Full Text DK-92-18

TREATMENT OF BENIGN PROSTATIC HYPERPLASIA:  PILOT STUDY

NIH GUIDE, Volume 21, Number 16, May 1, 1992

RFA:  DK-92-18

P.T. 34

Keywords: 
  Hyperplasia 
  Urogenital System 
  Clinical Trial 
  Data Management/Analysis+ 
  Chemotherapeutic Agents 


National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  June 2, 1992
Application Receipt Date:  June 17, 1992

PURPOSE

The Division of Kidney, Urologic and Hematologic Diseases (DKUHD)
invites cooperative agreement applications for investigators to design
and implement a pilot study trial to assess the feasibility of
conducting a full-scale multicenter randomized clinical trial to
evaluate the effects of drug treatment on the progression of and
symptoms due to benign prostatic hyperplasia (BPH).

The assistance mechanism used to support the study is the cooperative
agreement, which is similar to the traditional NIH research grant.  It
differs from a research grant in the extent and nature of NIDDK staff
involvement.  A center selected as a Clinical Center also may serve as
the Data Coordinating Center and/or the Diagnostic Center; however,
separate applications would be required for each of these study
components.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Treatment of Benign Prostatic Hyperplasia:
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 Number 017-001-00474-0) or "Healthy
People 2000" (Summary Report:  Stock Number 017-001-00473-1) through
the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Domestic universities, medical colleges, hospitals, and other public
and private research institutions, including State and local government
units, are eligible.  Applications from minority investigators and
women are especially encouraged.  Applications from foreign
institutions will not be considered since only a small number of
centers will be selected to participate in this pilot program.

The expertise appropriate for this research program includes a
knowledge of the clinical and epidemiological aspects of urologic
diseases and experience in the design and conduct of collaborative
clinical trials. Experience in recruitment and follow-up of a large
number of patients with urologic diseases in clinical trials as well as
clinical experience with a large number of patients with benign
prostatic hyperplasia, is especially useful for Clinical Centers.
Skills in data base management, biostatistics, and development of
clinical trial study design are appropriate for the Data Coordinating
Center.  For the Diagnostic Center, experience in collection, storage,
and pathological diagnosis of prostate biopsy specimens is helpful.  In
addition, expertise in use of serum markers (e.g., prostate specific
antigen, prostate specific acid phosphatase) to evaluate prostate
growth and activity and interpretation of radiological studies for
evaluation of prostate size and pathology is necessary.

An institution may apply to be a Clinical Center, the Data Coordinating
Center, and/or the Diagnostic Center.  However, a specific plan is
required within the applications for how the independent operation
(i.e., confidentiality of study-wide data) of each unit will be
maintained.  Collaboration among institutions to carry out the study is
encouraged.  Institutions wishing to collaborate and function as a
single Clinical Center are required to submit one application.

MECHANISM OF SUPPORT

The administrative and funding mechanism will be the cooperative
agreement (U01).  The cooperative agreement is an award instrument
establishing an assistance relationship between the NIH and the
recipients, in which substantial programmatic involvement is
anticipated between NIH and the recipients during performance of the
contemplated activity. Funding is expected to begin in September 1992;
total support for the project will be for 30 months.

FUNDS AVAILABLE

It is anticipated that six awards (four Clinical Centers, one Data
Coordinating Center, and one Diagnostic Center) will be made under this
RFA for a total of approximately $1,600,000 (direct and indirect costs)
during the first year.  The funding levels for the Clinical Centers
will be approximately $200,000 in total costs per center annually, and
the Data Coordinating Center will be funded at approximately $300,000
in total costs per year.  The Diagnostic Center will be funded at
approximately $500,000 in total costs per year.

RESEARCH OBJECTIVES

Background

Benign Prostatic Hyperplasia (BPH) is an abnormal, localized,
enlargement of the prostate gland of adult men. This enlargement is
known to occur in men in early adulthood, but it remains asymptomatic
for many decades. The symptoms of BPH vary among the affected men; they
range from symptoms of bladder outlet obstruction (e.g., decreased
urinary stream and hesitancy in starting stream) to irritative bladder
symptoms (e.g., increased frequency of urination during both day and
night) or a combination of both types of symptoms.  Although
enlargement of the prostate gland may be detected through routine
physical examination, there is at the present time no way to determine
who will develop symptomatic BPH, at what rate the prostate is
enlarging, or which constellation of symptoms will occur.  Although BPH
frequently occurs concurrently with chronic abacterial prostatitis and
prostate cancer, the interrelationship between these diseases has not
been demonstrated.

