MINIMALLY INVASIVE SURGICAL THERAPIES TREATMENT CONSORTIUM FOR BENIGN 
PROSTATIC HYPERPLASIA

Release Date:  November 29, 2000

RFA:  DK-01-024
  
National Institute of Diabetes and Digestive and Kidney Diseases

Applicant Information Forum Date:  January 12, 2001
Letter of Intent Receipt Date:     February 23, 2001
Application Receipt Date:          March 20, 2001

PURPOSE
 
The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of 
the National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) has a substantial and longstanding interest in evaluating the 
effectiveness of treatment strategies for the symptoms of benign 
prostatic hyperplasia (BPH). For many years, transurethral resection of 
the prostate (TURP) has been the standard of surgical therapy for 
treatment of symptomatic BPH.  Over the past decade there have been a 
number of technical innovations which have allowed the development of 
new surgical treatments which aim to achieve the same long-term 
outcomes of TURP but with the advantages of less morbidity, lower 
costs, shorter length of hospital stay, and more rapid recovery.  These 
new "minimally invasive" surgical approaches include laser therapy, 
hyperthermia and thermotherapy, transurethral electrovaporization, 
microwave therapy and transurethral needle ablation; with new 
techniques appearing regularly.  Published reports on the outcomes of 
these minimally invasive therapies are highly variable in their 
quality, often suffering from a lack of uniform outcome measurements, 
variable baseline or study entry criteria, a short period of follow-up, 
lack of information on the frequency of re-operation, inadequate 
documentation of adverse events, and absence of information on post-
surgical pharmacological treatment. The purpose of this Request for 
Applications (RFA) is to establish a group of collaborative Prostate 
Evaluation and Treatment Centers (PETCs) and a Biostatistical 
Coordinating Center (BCC) to develop and conduct randomized, controlled 
clinical trials of the long-term efficacy and safety of the major 
"minimally-invasive" approaches for the treatment of symptomatic BPH. 

HEALTHY PEOPLE 2010
 
The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of “Healthy People 2010”, a 
PHS-led national activity for setting priority areas.  This 
RFA,”Minimally Invasive Surgical Therapies Treatment Consortium for 
Benign Prostatic Hyperplasia”, is related to one or more of the 
priority areas.  Potential applicants may obtain a copy of “Healthy 
People 2010” at http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic, for-profit and non-profit 
institutions; public and private organizations, such as universities, 
colleges, hospitals, units of State and local government; 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.  

An institution may apply for both a PETC and the BCC; however, separate 
applications are required and a specific plan of the independent 
operation (i.e., confidentiality of the study-wide data) of each unit 
will be maintained is required in each application.

MECHANISM OF SUPPORT
 
The administrative and funding instrument to be used for these awards 
will be the cooperative agreement (U01). The cooperative agreement is 
an assistance mechanism in which substantial NIDDK scientific and 
programmatic involvement is anticipated during the performance of the 
activity. Under the cooperative agreement, the NIDDK's 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, 
prime responsibility, or dominance.  Details of the responsibilities, 
relationships, and governance of a study funded under a cooperative 
agreement are described under the section entitled "Terms and 
Conditions of Award."
 
The total project period for applications submitted in response to this 
RFA must not exceed five years.  The anticipated award date is 
September 30, 2001.  At this time, the NIDDK has not determined whether 
or how this solicitation will be continued beyond the present RFA.
 
FUNDS AVAILABLE
 
The NIDDK plans to make approximately 15 awards for PETCs and a single 
award for a BCC. Approximately $3,000,000 total cost (direct plus 
facilities and administrative costs) is expected to be available for 
the first year of support under this RFA.  It is anticipated that the 
award for each PETC will be about $150,000 total cost per year for the 
first year of the study.  The award to the BCC is anticipated to be 
$750,000 total costs for each year of the program.  Approximately 
$6,000,000 is expected to be available for years 2 through 5 for this 
project.  Total costs for each PETC will be approximately $350,000 for 
years 2 through 5.  
 
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 this program is provided for in the 
financial plans of the NIDDK, awards pursuant to this RFA are 
contingent upon the availability of funds and the receipt of a 
sufficient number of applications of outstanding scientific and 
technical merit.
 
RESEARCH OBJECTIVES
 
A. Background

Symptomatic benign prostatic hyperplasia (BPH) is one of the most 
common disorders for which men seek the care of a physician.  The 
effective treatment of BPH is of importance not only to the patient but 
also to third party payers, physicians in general, and particularly to 
urologists.  TURP is considered to be the "gold standard" in terms of 
reducing symptom scores, improving maximum urine flow rates, and 
decreasing post-void residual urine. The morbidity associated with TURP 
includes urinary incontinence, erectile dysfunction, retrograde 
ejaculation, infection, blood loss requiring transfusion, and the long-
term effects of bladder neck contracture and the need for reoperation.  

