ALTERNATIVE THERAPIES FOR BENIGN PROSTATE SYMPTOMS – CLINICAL TRIALS CONSORTIUM

Release Date:  January 16, 2002

RFA:  RFA-DK—02-026

Update: The following update relating to this announcement has been issued:

  September 17, 2009 - This RFA has been reissued as (RFA-DK-09-503).

PARTICIPATING INSTITUTES AND CENTERS (ICs):

National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov)
National Center for Complementary and Alternative Medicine
 (http://www.nccam.nih.gov)
Office of Dietary Supplements
 (http://dietary-supplements.info.nih.gov)

Letter of Intent Receipt Date:  March 15, 2002
Application Receipt Date:       April 15, 2002

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to become Principal Investigators
o Special Requirements
o Where to send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of 
the National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK), the National Center for Complementary and Alternative Medicine 
(NCCAM), and the Office of Dietary Supplements (ODS) invite cooperative 
agreement grant applications to establish a research consortium to 
conduct a randomized controlled clinical trial of Serenoa repens (Saw 
palmetto) and Pygeum africanum in men with benign prostatic hyperplasia (BPH).

As the population ages the number of men with lower urinary tract 
symptoms indicative of BPH is expected to increase substantially.  The 
segment of the United States population that utilizes alternative and 
complementary approaches to disease prevention and management is also 
increasing rapidly, including the use of phytotherapy to control the 
symptoms of BPH.  The most common phytotherapeutic agent is Serenoa 
repens or Saw palmetto.  Pygeum africanum is also frequently used in 
this country for the same purpose.  Little is known, however, about the 
long-term effects of these agents on the lower urinary tract symptoms 
experienced by men with BPH since rigorously conducted clinical trials 
for these agents have not been conducted.

In order to determine the effect of Serenoa repens and Pygeum africanum 
on the clinical progression of BPH the NIDDK and the NCCAM plan to 
establish a clinical trial consortium to conduct a large simple placebo 
controlled clinical trial of these two agents comparing saw palmetto to 
placebo, and Pygeum to placebo.  A secondary analysis will include 
head-to-head comparison of the two phytotherapy agents. The 
collaborative research group will consist of Clinical Evaluation and 
Treatment Centers (CETCs) to design and conduct the clinical trial and 
a single Data Coordinating Center (DCC) to collect, store, and analyze 
data generated by the CETCs.

RESEARCH OBJECTIVES

Background

More than one-half of the men 50 years of age or older have lower 
urinary tract symptoms associated with the development of benign 
prostatic hyperplasia (BPH).  The condition accounts for at least 1.7 
million office visits per year in the United States with estimated 
health care costs exceeding $4 billion a year.  In addition, these 
symptoms have been shown to have a significant negative impact on 
patient-reported quality of life and psychological well-being.  The use 
of alternative therapeutic agents to relieve the symptoms of BPH is 
increasing very rapidly.  In 1996 extracts of the saw palmetto berry 
was the 9th most common herbal remedy sold in the U.S increasing to the 
5th most common in 1997.  It is anticipated that the use of alternative 
therapies for BPH will continue to increase substantially as the U.S. 
male population continues to age.

Despite the widespread use of phytotherapy for BPH in the United 
States, most physicians are reluctant to either discuss or recommend 
their use since only a modest number of published reports have appeared 
in the peer-reviewed medical literature about their efficacy.  
Moreover, very few have met rigorous standards for reporting the 
results of clinical trials. Nonetheless, the available literature 
supports the hypothesis that these compounds may have some beneficial 
effects on BPH symptoms.  This is supported by a recent meta-analysis 
that suggests that Saw palmetto improves urinary flow-rate and nocturia 
in men with symptoms of BPH.  However, there are no statistically 
significant reports of rigorously conducted clinical trials on the 
long-term effects (both beneficial and adverse) and on patient-reported outcomes.

Research Scope

The objective of this RFA is to determine if Serenoa repens (Saw 
palmetto) and Pygeum africanum prevent the clinical progression of BPH, 
as defined by the development of one of the following:  acute urinary 
retention, renal insufficiency (due to BPH), recurrent urinary tract 
infections, incontinence, or an increase in the American Urological 
Association (AUA) symptom score index of four or more points.  This 
definition of the clinical progression of BPH is identical to that used 
in a soon-to-be-completed clinical trial supported by the NIDDK, the 
Medical Therapy of Prostatic Symptoms (MTOPS) Trial.  Results from the 
MTOPS Trial, in particular the event rate among the placebo group, will 
be made available to investigators participating in this consortium to 
assist in refinement of the trial design.  The investigators 
participating in this consortium will design and conduct a large simple 
clinical trial.  It is envisioned that the clinical trial will require 
a total of approximately 3,100 men with BPH who will be randomized over 
a two-year period.  The clinical trial will be double-masked and 
placebo controlled.  It is expected that each CETC will recruit and 
follow-up 300 men for the duration of the trial.  Men will be followed 
for a minimum of four (4) years and a maximum of six (6) years post-
randomization.  Innovative methods will be required to implement this 
clinical trial including recruitment of a large number of men with 
symptoms of BPH, use of multiple strategies to promote long-term 
adherence to these agents, maintenance of high rates for clinic visits, 
and complete ascertainment of endpoints.

