arbitration

Any disagreement that may arise on scientific/programmatic matters (within the
scope of the award) between recipients and the NIDDK may be brought to
arbitration.  An arbitration panel will be composed of three members - one
selected by the Steering and Planning Committee (with the NIDDK member not
voting) or by the individual awardee in the event of an individual disagreement,
a second member selected by NIDDK, and the third member selected by the two prior
selected members. This special arbitration procedure in no way affects the
awardee"s right to appeal an adverse action that is otherwise appealable in
accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS
regulation at 45 CFR Part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
sub-populations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research" which have been published in the Federal Register of March 28, 1994 (FR
59 14508-14513), and in the NIH Guide for Grants and Contracts of March 18, 1994,
Volume 23, Number 11, available at the web at:
https://grants.nih.gov/grants/guide/notice-files/not94-105.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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

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

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

LETTER OF INTENT

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

The letter of intent is to be sent to the Program Staff listed under INQUIRIES
by the letter of intent receipt date listed in the heading of this RFA.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants. Application kits are available at most institutional offices
of sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email:
[email protected].

The RFA label in the form PHS 398 must be affixed to the bottom of the face page. 
Failure to use this label could result in delayed processing of the application
such that it may not reach the review committee in time for review.  For purposes
of identification and processing, item 2 of the face page of the application must
be marked "YES" and the RFA number and title, "Polycystic Kidney Diseases:
Innovative Imaging to Assess Progression" must be typed in.

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

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

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

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes, Digestive, and Kidney Diseases
45 Center Drive, Room 6AS-37F MSC 6600
Bethesda, MD 20892-6600

Applications must be received by the application receipt date listed in the
heading of this RFA.  If an application is received after this date it will be
returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The CSR
will not accept any application that is essentially the same as one already
reviewed. This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an introduction
addressing the previous critique.

Information to be Included in Applications

Provision should be made for meeting the required appropriate representation of
genders, minorities and children, as required for successful accomplishment of
study goals.

Applicants for both the PCC and the DCIAC should respond with research protocols
involving multicenter participation to address the objectives of the study and
to reach the study goals. It is anticipated that applicants will develop criteria
for studying patients at high risk of progression, representing study populations
of particular interest.  Applicants should outline the rationale and background
of the proposed clinical/imaging correlative studies, study design and protocols,
eligibility criteria, and type of patients to be included in the protocols, and
baseline and outcome measures to be assessed in their applications.  For each of
the clinical protocols, the PCC applicants should discuss the characteristics and
number of potential participants that would be available from their own
geographic region.

An application for a PCC should provide evidence that the investigators are
capable of recruiting a sufficient number of participants for the proposed
studies.  Applicants for PCCs should describe the target population from which
they expect to recruit the required number of PKD patients as study participants,
and plans for recruitment of women, minorities, and children, as required.  PCCs
will be required to submit protocol data expeditiously, and to share patient data
and specimens.  The PCCs must work in concert with the DCIAC to implement
procedures for uniform data collection, handling and transmittal of data, as well
as data audits and other data quality control procedures as established by the
study protocol. The Principal Investigator and Co-Investigators in each PCC
should be skilled in collaborative clinical investigation. There should be
evidence of strong institutional support for the PCC, including adequate space
in which to conduct clinic activities and office space for staff.  An
organizational structure for the PCC 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 commonly agreed upon
protocols.

The applicant should include a succinct discussion of previous relevant research
efforts.  The applicant should also discuss in detail the recruitment strategies
to procure the expected number of study participants, and approaches to attain
high levels of adherence to the follow-up evaluations.  Specific plans for
recruitment of minority participants and children must also be discussed.

Applicants for the DCIAC should provide a detailed description of prior
experience in multicenter clinical studies.

Applications for the PCCs and the DCIAC must include year-by-year budgets that
are adequately justified.

For the PCCs, the proposed budget should include a minimum number of full-and
part-time staff to successfully carry out the proposed studies.  Typical
personnel at a PCC might include the part-time effort of a Principal
Investigator, Co-Investigator, and a designated Radiology Technician, and the
full time effort of a Study Coordinator and a Data Entry Clerk.  It is
anticipated that the standardization of radiologic techniques may require
designated personnel and uniform training.  The budget should include support for
travel for up to two key study personnel to attend monthly Steering and Planning
Committee Meetings during Phase I, quarterly meetings during Phase II, and bi-
monthly meetings during Phase III of the study. Steering and Planning Committee
Meetings will be held in the Washington, D.C., area.  The budget should also
include travel support for the Principal Investigator to attend the External
Advisory Committee Meetings to be held at the completion of Phase I, one meeting
per year during Phase II, and one meeting at the completion of Phase III of the
study.  Travel for centralized training of the study coordinator, radiology
technician and data entry clerk must also be budgeted (assume central training
to be held in the Washington, D.C., area, annually during years 1 and 2).