The potential for adverse outcomes for TURP and their attendant costs 
has prompted the development and use of both pharmacologic treatment 
and device-related surgery. Such device-related procedures have become 
to be known as minimally invasive surgical therapies.  These therapies 
include the use of ultrasound, laser, hyperthermia, microwave, needle 
ablation, electrovaporization, balloon dilation and intraurethral 
stents. Manufacturers claim that treatment with these devices reduce 
the morbidity, obviates the need for hospitalization and thereby 
reduces overall costs, and achieves a clinical effect similar to that 
of TURP.  However, there are very few well-documented, long- term, 
multi-center randomized clinical trials comparing subjective and 
objective outcomes of these minimally invasive surgical therapies.  
Thus, little is known about the clinical and other characteristics of 
patients with BPH who achieve successful outcomes, the rate of 
successful response and its duration, and the frequency of 
complications.  Often the specific enrollment criteria, the diagnostic 
criteria such as size of the prostate, documentation of subjective and 
objective symptoms, and use of widely accepted and uniform outcome 
criteria are lacking in the currently available literature. These 
reports also do not describe whether adjunctive medical therapy was 
utilized post-surgery, nor do they report on the outcomes of patients 
who drop out prior to study completion. Frequently these are not 
randomized nor do they include sham controls.    

B.  Research Goals and Scope of the Activity
 
The purpose of this RFA is to solicit applications from investigators 
to serve either as a PETC or a BCC to participate as a consortium to 
develop and conduct randomized controlled clinical trials to evaluate 
the long-term efficacy and safety of the most frequently used 
"minimally-invasive" surgical approaches for the treatment of 
symptomatic BPH. The major objective of this RFA is to cooperatively 
develop and carry out clinical trials, singly or concurrently, in order 
to evaluate the long-term efficacy and safety of these devices.  The 
cooperative group of investigators, to be known as the Minimally 
Invasive Surgical Therapy (MIST) Study Group, will also develop 
objective diagnostic and outcome measures.  Trials may focus on 
comparisons of a single surgical technique with a sham control or 
comparisons of multiple techniques with each other and sham controls.  
It is expected that PETCs will require expertise in urology and 
experience in the conduct of multi-center clinical trials related to 
the treatment of BPH.  The BCC must have expertise in biostatistics, 
data management, database development and computer programming as well 
as experience in coordinating multi-center clinical trials and/or 
epidemiological studies.

The specific goals of this solicitation are to:

1. establish a group of investigators (“The MIST Study Group”) who will 
participate in conducting multiple randomized clinical trials, either 
sequentially or concurrently, of minimally invasive surgical devices 
for the treatment of symptomatic BPH

2. evaluate the long-term efficacy and safety of the most commonly used 
minimally invasive surgical devices for the treatment of BPH. 

3. determine if baseline clinical characteristics and diagnostic 
criteria are predictive of successful outcomes of these therapies. 

4. assess the need for and if required, whether adjuvant medical 
therapy improves the long-term outcome of minimally invasive surgery 
for BPH.

5. determine whether one or more baseline urodynamic measurements are 
prognostic indicators for surgical success and the feasibility of using 
selected follow-up urodynamic measurement parameters as secondary 
outcomes.

Applicants are encouraged to collaborate with other investigators via 
subcontracts to establish satellite centers in order to increase the 
available pool of potentially eligible participants with the primary 
goal of enhancing racial and ethnic diversity of the population.

PHASES OF STUDY FOR BUDGET CONSIDERATIONS:

The timetable for the study may be subdivided into three phases over a 
five-year period.  

Phase I (Months 1-12): Protocol Development and Limited Patient 
Recruitment for Clinical Trial Number 1

This phase will include selecting the devices to be evaluated, planning 
and developing the protocol for the first clinical trial, establishing 
inclusion/exclusion criteria, baseline diagnostic criteria, and outcome 
criteria, including indices for measurement of quality of life and 
patient satisfaction.  Methods to evaluate the safety of these devices 
will also be developed.  The protocol for urodynamic studies will also 
be developed.  Also during this phase, the protocol for the first trial 
will be written and finalized and a manual of operations and data 
collection forms will be created.  The BCC will develop the database 
for the trial and implement procedures for data collection by the 
PETCs.  Upon completion of the protocol and manual of operations, 
centralized training of the study coordinators will be conducted.  
Subsequently, a small number of participants will be enrolled in the 
first clinical trial by each PETC during the last two months of Phase I 
to test recruitment procedures and methods for data collection and 
transmission.  Prior to implementation of the first trial, a Data and 
Safety Monitoring Board (DSMB), selected by the NIDDK, will review the 
protocol in terms of its scientific importance, safeguards for 
participants, and ethical considerations.