The current standard for management of BPH is surgical removal of the
enlarged portion of the prostate gland using an instrument inserted
through the urethra of the penis.  This procedure is called
transurethral resection of the prostate.  Costs for treatment of this
disorder exceed five billion dollars annually.  The continually rising
costs for this procedure, coupled with the desire to avoid surgery if
at all possible, has prompted the development of pharmacological
methods for the treatment of BPH.

Two recently developed categories of drugs used for treatment of
symptomatic BPH are available; one is an blocker of alpha-1
adrenoceptors and the other is an inhibitor of 5-alpha-reductase.
These drugs treat different, unique, aspects of symptomatic BPH.  At
the present time, the standard of care is not to institute therapy with
these drugs until prostate growth has advanced to the point where
symptoms persist and are significant enough for the patient to request
treatment.  Concurrent with the development of these drug therapies has
been an advance in diagnostic modalities that can accurately evaluate
the extent of prostate growth and its effect on bladder function.

There are many unanswered questions about drug treatment for BPH.  For
example, it is not known at what stage of prostate growth it is best to
intervene with drug therapy to prevent irreversible bladder damage.  It
is also not known which patients are most effectively treated by a
certain type of drug, whether a combination of two different classes of
drugs will be more effective than single drug therapy, and if some
patients are solely candidates for surgical therapy.  Based on the
development of both new drug therapy and technical advances in
assessment of prostate growth, the NIDDK believes that a randomized
controlled clinical trial is necessary to define the effectiveness of
these drug therapies on the morbidity of BPH patients.

Goal of the Activity

The primary purpose of this RFA is to initiate a collaborative pilot
study of drug therapy for benign prostatic hyperplasia in order to
reduce occurrence of symptoms and slow down or halt disease
progression.  The pilot study will test the feasibility of conducting
a full-scale randomized clinical trial in an adequately sized patient
population.

The pilot study has the following six 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
operations.

2.  To determine whether or not an adequate number of patients with
appropriate study eligibility criteria can be recruited efficiently
into the study.

3.  To observe any short-term adverse effects of the study.

4.  To obtain preliminary information on the usefulness of newly
emerging diagnostic procedures using serum, urine, as well as
mechanical studies to assess disease progression.

5.  To implement procedures for and evaluate compliance to drug
therapy.

6.  To allow the study participants 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, and the Chairperson of the
Steering Committee, with assistance from the NIDDK Project Officer.
The protocol will be subject to review by an uninvolved expert group,
the External Advisory Committee.  The study will move into its
operational phase only with the concurrence of the awardees, the
External Advisory Committee, and the Institute.

Scope of the Activity

It is expected that the study will take place in four Clinical Centers
over a period of thirty months.  Each clinical center will randomize a
minimum of 25 study participants over a twelve-month period of
recruitment. The study will be in three phases:  I) a nine month period
of collaborative protocol development; II) twelve months of patient
recruitment and follow-up; and III) nine months of close-out of the
pilot phase, data analysis, and reporting of results.

Each applicant should propose the study design he or she believes most
appropriate for this project.  Applicants should provide a detailed
justification for whatever strategy is proposed for subject selection
as well as an estimate of the number of subjects in the source
population and in the final examination sample, and an estimate of the
necessary time and effort needed for recruitment.  Applicants also
should address criteria and outcome measures for the pilot study
objectives by which success of this phase of the program will be judged
for extension into the full-scale study.

Study Outline

Applicants should propose in detail within their study design,
eligibility requirements including patient age, for study
participation.  In addition, exclusion criteria should be specified.
The use of a baseline or run-in period and the follow-up schedule also
should be provided in the application.  Outcome measures should be
chosen to address the efficacy and adverse effects of drug therapy for
benign prostatic hyperplasia in the study population.  It is
anticipated that 100 participants will be required for the pilot study.
The proposed approach to evaluate the impact of drug therapy on
measures of patient morbidity should also be addressed.