For applications for the DCIAC, the proposed budget should include the time and
effort of a Principal Investigator and Co-Investigator, Radiology Core Co-
Investigator, and key personnel needed to conduct the studies.  A required number
of and cost of computers to be used at the PCCs for distributed data entry should
also be included in the proposed budget. The proposed budget should include the
costs of transport of clinical specimens for central processing and analysis, and
subcontracting costs for necessary imaging assistance and software development. 
The budget should include support for travel for three to four investigators to
attend monthly Steering and Planning Committee Meetings during Phase I, quarterly
meetings during Phase II, and bi-monthly meetings during Phase III of the study. 
Meetings of the Steering and Planning Committee will be held in the Washington
D.C. area.  The budget should include costs to travel to Washington, D.C. for
External Advisory Committee Meetings.  Meetings of the External Advisory
Committee will be held at the completion of Phase I, one meeting per year during
Phase II, and one final meeting at the completion of Phase III of the study. 
Travel of the members of the External Advisory Committee to the DCIAC for
monitoring visits (one visit for years 2-5) should also be included in the
budget.  The DCIAC should also budget for travel for the Chairperson of the
Steering and Planning Committee to attend monthly meetings during Phase I,
quarterly meetings during Phase II, and bi-monthly meetings during Phase III of
the study.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIDDK. Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the NIDDK in accordance with the review criteria stated below.  As part of the
initial merit review, a process will be used by the initial review group in which
applications receive a written critique and undergo a process in which only those
applications deemed to have the highest scientific merit, generally the top half
of the applications under review, will be discussed, assigned a priority score,
and receive a second level review by the NIDDK National Advisory Council.

In addition to the scientific and technical merit, all applications will be
judged on the documented ability of the investigators to meet the research
objectives of the RFA, including for PCCs, the availability of study
participants, the ability to recruit minority participants and children, and the
geographic location, which will be part of the evaluation criteria.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written comments, reviewers will be asked to discuss the following aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in assigning the overall score and will be weighed
as appropriate for each application.  Note that the application does not need to
be strong in all categories to be judged likely to have major scientific impact
and thus deserve a high priority score.  For example, an investigator may propose
to carry out important work that by its nature is not innovative but is essential
to move the field forward.

(1) Significance:  Does this study address an important problem?  If the aims of
the application are achieved, how will scientific knowledge be advance?  What
will be the effect of these studies on the concepts or methods that drive this
field?

(2) Approach:  Are the conceptual framework, design methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

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

(4) Investigator:  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

In addition to the above criteria, in accordance with NIH policy, all
applications for a DCIAC and PCCs will also be reviewed with respect to the
following:

o  The adequacy of plans to include both genders, minorities and their sub-
groups, and children, as appropriate for the scientific goals of the research.

o  Plans for recruitment and retention of study participants.

o  The reasonableness of the proposed research.

The initial review group will also examine the provisions for the protection of
human subjects and the safety of the research environment.

Applicants are encouraged to submit and describe their own ideas about how best
to meet the goals of the cooperative study and their specific protocols. The
evaluation of applications for PCCs and the DCIAC will be based primarily on the
scientific merit of the proposed studies, as defined above. In addition,
scientific/technical merit criteria specific to the objectives of the RFA to be
used in the review, will be as follows:

For both Participating Clinical Centers and the Data Coordinating and Imaging
Analysis Center:

1.  The scientific merit of the proposed approach to study design(s) to address
the objectives of the RFA.

Understanding and awareness of the scientific, ethical, and practical issues
underlying the proposed trials and appropriateness of plans to deal with them.

3.  Demonstrable knowledge of the potential problems associated with the conduct
of this study and possible solutions must be demonstrated.

Adequacy of the facilities and space.

5.  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.

6.  Willingness to work cooperatively and carry out a commonly agreed upon study
protocol.

For Participating Clinical Centers:

1.  Documentation of the specific competence and previous experience of
professional, technical, and administrative staff pertinent to the operation of
a Clinical Center in previous collaborative clinical investigations, familiarity
with and experience in recruiting participants in a study, handling laboratory
specimens, working in collaboration with other investigators under a common
protocol, ability to implement study procedures, and meticulous and expeditious
handling of study data.

2.  Documentation of access to patient population(s) from which a substantial
number of clinical trial participants can be recruited in sufficient numbers to
meet the goals specified in the RFA.

3.  Ability to recruit representative minority populations and children, as
required.

4. Adequacy of plans to ensure accurate collection and timely transmission of
study data.

For the Data Coordinating and Imaging Analysis Center:

1.  The scientific merit of the proposed approach to data collection and
management of the studies as outlined in the RFA.

2.  Documentation of the specific competence and individual experience of
professional, technical, and administrative staff pertinent to both the imaging
and biostatistics and data coordination aspects for the proposed study.  Prior
experience in similar studies, in the collection of data and patient specimens
from multiple locations, as well as experience in monitoring the quality and
timeliness of such data, should be demonstrated.

3.  Suitability of proposed data management and data analysis plans.

4.  Ability to design, implement and maintain a distributed data entry system for
the PCCs.

5.  The approach to and likelihood of soliciting cooperation from the
participating PCCs and of exercising appropriate leadership in matters of study
design and protocol revisions, and data acquisition, management, and analysis. 
Specific plans for ensuring standardization of imaging data and quality control
of data collection across all study sites are required.

6.  The adequacy of the proposed technical hardware.

7.  The organizational and administrative structure of the proposed program.

SCHEDULE

Letter of Intent Receipt Date:  February 10, 1999
Application Receipt Date:       March 10, 1999
Special Review Committee:       June-July 1999
NDDK Advisory Council:          September 8-9, 1999
Anticipated Award Date:         September 30, 1999

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 (as determined by peer review), programmatic priorities,  (c)
program balance, including in this instance sufficient compatibility of features
to make a successful collaborative program a reasonable likelihood, (d)
availability of funds, (e) appropriate minority and children representation in
the trial, as required, and (f) geographic balance among clinical centers.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.  Direct inquiries
regarding programmatic issues to:

Gladys Hirschman M.D., or Paul L. Kimmel, M.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-13, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  [email protected]
Email:  [email protected]

Direct inquiries regarding fiscal and administrative matters to:

Aretina Perry-Jones
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-38B, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8862
FAX:  (301) 480-3504
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No
93.849.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC 241
and 285) and administered under PHS grants policies and Federal Regulations 42
CFR 52 and 45 CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency review.

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

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