Phase II (Months 13-54) Implementation of Additional Clinical Trials 
and Reporting of Results

Phase II is a period of patient recruitment, further protocol 
development and trial implementation, and interim and final data 
analysis.  During the first 12 months of Phase II (months 13-24 of the 
total project period) recruitment of patients to be enrolled in the 
first clinical trial will occur.  As recruitment proceeds for the first 
clinical trial, the protocol will be developed for the second trial.  
Depending upon the sample size, it is expected that at least 3-4 
randomized clinical trials will be completed during the five years of 
this program. This process of developing a protocol for a new trial 
during the recruitment period of an ongoing trial will continue 
throughout this Phase of the program. Depending upon the mix of 
surgical techniques and the number of trial participants that can be 
recruited by the successful applicants it may be possible to implement 
two trials concurrently.   It is anticipated that the follow-up of 
patients will be for a minimum of two years post-surgery.  As trials 
are completed final data analysis and reporting in the peer-reviewed 
literature will occur.

Phase III: (Months 55-60) Final Data Analysis and Close-out of Prostate 
Evaluation and Treatment Centers and the Biostatistical Coordinating 
Center.

Final analysis of results from the trials implemented in the latter 
stages of Phase II will be completed.  Reports of the findings of these 
trials will be prepared and manuscripts prepared for publication in 
peer-reviewed scientific journals.  The PETCs and the BCC will also be 
closed out in months 55-60 of the program. 

STUDY COMPONENTS
 
Prostate Evaluation and Treatment Center   
 
A Prostate Evaluation and Treatment Center is an institution that is 
actively involved in the recruitment, evaluation, treatment, and 
follow-up of study participants.  It should consist of a team of 
clinical investigators including physicians and a research coordinator 
and the appropriate support personnel, such data entry and clerical 
staff. Each PETC which proposes the establishment of a satellite center 
must specify the working arrangements between parent institution and 
satellite physicians, describe the potential pool of trial participants 
and the surgical techniques available at these sites, indicate where 
baseline and follow-up evaluations will be conducted, and describe how 
data will be transmitted to the BCC. 

It is not expected that each PETC will have either the equipment or 
experience with each type of minimally invasive therapy.  Establishment 
of satellite sites can be used to expand that expertise.  It is 
expected that there will be adequate expertise distributed among the 
participating PETCs to conduct randomized clinical trials with adequate 
statistical power to evaluate at least 3-4 of the most frequently used 
techniques. The purpose of establishing of satellite sites should be 
not only to expand the types surgical techniques that could be 
evaluated but also increase recruitment of racial and ethnic minority 
men.

PETC investigators must be capable of recruiting and retaining a 
sufficient number of men for the proposed clinical trials.  PETCs 
should document the available target population from which study 
participants can be recruited.  This documentation should include, in 
tabular form, the number of patients anticipated to be eligible for 
surgical intervention over the 5-year period of the program for each 5-
year age range and by race/ethnicity. The investigators must also 
include in their description of their target population, the sources of 
referral of their patients, and the estimated percentage who are prior 
treatment (both medical and surgical) failures. Realistic estimates of 
the rate of participation of men who are willing to join the trial and 
be followed at the PETC must be provided.  The investigators should 
describe strategies and techniques that have been found to be effective 
in patient recruitment for other clinical trials of BPH treatments, 
with supporting data. Information on the number of patients treated 
with these devices at their institution during the past 3 years should 
also be provided.  The Principal Investigator and co-investigators 
should document previous experience in collaborative clinical 
investigation, including randomized clinical trials.  Investigators 
will be required to submit protocol-specified data to the BCC 
expeditiously and to collaborate with other investigators in the 
consortium. PETCs must work in concert with the BCC and must be willing 
to submit to data audits and other data quality control procedures as 
established by the study protocol and as required by law for government 
agencies. 

