Full Text DK-94-018

MEDICAL THERAPY IN BENIGN PROSTATIC HYPERPLASIA:  FULL-SCALE TRIAL

NIH GUIDE, Volume 23, Number 22, June 10, 1994

RFA:  DK-94-018

P.T. 34

Keywords: 
  Clinical Trial 
  Hyperplasia 
  Urogenital System 


National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  August 2, 1994
Application Receipt Date:  August 30, 1994

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 from investigators
to serve as a Clinical Center, and/or the Data Coordinating Center
and/or the Diagnostic Center for the full-scale phase of the "Trial
of Medical Therapy in Benign Prostatic Hyperplasia (BPH)."

The BPH Trial is a prospective, multicenter, randomized,
placebo-controlled, double-masked clinical trial to determine if
medical therapy (finasteride and/or doxazosin) delays or prevents the
progression of benign prostatic hyperplasia (BPH).  Patients will be
randomly assigned to receive either finasteride, doxazosin, a
combination of finasteride and doxazosin, or placebo.  The primary
outcome of the trial is time to progression of BPH as defined in the
pilot study protocol.  A sample of full-scale study participants will
have prostate biopsies performed.  The protocol for the ongoing BPH
Pilot Study provides details on inclusion and exclusion criteria,
baseline and follow-up procedures for participants, and overall
organization of the trial.  The protocol and sample size requirements
were developed by awardees under a cooperative agreement mechanism
with NIDDK assistance.  It is recommended that applicants obtain a
copy of the protocol, available upon request from DKUHD, to assist
them in preparing their response to this RFA.

Successful applicants for Clinical Centers will be eligible to apply
for a second Request for Applications, "Basic Research Studies of
Benign Prostatic Hyperplasia," which will be issued by February 28,
1995.  Funding for this solicitation will be by means of supplements
to cooperative agreements (U01).

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), "Medical Therapy of Benign Prostatic
Hypertrophy: Full-Scale Trial" 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, minority institutions and institutions that may
contribute substantial minority representation in the trial are
encouraged.

The expertise appropriate for this research program for a Clinical
Center includes a knowledge of the clinical and epidemiological
aspects of urologic diseases as well as experience in the design and
conduct of collaborative clinical trials and/or clinical
investigations.  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 management of multicenter clinical trials, establishing and
maintaining a large data base, and analysis of complex data sets are
appropriate for the Data Coordinating Center.  For the Diagnostic
Center, experience in collection, storage and pathologic diagnosis of
prostate biopsy specimens is important.  The Diagnostic Center must
also have the capabilities to measure prostate-specific antigen and
the hormones noted in the protocol.

An institution may apply to serve as a Clinical Center, the Data
Coordinating Center, and the Diagnostic 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 type of center will be required from an
institution applying to serve as a Clinical Center, and/or the Data
Coordinating Center and/or the Diagnostic 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, 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.  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 $6.9 million.  It is
anticipated that one award for a Data Coordinating Center for
approximately $650,000 (including direct and indirect costs) per year
and one award for a Diagnostic Center for approximately $650,000
(direct and indirect costs).  Fourteen awards will be made for
Clinical Centers.  Funding for any one Clinical Center will be no
more than $400,000 in total costs (direct and indirect costs) for
each year.

Awards and level of support depend on receipt of a sufficient number
of applications of high scientific merit.  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
April 1, 1995.

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 early adulthood but it remains asymptomatic for
many decades.  The age of onset of symptoms is variable.  The
symptoms vary from those characteristic of bladder outlet obstruction
(e.g. decreased force of urinary stream, hesitancy in initiating the
stream, and significant dribbling after completion of urination) to
those characteristic of bladder irritation (e.g. increased daytime
and nighttime frequency of urination, and urgency in the need to
urinate).  There is frequently 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:

1.  who will develop symptomatic BPH,

2.  at what rate the prostate is enlarging,

3.  which constellation of symptoms will occur,

4.  the relationship between prostate size and the development of
symptoms, and

5.  the interrelationship between chronic abacterial prostatitis and
prostate cancer, although BPH frequently occurs concurrently with
these diseases.

The current standard for management of BPH is by means of surgical
intervention to relieve the obstruction of the enlarged portion of
the prostate.  Costs for this surgical intervention exceed five
billion dollars annually and are increasing.  The costs for this
procedure, the complications of surgical intervention,  and an
increased understanding into the biology of prostate growth, have
prompted the development of pharmacological methods for the treatment
of the symptoms of BPH.

Currently, there are two categories of drugs that have been developed
for the treatment of the symptoms of BPH; one blocks the alpha-1
adrenoreceptors, the other inhibits the enzyme 5-alpha reductase.
Each drug category treats different, unique aspects of BPH symptoms.

There are many unanswered questions about the pharmacologic treatment
of BPH as noted below.