All centers must be willing to implement the selection and examination
strategies developed cooperatively by the Steering Committee during
protocol development and to supply their data to the Data Coordinating
Center for combination and analysis.

Study Components

1.  Clinical Centers

A Clinical Center is an institution that is actively involved in the
recruitment, evaluation, treatment, and follow-up of study
participants.  It should consist of a small team of researchers,
including part-time effort from a Principal Investigator, a study
coordinator, and clerical staff.  Applications for Clinical Centers
should provide evidence that the center will be capable of randomizing
25 participants into the study during the twelve month period of
recruitment.  Clinical Centers should describe their experience in
recruiting and studying patients with benign prostatic hyperplasia.
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 common
protocol agreed upon in Phase I.

The applicant should include a succinct discussion of previous relevant
investigational efforts.  The applicant also should discuss in detail
the important design considerations for a clinical trial to investigate
drug therapy for benign prostatic hyperplasia, and suggest solutions to
perceived problems.  Clinical Centers will be required to submit
protocol data expeditiously.  The Principal Investigator in each
Clinical Center should be skilled in urology and collaborative clinical
investigation.

2.  Data Coordinating Center

The Data Coordinating Center will have primary responsibility for
collecting, editing, storing, and analyzing data generated by the
Clinical Centers and the Diagnostic Center.  It should be prepared to
assume a key role in protocol development, designing a distributed data
collection system, and quality control assurance.  The Data
Coordinating Center will be expected to provide appropriate
biostatistics, data management, and coordination expertise, and to make
a major contribution to the development of the study protocol and
manual of operations.  The Data Coordinating Center also will be
expected to provide appropriate detailed reports to the Steering
Committee and to the External Advisory Committee at regular intervals
and will be responsible for the logistics and planning of meetings of
these committees and their subcommittees.  The NIDDK Project
Coordinator will serve as a liaison between the Data Coordinating
Center and these committees.  Applicants for the Data Coordinating
Center should provide a detailed description of prior experience in
multicenter studies.  The applicant also should discuss in detail the
important design considerations for a clinical trial of drug therapy
for benign prostatic hyperplasia and suggest solutions to key problems.

3.  Diagnostic Center

The Diagnostic Center will have primary responsibility for collecting,
storing, analyzing serum samples and pathological tissue (including
prostate biopsy specimens) provided by the Clinical Centers.  The
Diagnostic Center also will be responsible for interpreting
radiological studies of the prostate carried out by the Clinical
Centers.  The results of all of these studies will be reported to the
Data Coordinating Center.  The Diagnostic Center, in collaboration with
the Principal Investigators of the Clinical Centers and the Data
Coordinating Center, will develop the protocol.  For any component of
the Diagnostic Center supported by a subcontract, all NIH policies and
procedures governing consortium grants must be followed.

4.  Steering Committee

A Steering Committee will be comprised of each of the Principal
Investigators of the Clinical Centers, the Principal Investigator of
the Data Coordinating Center, the Principal Investigator of the
Diagnostic 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 urology and clinical trials not
participating directly in the study.

It is anticipated that the Steering Committee will meet on a monthly
basis during protocol development (Phase I), three times in Phase II,
and two times in Phase III. Subcommittees of the Steering Committee may
be established as necessary.  The NIDDK Project Coordinator also will
be a member of these subcommittees.

5.  External Advisory Committee

An External Advisory Committee composed of experts in relevant medical,
statistical, and bioethical fields will be established to review
periodically the progress of the study, oversee participant safety,
evaluate results, and provide advice to NIDDK regarding the status of
the study.  The Chairman of the Steering Committee, the Principal
Investigator of the Data Coordinating Center, the Principal
Investigator of the Diagnostic Center, and the NIDDK Project
Coordinator may participate as ex-officio non-voting members of this
Committee.  External Advisory Committee members will be appointed by
the Director, Division of Kidney, Urologic, and Hematologic Diseases,
NIDDK in consultation with Steering Committee members.

6.  Project Coordinator

The NIDDK will name the Urology 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 performance monitoring.

Study Phases

This Pilot Study is envisioned as involving four Clinical Centers, one
Data Coordinating Center, and one Diagnostic Center, and lasting for a
period of thirty months.