Biostatistical Coordinating Center

The BCC will assist investigators in developing the design and protocol 
for the clinical trials to be conducted by the consortium, including 
determination of the final sample size and power calculations. The BCC 
will also have primary responsibility for collecting, editing, storing, 
and analyzing data generated by the PETCs.  It should be prepared to 
assume a key role in overseeing implementation and adherence to the 
trial protocols, and assuring quality control of the data collected. It 
is expected that a web-based method for data transmission from the 
PETCs to the BCC will be implemented. Staff required for a BCC should 
include biostatisticians, a project manager, computer programmers, and 
a study coordinator.  The BCC will also be expected to provide 
appropriately detailed reports to the Steering and Planning Committee, 
the Executive Committee, and a group of external advisors at regular 
intervals, and will be responsible for the logistics and planning of 
the meetings (including conference calls) of these committees and their 
subcommittees.  The BCC will play a key role in analyzing data to 
support the efforts of the PETCs in writing manuscripts suitable for 
publication in peer-reviewed scientific journals.

Steering and Planning Committee
 
The primary governing body of the study will be the Steering and 
Planning Committee comprised of each of the principal investigators of 
the PETCs and the BCC, the Chairperson of the Steering and Planning 
Committee, and the NIDDK Project Scientists (described in detail under 
Terms and Conditions).  The Steering and Planning Committee will, in 
addition to developing the study protocols, propose plans for interim 
and final data analysis, and along with their staff at the PETCs, 
recruit, perform surgery and follow-up study participants. The members 
of the Steering and Planning Committee will serve as chairs of the 
various subcommittees established to develop the protocols for the 
trials and to monitor the progress of the consortium.

Executive Committee

An Executive Committee, including the Chairperson of the Steering and 
Planing Committee, the Principal Investigator of the BCC, NIDDK Project 
Scientists, and when necessary, Chairpersons of the various 
subcommittees of the Steering and Planning Committee, will be 
established.  The purpose of this committee is to handle problems that 
arise during the interim of regularly scheduled Steering and Planing 
Committee meetings.
 
Data and Safety Monitoring Board
 
An independent group of experts in urology, biostatistics, clinical 
trials, and ethics who are not otherwise involved in the study will be 
recruited by the NIDDK to review periodically the scientific merit of 
the proposed trial designs (including ethical aspects), and the 
progress and safety of ongoing trials (described in detail under Terms 
and Conditions). 
 
Project Scientists
 
The NIDDK will identify two Project Scientists for the study.  The 
Project Scientists will assist the Steering and Planning Committee and 
external advisors in carrying out the study (described in detail under 
Terms and Conditions).  

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 HHS, and NIH Grants 
Administration policy statements.
 
The participating PETCs will have primary responsibility for recruiting 
a sufficient number of patients (with a focus on recruiting a 
sufficient number of racial and ethnic minority participants to permit 
subgroup analyses), maintaining high rates of follow-up and high 
quality and complete data collection, and interpreting, presenting, and 
publishing findings from the trials.  It is expected that the PETCs 
will carry out the protocol agreed upon by the Steering and Planning 
Committee and approved by the Data and Safety Monitoring Board.  The 
BCC will have the primary responsibility for developing the various 
trial designs (in concert with the PETCs), coordinating the writing of 
the study protocol, manual of procedures and data collection forms, and 
collection, quality control, and analysis of the data. 

1) Collaborative Responsibilities

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 awardees 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 reside 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 NIDDK 
Project Scientists.

2) Awardees Rights and Responsibilities

Awardees will have substantial and lead responsibilities in all tasks 
and activities.  These include patient recruitment, performance of the 
surgery, follow-up, data collection, quality control, final data 
analysis and interpretation, and preparation of publications. The 
awardees agree to work cooperatively with the other PETCs and the BCC 
and agree to follow the common protocols and Manual of Operations 
developed by the Steering and Planning Committee.  The awardees agree 
also to transmit all study data to the BCC 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, or PHS) rights or access consistent with current HHS, and 
NIH policies.
 
3) NIDDK Staff Responsibilities

The NIDDK will name two Project Scientists from within the Division of 
Kidney, Urologic and Hematologic Diseases whose function will be to 
assist the Steering and Planning Committee in carrying out the study.  
One Project Scientist will have clinical expertise in urology and the 
other will have experience in the development and conduct of multi-
center clinical studies. The Project Scientists will be entitled to one 
vote between them for all key study group subcommittees.  The Project 
Scientists will have substantial scientific-programmatic involvement in 
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 
Scientists.
 
The NIDDK Project Scientists will have voting membership on the 
Steering and Planning Committee and, as determined by that committee, 
its subcommittees and will have one vote between them. One of the NIDDK 
Project Scientists will also serve as Executive Secretary of the group 
of the Data and Safety Monitoring Board.
 
The NIDDK reserves the right to terminate or curtail the study (or an 
individual award) in the event of difficulties in recruiting 
participants to the study, maintaining high rates of patient follow-up 
and data collection and in timely data transmission, achieving high 
levels of data quality, working with cooperatively or other major 
breaches of the protocol, or human subject ethical issues that may 
dictate a premature termination.
 