Procedures established by NCCAM will be used to select the purveyors of 
the phytotherapeutic agents prior to beginning these studies.

Organization of the Clinical Trial Consortium

Clinical Evaluation and Treatment Center

A Clinical 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 with expertise in conducting 
multicenter clinical trials and with expertise in evaluating and 
treating patients who desire non-surgical treatment for the lower 
urinary tract symptoms associated with BPH.  It is expected that each 
CETC will have physicians with clinical expertise in urology, general 
medicine and other relevant clinical specialties.   

Data Coordinating Center

The DCC will assist investigators in developing the design and protocol 
for the clinical trial.  This includes reconfirmation of the sample 
size and power calculations.  The DCC will also have the primary 
responsibility for collecting, editing, storing and analyzing data 
generated by the CETCs.  The DCC should be prepared to assume a key 
role in overseeing implementation and adherence to the trial protocol, 
and assuring quality control of the data collected.  It is expected 
that a web-based method for data transmission from the CETCs to the DCC 
will be implemented.  The DCC will also be expected to provide 
appropriately detailed reports to the Steering and Planning Committee, 
the Executive Committee, and the DSMB at regular intervals, and will be 
responsible for the logistics and planning of the meetings (including 
monthly committee conference calls) of these committees and 
subcommittees. The DCC will play a key role in analyzing data and 
participating in and supporting the CETC members in preparing and 
writing abstracts and manuscripts for presentation at meetings and for 
publication in peer-reviewed scientific journals.   The DCC will 
identify and establish a Phytotherapy Distribution Center to coordinate 
the supply of Serenoa repens, Pygeum africanum, and placebo to the CETCs.

Governance

Steering and Planning Committee:

The primary governing body of the study will be the Steering and 
Planning Committee.  This committee will be comprised of each of the 
principal investigators of the CETCs and the DCC, the Chairperson of 
the Steering and Planning Committee, and the NIDDK and the NCCAM 
Project Scientists (described under Terms and Conditions).   

Executive Committee:

An Executive Committee will be established to resolve problems and 
monitor progress, during the interim of regularly scheduled Steering 
and Planning Committee meetings.  The Executive Committee will include 
the Chairperson of the Steering and Planning Committee, the Principal 
Investigator of the DCC, the NIDDK and the NCCAM Project Scientists, 
and when necessary, Chairpersons of the various subcommittees.

Data and Safety Monitory Board (DSMB)

A independent group of experts in urology and other relevant medical 
specialties, biostatistics, behavioral medicine, clinical trials and 
ethics, who are not otherwise involved in the study will be named by 
the NIDDK and the NCCAM.  Prior to implementation of the trial the DSMB 
will review the scientific rigor of the design and any ethical issues.  
They will also periodically review outcome data and reports of patient 
safety including adverse events through pre-planned and any special 
interim analyses (further detail under Terms and Conditions).

NIDDK and NCCAM Project Scientists

The NIDDK and the NCCAM will each identify a Project Scientist for the 
trial.  The Project Scientists will assist the Steering and Planning 
Committee in planning and carrying out the trial (described in detail 
under Terms and Conditions).

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) cooperative 
clinical research (U01) agreement award mechanism, an "assistance" 
mechanism (rather than an "acquisition" mechanism) in which substantial 
NIH scientific and/or programmatic involvement is anticipated during 
the performance of the activity.  Under the cooperative agreement, the 
NIDDK purpose is to support and stimulate the recipients" activity by 
involvement in the activity and otherwise working jointly with the 
award recipients in a partner role, but not to assume direction, prime 
responsibility, or a dominant role in the activity. This is a one-time 
solicitation to support a Clinical Trials Consortium for seven years.
The anticipated award date is September 30, 2002.

Modular Grant applications will NOT be accepted for this RFA. However, 
the standard PHS 398 application instructions apply.