1.  At what stage of prostate growth or symptoms is it best to
intervene to prevent progression or to initiate regression and
cessation of symptoms?

2.  What is the relationship between the reduction in prostate size
and the regression of specific types of symptoms?

3.  Can objective diagnostic and pathological tests determine which
symptomatic patients are candidates for the various pharmacologic
therapies and which patients will not respond to medical therapy and
thus are solely candidates for surgical intervention?

4.  Does pharmacologic therapy affect the other two frequently
concurrent diseases of the prostate, chronic prostatitis and cancer?

BPH Pilot Study

In 1992 the NIDDK issued the RFA, "Treatment of Benign Prostatic
Hyperplasia:  Pilot Study."  Six Clinical Centers, one Data
Coordinating Center, and one Diagnostic Center were selected to
develop the study protocol and carry out a pilot study.  The Pilot
Study protocol was developed from October 1992 through October 1993.
Recruitment, treatment and follow-up of approximately 150 patients
began in December 1993 and will continue through November 1994.  It
is anticipated that the full-scale trial will begin April 1, 1995.

Goal of the Activity

The primary goal of this RFA is to initiate a collaborative
full-scale trial to test whether medical therapy (finasteride and/or
doxazosin) delays or prevents the progression of symptoms of BPH or
if it relieves these symptoms, and the duration of these effects.
The primary outcome will be the time to progression of BPH.  Clinical
progression is defined as the occurrence of the following in the
Pilot Study protocol; (1) acute urinary retention, (2) renal
insufficiency due to BPH, as indicated by a 50 percent increase from
baseline in serum creatinine, (3) recurrent urinary tract infections,
(4) incontinence, and (5) an increase from baseline in the American
Urological Association (AUA) symptom score index of four or more
points.

Scope of the Activity

It is estimated that 2,800 study participants, recruited by 14
clinical centers, will be required for the full-scale trial.  Thus
each Clinical Research Center is expected to randomize at least 200
study participants during an 24- month initial 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 their
applications using patient eligibility criteria set forth in the BPH
Pilot Study protocol.  Major entry and exclusion characteristics are
briefly described as follows.  The study participants in this trial
will be males of all races at least 50 years of age who have a peak
urinary flow rate at least 4 ml/second, but not greater than 15
ml/second, and the voided volume is at least 125 ml.  In addition,
the AUA symptom severity score should be greater than or equal to
eight.  Selected exclusion criteria include any prior medical or
surgical intervention for BPH, prior experimental intervention for
prostate disease, significant renal or hepatic impairment,
orthostatic hypertension, among others.

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. However, contrary to the Pilot Study Protocol, urodynamic
studies will not be conducted during the full-scale trial. It is
expected that investigators will carry out the already developed
protocol, however, modifications to this protocol beyond that noted
above are expected.

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 an interdisciplinary team of
clinical investigators and appropriate personnel, such as a research
coordinator, and clerical staff.  An application for a Clinical
Center should provide evidence that the investigators are capable of
randomizing at least 200 participants into the study during the
24-month period of recruitment.  Of the 200 randomized participants
at each Clinical Center, 40 (20%) will have prostate biopsies
performed.  Applicants for Clinical Centers should describe the
target population from which they expect to randomize the required
number of study participants.  Clinical Centers will be required to
submit protocol data expeditiously.  Clinical Centers must work in
concert with the Data Coordinating Center to implement procedures for
data audits and other data quality control procedures as established
by the study protocol.  The Principal Investigator and
Co-Investigators in each Clinical Center should be skilled in
collaborative clinical investigation.  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 intervention, and high rates of follow-up.

In order to attain the required number of randomized study
participants it is anticipated that Clinical Centers will have to
rely on referrals from individual physicians and recruit from health
maintenance organizations, physician group practices, and other
sources.  Clinical Centers may wish to consider the establishment of
procedures to follow-up study participants recruited from "satellite"
clinics and/or the sites of recruitment noted above.  However, the
technical feasibility and cost of such an approach should be clearly
described in the application.

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 of the data collected.  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.  Applicants for
the Data Coordinating Center should provide a detailed description of
prior experience in multicenter studies.

The Diagnostic Center will have primary responsibility for
collecting, storing and analyzing serum samples and pathological
tissue, including prostate biopsy specimens, provided by the Clinical
Centers.  The Diagnostic Center will also be responsible for
interpreting radiological studies of the prostate carried out by the
Clinical Centers.  The Principal Investigator of the Diagnostic
Center should be skilled in pathology or urology.  The results of all
of these studies will be reported to the Data Coordinating Center.
The results of selected studies may be transmitted directly to the
Clinical Centers for patient management.  For any component of the
Diagnostic Center supported by a subcontract, all NIH policies and
procedures governing consortium grants must be followed.