4) Governance

a) The Steering and Planning Committee, composed of each of the 
Principal Investigators of the PETCs, the Principal Investigator of the 
BCC, the NIDDK Project Scientists, and the Chairman of the Steering and 
Planning Committee, will be the main governing board of the study.  
This committee will have the primary responsibility for developing the 
common protocol, performing surgery, facilitating the conduct of 
participant follow-up, monitoring completeness of data collection and 
timely transmission of data to the BCC, and reporting the study 
results.  It will also be responsible for establishing study policies 
in such areas as access to patient data, ancillary studies, 
publications and presentations, and performance standards.  Each member 
of the Steering and Planing Committee will have one vote (NIDDK Project 
Scientists will have one vote between them), and all major scientific 
decisions will be determined by a majority vote of the Steering and 
Planing Committee.  A Chairperson will be chosen from among the 
Steering and Planing Committee members (but not one of the NIDDK 
Project Scientist or Biostatistical Coordinating Center Principal 
Investigator), or alternatively, from among experts in the field of 
urology and the treatment of BPH who are not participating directly in 
the study.  Subcommittees will be established from among members of the 
full complement of PETCs and the BCC on topics such as ancillary 
studies, publications and presentations, quality control, recruitment, 
protocol adherence, among others.  

b) An Executive Committee comprised of the Steering and Planning 
Committee Chairperson, the Principal Investigator of the BCC, and the 
NIDDK Project Scientists also will be convened to effect management 
decisions required between the Steering and Planning Committee 
meetings, as needed for efficient progress of the trials.  Each member 
of the Executive Committee will have one vote (the NIDDK Project 
Scientists are entitled to one vote between them).  The Executive 
Committee will report its actions to the Steering and Planning 
Committee on a regular basis.  Meetings of the Executive Committee will 
generally be by conference call.

c) An independent group of external advisors, selected by the Director, 
NIDDK, known as the Data and Safety Monitoring Board, will review 
periodically the progress of the trials.  This group will include 
experts in the relevant medical, statistical, and ethics fields that 
are not otherwise involved in the trials.  The Data and Safety 
Monitoring Board will review the protocols for the various trials and 
evaluate results, monitor data quality, participant safety, and provide 
operational and policy advice to the Steering and Planning Committee 
and to the NIDDK regarding the status of the trials.  One of the NIDDK 
Project Scientists will serve as Executive Secretary of the group of 
the Data and Safety Monitoring Board.

5) 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 MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that 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 1003-43).  All 
investigators proposing research involving human subjects should read 
the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as 
Subjects in Clinical Research" published in the NIH Guide for Grants 
and Contracts on August 2, 2000
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: 
The revisions relate to NIH defined Phase III clinical trials and 
require:  a) all applications or proposals and/or protocols to provide 
a description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable; and b) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained 
within specified page limitations.  Unless otherwise specified in an 
NIH solicitation, Internet addresses (URLs) should not be used to 
provide information necessary to the review because reviewers are under 
no obligation to view the Internet sites.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.

INFORMATION FOR PROSPECTIVE APPLICANTS

Open Forum

A one-day open information forum will be held for prospective 
applicants on January 12, 2001, from 12 p.m. to 3:30 p.m. (EST). The 
meeting will be held on the NIH Campus, Conference Room B in the 
Natcher Conference Center located in Building 45 (the Natcher 
Building), located at 45 Center Drive, Bethesda, Maryland. At this 
forum NIDDK program staff will address any questions that prospective 
applicants might have regarding the clinical/scientific concepts of the 
RFA.  Attendance is not required and is not a pre-condition for 
submission of an application. Applicants planning to attend this 
meeting should submit their questions in writing (electronic mail is 
acceptable) to John W. Kusek, Ph.D. at the address listed INQUIRIES at 
least two weeks in advance of the forum.

Information on the Web

For those who cannot attend the January 12,2001 forum, a website will 
contain a summary of that meeting.  It will also contain questions of 
general interest asked by prospective applicants and their answers.  
Prospective applicants are encouraged to check this website frequently 
while preparing an application.  The website can be reached though the 
following URL:  http://www.niddk.nih.gov/fund/crfo/rfas.htm.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 23, 2001, a 
letter of intent that includes a descriptive title of the proposed 
research, name, address, and telephone number of the Principal 
Investigator, 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:
 
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes, Digestive, and Kidney Diseases
6707 Democracy Boulevard
Room 653, MSC 5452
Bethesda, MD 20892-5452 (for express/courier service use 20817)
Telephone:  (301) 594-8885
FAX: (301) 480-3505
Email: hagana@extra.niddk.nih.gov
 
APPLICATION PROCEDURES
 
Applications must be submitted on the standard research grant 
application form PHS 398 (rev. 4/98).  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) 435-0714, E-mail: 
GrantsInfo@nih.gov.
 