The entire Pilot Study will consist of three sequential phases as
follows:

Phase I    Protocol development (9 months)

Phase II   Sample recruitment and data collection (12 months)

Phase III  Study close-out and data analysis (9 months)

The protocol development phase (Phase I) will be nine months long.
After the protocol is completed, it will be reviewed by the External
Advisory Committee.  Progression to Phase II is dependent on the
favorable recommendation of the protocol by the External Advisory
Committee, and the concurrence of the NIDDK.  At the end of the
nine-month period of Phase I, the Data Coordinating Center should be
ready to implement data collection and quality control systems.  The
Diagnostic Center also should be ready to implement procedures for
sample receipt, processing, and analysis.

The protocol for the Pilot Study will be implemented in Phase II.  It
is anticipated that four Clinical Centers will recruit and randomize
participants, and collect the outcome data specified in the protocol,
and provide data to the Data Coordinating Center.  At that time,
Clinical Centers also will be responsible for collecting and shipping
patients samples to the Diagnostic Center.  The Data Coordinating
Center will receive, process and analyze the data and provide reports
to the Steering Committee which will be responsible for monitoring the
progress of the Pilot Study.  The Diagnostic Center will analyze tissue
and serum samples and interpret radiological studies provided by the
Clinical Centers.  The Diagnostic Center will report test results to
the Data Coordinating Center.

The final phase (Phase III) of the Pilot Study will be for close-out of
Clinical Center activities, final data analysis, and reporting of
results.  Phase III will be for a period of nine months.

It is anticipated that the long-range operational plan of the entire
study, including the Pilot Study, will consist of five sequential
phases as follows:

Phase I    Development of Pilot Study Protocol (9 months)

Phase II   Conduct of Pilot Study (12 months)

Phase III  Close-out and Analysis of Pilot Study Data (9 months)

Phase IV   Conduct of Full-Scale Cooperative Clinical Trial (72 months)

Phase V    Data Analysis and Reporting of Results of the Full-Scale
Study (12 months)

Based upon meeting the goals and objectives of the Pilot Study and a
recommendation from the External Advisory Committee, the NIDDK will
issue a separate Request for Applications for Clinical Centers to
participate in the Full-Scale Study in order to provide a sufficient
recruitment base.  RFAs will also be issued for one Data Coordinating
Center and one Diagnostic Center.  Existing Centers in the Pilot Study
also will have to re-compete if they wish to participate in the
Full-Scale Study.  It is not anticipated that there will be a hiatus
between the pilot and full-scale phases.  The clinical centers will
terminate data collection at the end of Phase II and, as they enter the
Analysis Phase (Phase III), the RFA for the Full Scale Trial will be
issued.  Centers for the Full-Scale trial will be awarded prior at the
termination of Phase III.  It is also anticipated that the Full-Scale
Study will be supported by cooperative agreements.

Budget Preparation by Study Phase

Each applicant for a Clinical Center, the Data Coordinating Center, and
the Diagnostic Center should submit adequately justified budgets for
the entire anticipated project period of thirty 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.  Applicants should prepare individual budgets for
the following time periods.  The 01 budget period of the award will be
for a nine month period, September 30, 1992 through June 30, 1993.
This budget period will be for protocol development (Phase I).  The
second budget period (Phase II) will be for twelve months; July 1, 1993
through June 30, 1994.  Activities in the second budget period will
include recruitment, randomization, treatment, and clinical assessment
of randomized study participants.  The third budget period (Phase III)
will be for nine months; July 1, 1994 through March 31, 1995.  This
budget period will be concerned with study close-out, analysis of Pilot
Study 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 meetings in Bethesda, Maryland during
Phase I, three evenly spaced meetings during Phase II, and two meetings
in Phase III.

For Data Coordinating Center applications, the estimate also should
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 should be detailed in the application.  Data
Coordinating Center and Diagnostic 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 estimate also
should include time and effort of key personnel for the Diagnostic
Center required to write the diagnostic protocol and manual of
procedures.

Detailed budget estimates for Phase II and III should be based on the
applicant's proposed plan.  Budgets for both Phases II and III may be
modified based on the final protocol developed during Phase I.