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, the Data Coordinating Center, and the Diagnostic
Center, the Chairperson of the Steering Committee, the NIDDK Urology
Program Director 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 urology, pathology, 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).  This Committee
will also be responsible for reviewing the acceptability of initial
data quality monitoring plans established by the Steering Committee
and the subsequent monitoring of data quality by means of reports
prepared by the Data Coordinating Center.

5.  Project Coordinator

The Clinical Trial 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 14 Clinical
Centers, one Data Coordinating Center and one Diagnostic 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 randomize at least 200
study participants during an initial 24-month period.  Follow-up
procedures will be carried out over a period of 48-months.  It is
important to note, however, that as participants are randomized,
intervention and follow-up will begin immediately.  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, appointed by the
Institute, will review progress at least semi-annually and provide
advice to the Institute.

Guidelines for Budget Preparation by Study Phases

Each applicant for a Clinical Center, the Data Coordinating Center or
the Diagnostic 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        4/1/95 through 3/31/96         Recruitment, Intervention and
                                        Follow-Up

2       4/1/96 through 3/31/97         Recruitment, Intervention and
                                       Follow-Up

3       4/1/97 through 3/31/98         Intervention & Follow-Up

4       4/1/98 through 3/31/99         Intervention & Follow-Up

5       4/1/99 through 3/31/2000       Intervention & Follow-Up

6       4/1/2000 through 3/31/2001     Intervention & Follow-Up

7       4/1/2001 through 3/31/2002     Close-Out of Clinical
                                       Centers/Data Analysis and
                                       Reporting of Results

*An initial recruitment period of 24 months is delineated to obtain a
sample size of 2,800 among 14 Clinical Centers.  However,
intervention and follow-up will begin immediately after
randomization.

For a Clinical Center, the budget should request support for the
minimum number of full-and/or part-time staff to successfully carry
out the trial.  A Clinical Center could include a Principal
Investigator, Co-Investigator, 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
within the budget.  Steering Committee meetings will be held in the
Washington, DC area.  Travel for centralized training of the study
coordinator and data entry clerk must also be budgeted (assume
central training to be held in the Washington, DC area annually
during years 1 through 6).

For applications for the Data Coordinating Center, the budget should
also 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 trips annually for years 1 through 5 of the project period) is
also to be included in the budget.  The Data Coordinating Center
should also budget for travel for the Chairperson of the Steering and
Planning Committee (three meetings per year).

Staff for the Diagnostic Center could include a Principal
Investigator, Co-investigator, laboratory technologist and support
staff to process specimens.  Travel to the Steering Committee
meetings and centralized training as noted above should also be
budgeted.

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 other HHS, PHS, and
NIH grant administration policy statements.

1.  Awardee Activities

The tasks or activities in which awardees will have substantial and
lead responsibilities include protocol revision, patient recruitment
and follow-up, data collection, data 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.  The awardees also
agree to transmit all study data to a central Data Coordinating
Center for combination and analysis.

Awardees will retain custody of and have primary rights to the data
developed under these awards, subject to Government rights of access
consistent with current HHS, PHS, and NIH policies.

2.  NIDDK Activities

The function of the NIDDK Project Coordinator and the Urology Program
Director, Division of Kidney, Urologic and Hematologic Diseases will
be to assist the Steering Committee and External Advisory Committee
in carrying out the trial.  The NIDDK Project Coordinator 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 Urology Program Director will assist in clarification of specific
clinical and scientific problems and concerns.

The NIDDK Urology Program Director and NIDDK Project Coordinator will
have voting membership (one vote between them) 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 substantial shortfall in
participant recruitment, follow-up, data reporting, quality control
or other major breach in the program.  Early termination may also
occur due to adverse effects of the interventions and reaching study
endpoints.  If the NIDDK does not agree with the protocol approved by
the Steering Committee, the arbitration process described elsewhere
should be used to resolve the differences between the parties.

3.  Cooperative Activities

A Steering Committee, composed of the Principal Investigator of each
Clinical Center, the principal investigator of the Data Coordinating
Center, the NIDDK Project Coordinator, the NIDDK Urology Program
Director 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, monitoring interim
measures of trial progress, and reporting trial results.  The
Steering Committee, or one of its subcommittees, will have primary
responsibility for the ongoing monitoring of the quality of
study-wide data provided by the Clinical Centers.  The chairperson,
who will be someone other than the NIDDK staff members, will be
selected by the Steering Committee from among their members, or
alternatively, from among experts in the fields of urology 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 and Urology Program
Director 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.

It is anticipated that awardees will have lead responsibilities in
all joint tasks and activities.

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.  Each member of the Steering Committee will have one vote.
However, the NIDDK Urology Program Director and the NIDDK Program
Director will have one vote between them.  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 or the Urology Program
Director 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, the NIDDK Urology Program Director 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.