The RFA label in the form PHS 398 (rev. 4/98) 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 the words Minimally Invasive 
Surgical Therapies for BPH- Treatment Consortium" must be typed in. 
 
The RFA label and line 2 of the application should both indicate the 
RFA number.  The RFA label must be affixed to the bottom of the face 
page.  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.

The sample RFA label available at:  
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change.  Please note this is in pdf format.

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
6707 Democracy Boulevard
Room 653, MSC 5452
Bethesda, MD 20892- 5452 (for express/courier service use 20817)

Applications must be received by March 20, 2001.  An application that 
is received after this date 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.  

Information to be Included in Applications

Clinical Trial Design:  Applications for a PETC and the BCC must 
include a proposed design for a single clinical trial to achieve the 
goals of this RFA.  The design must include the surgical technique(s) 
proposed to be evaluated, entry and exclusion criteria, primary and 
secondary outcomes, methodological issues surrounding the use of sham 
controls, frequency and type of measurements during follow-up, and 
plans for data analysis.  Plans for data analysis must be more detailed 
for applications for a BCC than a PETC.  For applications for both the 
PETC and the BCC sample size estimates and power calculations must be 
included.

Information on Patient Pool (for PETCs only):  Detailed information on 
the number, age, race, ethnicity of men who have been evaluated for 
symptoms of BPH, and also those who have undergone surgery for BPH 
during the past three years at the applicant institution and any 
proposed satellite sites should be provided. The distribution of men 
who have undergone therapy with minimally invasive surgical techniques 
over this time period must also be quantified by each technique.  
Information on the number of cases of new versus repeat surgical 
procedures in this patient population must also be provided.

Previous Experience and Prior Participation in a Collaborative Program:  
To promote the development of a collaborative program among the 
awardees, the applicant should present evidence of prior experience in 
working cooperatively with other institutions serving to recruit 
patients into studies of treatment of BPH and similar multi-center 
clinical studies and follow them long-term.  In the case of the BCC, 
evidence of coordinating multi-center clinical studies, including 
clinical trials, should be included in the application. 

Institutional Support:  There should be documentation of strong 
institutional support for the study, including adequate space in which 
to conduct clinic activities (PETCs) or in the case of the BCC adequate 
space to permit data collection, data analysis, and the other 
activities described for the BCC in this RFA. An organizational 
structure for the study should be set forth in the application, 
delineating lines of authority, communication and responsibility for 
dealing with problems in all general areas as well as stated 
willingness to follow the commonly agreed upon protocol.
 
Suggested Personnel Requirements:  The staff of a PETC should include 
urologists with documented expertise in the treatment of BPH.  The PETC 
team is anticipated to include members who perform in roles similar to 
those cited below.  Members may be full or part-time and may serve in 
more than one capacity, as appropriate. The application must describe 
the expertise of key scientific, technical and administrative personnel 
and include a mechanism for replacing key professional or technical 
personnel should the need arise.   The following suggested roles are 
intended to be illustrative, not prescriptive:

o Principal Investigator to provide overall scientific guidance.

o Physician(s)/clinicians  with expertise in the surgical, and 
pharmacological and management of patients with BPH.

o Project Coordinator who can provide full-time attention to 
administration and management of the trials.

o Individual(s) for clerical and technical support, including data 
entry.

The expertise required for the BCC includes statistics, data 
management, computer programming, data base development, and project 
management.  Clinical consultants with expertise in urology, including 
familiarity with the major minimally invasive surgical techniques is 
necessary. 

The following personnel requirements are suggested for the BCC.

Principal investigator to provide overall scientific guidance.

Statisticians to perform analysis to support the development of the 
protocols, provide data for meetings of the Steering and Planning 
Committee, the group of external advisors, and work with PETC 
investigators on interim and final publications.

Project Coordinator who can provide full-time attention to the 
administrative and management aspects of the trials.

Computer programmers to develop the necessary database.  

Individuals for clerical and technical support.

Part-time medical consultants with expertise in the treatment of BPH, 
with experience with the most commonly used minimally invasive surgical 
therapies.

Budget Preparation by Year
 
Applicants for the PETCs and the BCC must include an adequately 
justified year-by-year budget, reflecting the major changes in the 
proposed activities as the study progresses through its various phases.  
Note that budgets are NOT to be prepared in modules.  