The NIH U01 is a cooperative agreement award mechanism in which the 
Principal Investigator retains the primary responsibility and dominant 
role for planning, directing, and executing the proposed project, with 
NIH staff being substantially involved as a partner with the Principal 
Investigator, as described under the section "Cooperative Agreement 
Terms and Conditions of Award"

FUNDS AVAILABLE

The NIDDK, NCCAM  and ODS intend to commit approximately $2 million in 
total costs (direct plus Facilities and Administrative (F&A)) in Fiscal 
Year 2002 to fund up to 10 CETCs and one Data Coordinating Center 
application in response to this RFA. It is anticipated that the award 
for each CETC will be about $135,000 total cost for the first year, and 
$ 650,000 total costs for the DCC for the first year of the study. A 
total of approximately $ 4,500,000 is expected to be available for each 
year beginning in year 2 of the program. Beginning in year 2 and for 
each year of the program the total cost for each CETC will be 
approximately $375,000 per year and $750,000 in total costs for the DCC.  

Although the financial plans of the NIDDK, NCCAM and ODS provide 
support for this program, 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.  
Designated funding levels are subject to change at any time prior to 
final award, due to unforeseen budgetary, administrative, or 
scientific developments.

ELIGIBILITY INSTITUTIONS

You may submit (an) application(s) if your institution has any of the 
following characteristics:
	
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.

Among the disciplines and expertise that may be appropriate for this 
program are urology, general medicine, other medical specialties, 
biostatistics, and clinical trial specialists.

SPECIAL REQUIREMENTS 

A Data Coordinating Center will be part of this clinical trials 
consortium.  In order to ensure that data analysis is done 
independently of data acquisition, the DCC cannot have the same 
Principal Investigator as a CETC.  Within the Consortium an institution 
may apply for both a CETC and the DCC, but each must have separate 
Principal Investigators and submit a separate application with a 
specific plan of how the independent operation of each unit of the CETC 
and DCC will be maintained.

Cooperative Agreement Terms and Conditions of Award

The following terms and conditions will be incorporated into the award 
statement and provided to the Principal Investigators as well as to the 
institutional officials at the time of the award.  These special Terms 
of Award are in addition to and 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, the NIH 
Grant Policy statement.

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 
this concept, the dominant role and prime responsibility for the 
activity resides with the awardees for the project as a whole, although 
specific tasks and activities in carrying out the activity will be 
shared among the awardees and NIDDK and NCCAM Project Scientists.

1) Awardees Rights and Responsibilities

The awardees will have lead responsibilities in all aspects of the 
protocol, including any modification of study design, conduct of the 
study, quality control, data analysis and interpretation, preparation 
of publications, and collaboration with other investigators, unless 
otherwise provided for in these terms or by action of the Steering and 
Planning Committee.  Awardees will retain custody of and have primary 
rights to their data developed under these awards, subject to 
Government rights or access consistent with current HHS, PHS, and NIH 
policies.  The collaborative protocol will call for the continued 
submission of data centrally to the DCC for a collaborative database, 
procedures for data analysis, reporting and publication, and procedures 
to protect and ensure the privacy of medical records of individuals.  
The NIDDK and NCCAM Project Scientists will have the same access, 
privileges and responsibilities regarding the collaborative data as the 
other members of the Steering and Planning Committee.  The DCC will be 
involved in collaborations with the NIDDK and the NCCAM and the CETCs 
during all phases of the trial.  The awardee is expected to work 
cooperatively with CETCs and sponsoring organizations in a multicenter 
trial and oversee the implementation of and adherence to a common 
protocol, as well as assure quality control of the data collected.  In 
addition to organizing and attending regular meetings of the Steering 
and Planning Committee, the DCC will be expected to maintain close 
communications with the NIDDK and the NCCAM Project Scientists and the 
Principal Investigators of the CETCs.  

2) NIDDK and NCCAM Staff Responsibilities

The NIDDK and the NCCAM will each name a Project Scientist whose 
function will be to assist the Steering and Planning Committee in 
carrying out the trial. The Project Scientists will have substantial 
scientific-programmatic involvement in overall 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 and NCCAM Project 
Scientists.

The NIDDK and the NCCAM 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. 

The NIDDK and the NCCAM reserve the right to terminate or curtail the 
study (or an individual award) in the event of (a) failure to develop 
or implement a mutually agreeable collaborative protocol, (b) 
substantial shortfall in participant recruitment, follow-up, data 
reporting, quality control, or other major breach of the protocol, (c) 
substantive changes in the agreed-upon protocol with which the NIDDK 
and the NCCAM cannot concur, (d) reach a major study endpoint 
substantially before schedule with persuasive statistical significance, 
or (e) human subject safety and ethical issues that may dictate a 
premature termination.