SPECIAL REQUIREMENTS

The tasks or activities in which awardees will have substantial and
lead responsibilities include protocol development, patient recruitment
and follow-up, data, and patient sample collection, quality control,
final data analysis and interpretation, preparation of publications,
and collaboration with other awardees.  The NIDDK Project Coordinator
will assist in protocol development, quality control, interim data and
safety monitoring, final data analysis and interpretation, preparation
of publications, and performance monitoring.

Terms and Conditions

The following will be presented in the Notice of Grant Award as terms
and conditions of the award:  The NIDDK reserves the right to terminate
or curtail the study (or an individual award) in the event of a
substantial shortfall in subject recruitment or retention or:  (a) a
major breach of 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.  The criteria
for these shortfalls, breaches, or human subject ethical issues will be
established by the Steering Committee with the assistance of the
Project Coordinator.

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 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
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.

The NIDDK may not use the Pilot Study data in any manner without
explicit approval of the awardee investigators. The individual awardees
have custody and primary rights to their individual data as consistent
with OER 90-7.

The policy source for the award of applications can be found in the
Grants Policy Statement , DHHS Publication No. (OASH) 90-50,000 (Rev.)
October 1, 1991.  Manual 4815 F3f advises specific RFA requirements
regarding the special terms and conditions for this award.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF MINORITIES AND WOMEN IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH and ADAMHA policy is that applications 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.  Since
women do not have prostate glands they are automatically excluded from
the scope of this study.  However, if 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 racial/ethnic group, together with a rationale for its choice.
In  addition, 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 Sections 1-4 of the Research Plan AND summarized in
Section 5, Human Subjects.  Applicants are urged to assess carefully
the feasibility of including the broadest possible representation of
minority groups.  However, 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 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
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.

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 other 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 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 are to be received no later than June 2, 1992, and
are to be addressed to:

Dr. Robert D. Hammond
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 496-7083
FAX:  (301) 402-1277

Technical Assistance Seminar

A special technical assistance seminar will be offered to assist
potential applicants who have limited experience with the NIH
application process or who wish further clarification of the
cooperative agreement application process.  The NIH cannot support
individuals who wish to attend the conference but it will be open to
any individual who wishes to attend.  This meeting will be held
approximately May 22 at the NIH, Bethesda, MD.  for specific details,
contact the Program Director listed under INQUIRIES.

APPLICATION PROCEDURES

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the 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 must be included with the
application.

Submit applications on form PHS 398 (rev. 9/91), 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:

Office of Grants Inquiries
Division of Research Grants
National Institutes of Health
Westwood Building, Room 449
Bethesda, MD  20892
Telephone:  (301) 496-7441

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 2a of page 1 of the
application and enter the title  "Treatment of Benign Prostatic
Hyperplasia:  Pilot Study" and enter the RFA number DK-92-18 in the
space provided.  Groups of investigators wishing to apply as a Clinical
Center, and/or the Data Coordinating Center, and/or the Diagnostic
Center must submit separate applications.

THE RFA LABEL FOUND IN THE FORM PHS 398 APPLICATION KIT MUST BE AFFIXED
TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL COMPLETED APPLICATION
FORM.  FAILURE TO USE THIS LABEL COULD RESULT IN DELAYED PROCESSING OF
THE APPLICATION SUCH THAT IT MAY NOT REACH THE REVIEW COMMITTEE IN TIME
FOR REVIEW.

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:

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 June 17, 1992.  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 unresponsive, the applicant will be contacted and
given the opportunity to withdraw the application or have it considered
for the unsolicited NIH grant program.

If the number of applications is large compared to the number of awards
to be made, the NIDDK will conduct a preliminary scientific peer review
and 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.

If the application submitted in response to this RFA is substantially
similar to a grant application already submitted to the NIH for review,
but has not yet been reviewed, the applicant will be asked to withdraw
either the pending application or the new one.  Simultaneous submission
of identical applications will not be allowed, nor will essentially
identical applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this RFA
that is essentially identical to one that has already been reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.

Review Criteria

Specific criteria for review of applications will be as follows.