Phase I (Months 1-12):  The budget should reflect the level of effort 
necessary to develop the protocol for the first clinical trial.  During 
this phase the BCC will create the data collection forms and computer 
database necessary for trial number 1.  During the last two months of 
Phase I a small number of participants will be randomized into the 
first trial.

Phase II (Months 13-54):  The major activities during this phase are 
completion of recruitment for trial number 1 (anticipated recruitment 
period of 12 months) and follow-up data collection.  Protocols for 
subsequent trials will be developed, patients recruited, and followed-
up per study protocol.  Interim and final data analysis will occur as 
well as reporting of findings to the group of external advisors.  

Phase III (Months 55-60):  During this phase of the program final 
reporting of the results of trials implemented during the latter part 
of Phase II will occur.  Computer files of the data for each of the 
trials will be prepared and submitted to the NIDDK for archiving.  The 
PETCs and the BCC will be closed-out. 

The project will require meeting approximately every four months in the 
Washington, D.C. area for each year of the study.  The travel budget 
should be estimated based on travel for the Principal Investigator, a 
co-investigator and a Study Coordinator. Key personnel from satellite 
centers may also be included in the travel budget.

REVIEW CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and for 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 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 National Diabetes and 
Digestive and Kidney Diseases Advisory Council.

Review Criteria

Applicants are expected to address issues identified under INFORMATION 
TO BE INCLUDED IN APPLICATIONS. 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 goals of this solicitation.  Each of the 
criteria will be addressed and considered in assigning the overall 
score, weighting them 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.

A design for a single clinical trial must be included in the grant 
applications for both PETCs and the BCC.

Review Criteria for Prostate Evaluation and Treatment Centers are as 
follows.

o Significance:  The applicant must demonstrate an understanding of the 
need for conducting randomized controlled clinical trials of the 
various minimally invasive surgical procedures for BPH.    

o Proposed Study Design for a Clinical Trial:  Is the proposed design 
for the first clinical trial well-justified and appropriate?  Have the 
sample size and power calculations been presented and the underlying 
assumptions for treatment effect been adequately described?  Have the 
outcome measures been fully considered and length of follow-up 
justified?  Have the technical issues surrounding the use of sham-
controls been adequately discussed?  Are the plans for data analysis 
described?

o Recruitment and Retention Capabilities:  Applicants must demonstrate  
the ability to recruit a large number of men who are candidates for 
surgery for BPH and follow them prospectively post-surgery.  
Recruitment of racial and ethnic minority men should be described in 
detail.  The importance of complete follow-up of study participants and 
collection of high quality data should be considered.    Procedures for 
the maintenance of the long-term participation of study subjects must 
be provided.  Experience and performance in prior NIH-sponsored 
clinical trials of BPH must be described in detail, including rates of 
treatment (medication) adherence and follow-up.  The number of surgical 
procedures for new and repeat procedures for BPH must be described for 
the past three years.

o Investigator:  This criterion will focus on the following questions: 
Is there documented evidence of the investigator's training and 
experience relevant to the operation of a PETC for BPH?  Is there 
evidence of successful collaborative interactions with other 
investigators under a common protocol in a multi-center study? 

o Environment:  Does the clinical environment in which the work will be 
done contribute to the probability of success?  Is there evidence of 
institutional support and commitment for the proposed program?

o Staff Qualifications: Documented specific competence and relevant 
experience of professional, technical, and administrative staff 
pertinent to the operation of a PETC and the ability to carry out BPH 
treatment studies.

o Documented experience in surgical treatment with minimally invasive 
devices for BPH is required.  Demonstrated knowledge of clinical 
aspects of BPH is also necessary. 

o Resources:  Documented adequacy of the proposed facility and space is 
necessary.  Evidence of institutional support and commitment is also 
required.

o Data Management and Transmission: Adequacy of plans to ensure 
complete, reliable, and timely transmission of the study data to the 
BCC.

o Cooperative Experience: Evidence of prior experience in working 
collaboratively to carry out a developed study protocol.  Willingness 
to work cooperatively in this study is required.  An explicit statement 
of willingness to implement trial protocols developed collaboratively 
by the Steering and Planning Committee must be included in the grant 
application.

o Collaboration between institutions in a single PETC application: For 
those applications proposing collaborative efforts between one or more 
applicants from different institutions to form a single PETC additional 
factors to be considered include the advantages of collaboration in 
terms of cost, recruitment capabilities, and availability of additional 
minimally invasive surgical techniques.  The organizational and 
administrative plan for such arrangements needs to be clearly 
delineated.