3) Collaborative Responsibilities

The Steering and Planning Committee, composed of each of the Principal 
Investigators of the CETCs and the DCC, the NIDDK and the NCCAM 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 final common 
protocol, facilitating the follow-up of participants, monitoring 
completeness of data collection and timely transmission of data to the 
DCC, and reporting the trial 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 Planning Committee will 
have one vote (NIDDK/NCCAM Project Scientists will have one vote 
between them), and all major scientific decisions will be determined by 
a majority vote of the Steering and Planning Committee.  A Chairperson 
will be chosen from among the Steering and Planning Committee members 
(but not one of the Project Scientists or DCC Principal Investigator), 
or alternatively, from among experts in the field of the treatment of 
BPH who are not participating directly in the trial.  Subcommittees 
will be established from among members of the full complement of CETCs 
and the DCC on topics such as ancillary studies, publications and 
presentations, quality control, recruitment, protocol adherence 
(including adherence to the intervention), among others.  

An Executive Committee comprised of the Steering and Planning Committee 
Chairperson, the Principal Investigator of the DCC, and the NIDDK/NCCAM 
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 trial.  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.

4) Arbitration
 
Any disagreement that may arise on scientific/programmatic matters 
(within the scope of the award) between recipients and the NIDDK/NCCAM 
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/NCCAM members not voting) or by the individual awardee 
in the event of an individual disagreement, a second member selected by 
the NIDDK/NCCAM, and the third member selected by the two prior 
selected members. This special arbitration procedure in no way affects 
the awardees right to appeal an adverse action that is otherwise 
subject to appeal in accordance with the PHS regulations at 42 CFR Part 
50, Subpart D and HHS regulation at 45 CFR Part 16, or the rights of 
NIDDK/NCCAM under applicable statutes, regulations and terms of the 
award.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
three areas:  scientific/research, peer review, and financial or grants 
management issues:

o Direct your questions about scientific/research 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 (Dr. Nyberg)/(301) 594-7735 (Dr. Kusek)
Fax:  (301) 480-3510
Email:  jk61x@nih.gov or ln10f@nih.gov
 
o Direct your questions about peer review issues to:
 
Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and 
Digestive and Kidney Diseases
6707 Democracy Boulevard
Room 752, MSC 5452
Bethesda, Maryland  20892-5452
(for express/courier service:  Bethesda, MD  20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
Email:  fc15y@nih.gov

o Direct your questions about financial or grants management matters to:
 
Trude W. Hilliard
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Room 717
Two Democracy Plaza
6707 Democracy Boulevard
Bethesda, Maryland  20892
Telephone:  (301) 594-8859
FAX:  (301) 480-4237
Email:  th105x@nih.gov

LETTER OF INTENT 

Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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 IC staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning 
of this document.  The letter of intent should be sent to:

Dr. Francisco O. Calvo at the address listed under INQUIRIES, above.

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email:  GrantsInfo@nih.gov.
 
SUPPLEMENTAL INSTRUCTIONS:

Applicants must describe plans to accommodate the stated program 
requirements, criteria, and staff involvement.  Applicants must address 
points discussed in the SPECIAL REQUIREMENTS section of this RFA.

Information to be Included in Applications

Information Pertaining to Recruitment (CETC applicants only):  Each 
CETC is expected to randomize a total of 300 men with BPH over a two-
year period of recruitment.  Applications for a CETC must provide 
convincing evidence that they will be able to achieve this goal given 
the level of resources provided under this RFA.  The CETC application 
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 the 
trial, by five-year age ranges 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 have not received any form of previous therapy 
(i.e. alternative, pharmacological or surgical).  Realistic estimates 
of the rate of participation of men who are willing to join the trial 
and be followed at the CETC must be provided.  The applicant must 
describe strategies and techniques that have been found to be effective 
in patient recruitment for other clinical trials in which they have 
participated.  Applicants who have participated in previous NIH funded 
trials as Principal Investigator or Co-Investigators must provide the 
following information for all trials that are included as documentation 
of previous success in recruitment:  name of study, brief description 
of entry criteria, number of participants recruited, duration of 
recruitment, percent of study recruitment goal achieved, number/percent 
of patients who adhered to treatment protocol for duration of study, 
the number of patients available for evaluation of end of study, and 
the duration of the study.  Information pertaining to NIH-sponsored 
trials will be reviewed for accuracy by NIDDK program staff.  Each CETC 
that proposes the establishment of a satellite center to increase the 
pool of eligible participants from which to recruit from must specify 
the administrative and financial arrangements between the parent 
institution and the satellite facility.  The likely number of 
participants to be recruited (randomized) from satellite clinics must 
be specified.  The applicant must also indicate where baseline and 
follow-up evaluations will be conducted and describe how data will be 
transmitted to the DCC.  CETCs must work in concert with the DCC 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.  Applications for the DCC should provide 
examples of the types of reports on recruitment performance that they 
will generate and feed back to the CETCs.  