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.

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 grant policy statements.

STUDY POPULATIONS

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 subpopulations 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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.

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 9, 1994 (FR 59 11146-11151), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also
provide additional relevant information concerning the policy.

Since only men have prostate glands, discussion of issues related to
recruitment of women need not be included in the application.

LETTER OF INTENT

Prospective applicants are asked to submit, by August 2, 1994, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the 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 subsequent applications, the information
that it contains allows NIDDK staff to estimate the potential review
workload and to avoid conflict of interest in the review.

A letter of intent is to be sent to:

Dr. Robert D. Hammond
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892

APPLICATIONS 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 301/435-0714; and from the NIH program administrators
listed under INQUIRIES.

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 "Medical Therapy of Benign Prostatic
Hypertrophy:  Full Scale Trial" and enter the RFA number DK-94-018 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 August 30, 1994.  An application not
received by this date will be returned to the applicant.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants and for responsiveness by the NIDDK.
Incomplete applications will be returned to the applicant without
further consideration. If the application is not responsive to the
RFA, NIDDK staff will return the application to the applicant.

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 (triage) may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be
competitive will be discussed and be assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the Principal Investigator and the official
signing for the applicant organization will be notified.

Review Criteria

The Initial Review Group evaluates the merit of each grant
application on the meeting agenda according to specific criteria.
The principal criteria for the initial review of all research
applications, as required in the PHS Scientific Peer Review
Regulations, include:

1.  scientific, technical, or medical significance and originality of
the proposed research;

2.  appropriateness and adequacy of the experimental approach and
methodology to be used;

3.  qualifications of the principal investigator and staff in the
area of the research;

4.  the principal investigator's experience and record in previous
research activity;

5.  reasonable availability of resources;

6.  reasonableness and adequacy of justification of the proposed
budget and duration of support; and

7.  adequacy of the proposed means for protecting against adverse
effects upon humans, vertebrate animals, or the environment.

The evaluation of applications for Clinical Centers, the Data
Coordinating Center and the Diagnostic Center will be based primarily
on the scientific merit of the proposed study.  Specific criteria for
review of applications will be as follows:

For 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 the proposed Clinical Trial.
Evaluation will include the following:  familiarity with and
experience in recruiting participants in a randomized trial; 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 trial participants can be recruited in
sufficient numbers to meet the goals specified in the RFA.

3.  Ability to recruit representative minority populations.

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

5.  Responsible budgeting and staffing and distribution of available
resources appropriate for the work proposed.

6.  Adequacy of the proposed facility and space.

7.  Evidence of the degree of institutional commitment and support
for the proposed program, including the relative position of the
proposed project staff within the applicant's organizational
structure.

8.  Willingness to work cooperatively with other centers in the
manner summarized in the RFA.

9.  Willingness to carry out a developed study protocol.

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

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 availability of the medical consultation of a
qualified urologist, 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.  A knowledge of the potential problems associated with the conduct
of this study and possible solutions must 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 Clinical Centers.

5.  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.  Specific plans for ensuring
quality control of data collection across all study sites (Clinical
Centers and Diagnostic Center) are required.

6.  Appropriateness of the budget for the work proposed.

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

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

9.  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:

1.  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
as defined in the Pilot Study protocol.

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

3.  Appropriateness of a plan to correlate results of testing patient
samples with the major endpoints of the trial.

4.  Acceptability of a sampling and analysis scheme for prostate
biopsies in a subset of study participants.

5.  Appropriateness of the budget for the proposed work.

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

7.  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.

8.  Evidence of willingness to work cooperatively with other centers
in the manner summarized in the RFA and Pilot Study protocol.

9.  Plans for internal quality control and quality control for
specimen collection by the Clinical Centers.

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; (c)
availability of funds; (d) appropriate minority representation in the
trial; and (e) geographic balance among clinical centers.

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.

Direct inquiries regarding programmatic issues to:

John W. Kusek, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A04
Bethesda, MD  20892
Telephone:  (301) 594-7522
FAX:  (301) 594-7501

Inquiries regarding fiscal matters may be directed to:

Trude H. McCain
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 653
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:  August 2, 1994
Application Receipt Date:       August 30, 1994
Initial Review:                 November/December 1994
Review by Council:              February 1995
Anticipated Award Date:         April 1, 1995

Request for Applications for Basic Research in BPH

As noted previously, a separate RFA, "Basic Research Studies in
Benign Prostatic Hyperplasia" may be issued no later than February
28, 1995.  Those institutions selected as Clinical Centers for the
full-scale will be eligible to apply for supplements to the
cooperative agreements (U01).  It is anticipated that patient
material and data acquired by the Clinical Centers during the
full-scale trial will be available for use in the studies proposed in
response to this RFA, contingent upon agreement by the Steering
Committee.

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.

The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

.

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