Review Criteria for the BCC are as follows.

o Significance:  The applicant must demonstrate an understanding of the 
need for conducting randomized controlled clinical trials of the 
various minimally invasive surgical procedures for BPH.    

o Approach:  For the proposed clinical trial, are the conceptual 
framework, design, methods, and analyses adequately developed, well 
integrated, and appropriate to the aims of the program?  Does the 
applicant acknowledge potential problem areas and consider alternative 
tactics?  

o Proposed Study Design for a Clinical Trial:  Is the proposed design 
for the first clinical trial well-justified and appropriate?  Are the 
sample size and power calculations been presented and documentation of 
the underlying assumptions for treatment effect been described.  Have 
the outcome measures been fully considered and length of follow-up 
justified?  Have the technical issues surrounding the use of sham-
controls been adequately discussed?  

o Proposed Plans for Data Analysis:  Have adequate plans been 
established for analyzing the data from the proposed trial, including 
plans for interim monitoring of results for the Data and Safety 
Monitoring Board?

The Steering and Planning Committee will collaboratively develop the 
design for each of the clinical trials to be implemented.  Thus, the 
peer review group will focus on evidence that the applicant has 
carefully thought about the issues involved and possesses the knowledge 
necessary to contribute meaningfully to the final designs, including 
understanding of the scientific, ethical, and practical issues 
underlying the proposed study.

o Environment:  Does the clinical environment in which the work will be 
done contribute to the probability of success?  Is there evidence of 
institutional support and commitment for the proposed program?

o Staff Qualifications: Documented specific competence and relevant 
experience of professional, technical, and administrative staff 
pertinent to the operation of a BCC.

o By means of consultants, documented experience in surgical treatment 
with minimally invasive devices for BPH is required.  Demonstrated 
knowledge of clinical aspects of BPH is also required. 

o Resources:  Documented adequacy of the proposed facility and space is 
necessary.  Evidence of institutional support and commitment is also 
required.

o Data Management and Quality Control: Adequacy of plans to ensure 
complete, reliable, and timely transmission of the study data by the 
PETCs.  Have plans been developed to ensure high quality data from the 
PETCs?

o Web-based data transmission:  It is expected that the BCC will 
implement web-based data transmission system between the PETCs and the 
BCC.  A plan for data transmission via the world wide web, including 
maintaining data privacy, must be included in the grant application.  
Prior experience in the use of a web-based system of data transmission 
in previous clinical trials/studies should be provided.

o Cooperative Experience: Evidence of prior experience in working 
collaboratively to carry out a developed study protocol.  Willingness 
to work cooperatively in this study is required.  

o Plans for Reporting to the Data and Safety Monitoring Board:  Have 
adequate plans been proposed for reporting the results of the trials, 
including adverse events and safety of the interventions?

In addition to the above criteria for PETCs and the BCC, in accordance 
with NIH policy, applications will also be reviewed with respect to the 
following.

o The reasonableness of the proposed budget.

o The adequacy of the proposed protection for humans or the 
environment, to the extent they may be adversely affected by the 
interventions proposed in the application.  The initial review group 
will also examine the safety of the research environment.

AWARD CRITERIA

Criteria that will be used to make award decisions include:

o Scientific merit as determined by peer review

o Availability of funds

o Cost

o Geographic distribution (for PTECs only)

o The frequency and type of surgical procedures available at each PETC

o Potential for recruitment of racial and ethnic minorities

o Success in the recruitment and retention of trial participants, and 
the promotion of adherence in other NIDDK funded clinical 
trials/studies.

Schedule

Applicant Information Forum Date:  January 12,2001
Letter of Intent Receipt Date:     February 23, 2001
Application Receipt Date:          March 20, 2001
Special Review Committee:          July/August 2001
NIDDK Advisory Council:            September 20-21, 2001
Anticipated Award Date:            September 30, 2001
 
INQUIRIES
 
Written and telephone inquiries concerning this RFA are strongly 
encouraged. 
 
Direct inquiries regarding programmatic issues to:
 
John W. Kusek, Ph.D.
Clinical Trials Program Director or
Leroy M. Nyberg, Ph.D., M.D.
Urology Program Director
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Two Democracy Plaza, Room 617
6707 Democracy Boulevard
Bethesda, MD 20892-5458
Telephone: (301) 594-7717
Fax:  (301) 480-3510
Email: kusekj@extra.niddk.nih.gov 
or nybergl@extra.niddk.gov
 
Direct inquiries regarding fiscal and administrative matters to:
 
Trude Hilliard
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Telephone:  (301) 594-8859
FAX:  (301) 480-3504
Email: hilliardt@extra.niddk.nih.gov
 
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 Public Health 
Service 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 Public Health Service 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 Public Health Service mission to protect and advance the physical 
and mental health of the American people.


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