For Clinical Centers:

o  The scientific merit of the proposed study design to address the
objectives of the RFA.  This includes diagnostic criteria for patient
selection, plans for recruitment of patients, proposed data and patient
sample collection during follow-up, proposed diagnostic and therapeutic
modalities, and techniques for monitoring and maintaining continued
contact with patients during the course of the study.

o  Documentation of the specific competence and previous experience of
professional, technical, and administrative staff pertinent to the
operation of a Clinical Center in the proposed study.  Evaluation
criteria will include the following:  familiarity with and experience
in recruiting urological patients in a randomized trial or other
clinical studies; working in collaboration with other investigators
under a common protocol; and careful and expeditious handling of study
data.

o  Documentation of a well-established practice and experience in the
treatment of persons with benign prostatic hyperplasia and other
prostate disorders.  This includes documentation of a sufficient
patient population from which to recruit in order to meet the
individual Clinical Center goal for number of randomized study
participants.

o  Understanding and awareness of the scientific, ethical, and
practical issues underlying the proposed study and appropriateness of
plans to address them.

o  Appropriateness of the budget for the work proposed.

o  Adequacy of the proposed facility and space.

o  Evidence of the degree of institutional commitment and support for
the proposed program.

o  A willingness to work cooperatively with other centers in a manner
summarized in the RFA.

For the Data Coordinating Center:

o  The scientific merit of the proposed approach to study design, data
collection and management, and intervention as outlined in the RFA.

o.  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 and available on-site medical consultation in urology and the
amount of time these professionals will devote to the project.  Prior
experience in the collection of data from multiple clinical sites and
experience in monitoring the quality and timeliness of such data must
be demonstrated.

o  The approach to and likelihood of soliciting cooperation from the
participating Clinical Centers and exercising appropriate leadership in
matters of study design, data acquisition, data management, and data
analysis.

o  Suitability of the proposed data management and data analysis plans.

o  Suitability of proposed plans for receiving results from the
Diagnostic Center and reporting of these data to the Clinical Centers.

o  Appropriateness of the budget for the proposed work.

o  The adequacy of the proposed facility, technical hardware, and
space.

o  The organizational and administrative structure of the proposed
program.

o  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.

For the Diagnostic Center:

o  The scientific merit of the proposed approach to study design and
patient sample testing and diagnostic studies as outlined in the RFA.

o  Documentation of the specific competence and previous experience of
professional, technical, and administrative staff pertinent to the
operation of a Diagnostic Center for a collaborative clinical trial.
This includes pathological interpretation of prostate tissue specimens,
monitoring prostate growth by such tests as prostate specific antigen
and prostate specific acid phosphatase, and evaluation of imaging
studies of the prostate.

o  Suitability of proposed plans for collection and testing of patient
samples and evaluation of diagnostic tests carried out by the Clinical
Centers.

o  Appropriateness of the budget for the work proposed.

o  The adequacy of the proposed facility, technical hardware, and
space.

o  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.

o  Evidence of willingness to work cooperatively with other centers in
the manner summarized in the RFA.

AWARD CRITERIA

The anticipated date of award is September 30, 1992.  Applications will
compete for available funds with all other approved applications
submitted in response to this RFA.  The following will be considered in
making funding decisions:

o  Quality of the proposed work as determined by peer review.

o  Availability of funds

o  Program balance among all applications considered for funding under
this RFA.

Timetable

Letter of Intent Receipt Date:          June 2, 1992
Application Receipt Date:               June 17, 1992
Initial Review:                         July/August 1992
Review by the NDDKD Advisory Council:   September 1992
Anticipated Award Date:                 September 1992

INQUIRIES

Inquiries regarding this announcement may directed to:

Leroy M. Nyberg, Jr., Ph.D., M.D.
Director, Urology Program
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A05
5333 Westbard Avenue
Bethesda, MD  20892
Telephone:  (301) 496-7133
FAX:  (301) 402-0223

For fiscal and administrative matters, contact:

Nancy Dixon
Supervisory Grants Management Specialist
Grants Management Branch, DEA
National Institutes of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649B
Bethesda, MD  20892
Telephone:  (301) 496-7467

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.849, Kidney, Urologic and Hematologic Diseases Research.  Awards
will be made under the authority of the Public Health Service Act,
Title III, Section 301 (Public Law 78-4110, as amended:  42 USC 241)
and administered under PHS Grants Policies and Federal Regulations 42
CFR Part 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

.

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