Clinical Trial Design Issues:  Applications for a CETC and the BCC 
should follow the design for a clinical trial of Serenoa repens (Saw 
palmetto) and Pygeum africanum as described in this RFA.  Serenoa will 
be compared to placebo and Pygeum will be compared to placebo.  
Secondary analyses will include a head-to-head comparison of Serenoa 
and Pygeum.  Additional details of the trial design must be described 
including entry and exclusion criteria, secondary outcomes, and 
frequency and type of measurements (including validated instruments to 
assess primary and secondary outcomes) during follow-up. Applications 
for the DCC must also include a detailed data analysis plan.  
Applications for a CETC need not include an analysis plan but must 
comment on the clinical relevance of the primary outcome for the 
clinical trial (clinical progression of BPH) as described in this RFA.

Plans for Establishing and Maintaining Adherence to Assigned Agents:  
Applicants for a CETC must provide a comprehensive plan to maintain 
long-term adherence to the randomly assigned agent.  The plan must be 
behaviorally based and include goals for use of their assigned agent, 
approaches to be used to establish and maintain high rates of adherence 
and plans to identify barriers for non-adherence and solutions to this 
problem.  Applicants for the DCC must include a description of the type 
of trial-wide reports they will generate to monitor adherence to the 
assigned agents and the role they will play in promoting adherence to 
agent use.

Promotion of Clinic Visit Attendance:  A goal of follow-up in excess of 
90% of the randomized participants at the end of the trial is expected.  
CETC applications must provide an action-based plan for the long-term 
follow-up (maintenance of the established clinic visit schedule) of all 
study participants, including those who choose to discontinue use of 
their assigned agent, and men recruited from satellite clinics.

Previous Experience and Prior Participation in a Collaborative Program: 
To promote the development of a collaborative program among the 
awardees, an applicant for a CETC 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.  Applications for 
the DCC must provide evidence of coordinating multi-center clinical 
studies, including clinical trials. 

Institutional Support:  There should be documentation of strong 
institutional support for the program, including adequate space in 
which to conduct clinic activities (CETCs) or in the case of the DCC 
adequate space and other resources to permit data collection, data 
analysis, and the other activities described for the DCC in this RFA. 
An organizational structure for the study should be set forth in the 
application for both a CETC and the DCC 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 CETC must include 
urologists and general medical physicians with documented expertise in 
the assessment and non-surgical treatment of BPH.  The CETC 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/clinical  
guidance. This may be a physician of any relevant medical specialty. 

o  Physician(s)/clinicians serving as co-investigators or consultants 
with expertise in assessment of the symptoms of BPH and the 
pharmacological management of patients with BPH.

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

o Individual(s) for clerical and technical support, including data 
entry and culturally competent recruitment/outreach staff. 

The expertise required for the DCC includes statistics, data 
management, computer programming, data base development, and project 
management.  Clinical consultants with expertise in the assessment and 
medical management of persons with lower urinary tract symptoms 
associated with BPH is advised.  

The following personnel requirements are suggested for the DCC.

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 DSMB, and work with CETC investigators on interim and 
final publications.

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

Computer programmers to develop the necessary database.  

Individuals for clerical and technical support.

Budget

To assist in preparation of the budget for each year of the program a 
timetable in three phases, by calendar time and the tasks to be 
performed during each phase is presented below:
 
Phase I (Months 1-6) Protocol Development/Centralized Staff Training:
 
The major task during Phase I is refinement of the clinical trial 
protocol.  Uniform entry and exclusion criteria will be established.  
Baseline data collection will also be agreed upon.  The frequency of 
follow-up and data to be collected post-randomization will be 
described.  The trial protocol and manual of operations will be 
written.  Data collection forms will be produced and the database 
established.  Prior to implementation, the protocol will be reviewed by 
the Data and Safety Monitoring Board (DSMB).  Centralized training of 
study coordinators and other key personnel will be conducted at the end 
of Phase I.  The purveyors of Serenoa repens and Pygeum africanum will 
be selected by standard procedures established by the NCCAM and the 
agents and their matching placebo will be manufactured.  A Phytotherapy 
Distribution Center, to be established by the DCC, will be identified 
and become operational.  It is anticipate that the Steering Committee 
will meet in the Washington, D.C. area three times in Phase 1.  One 
meeting of the DSMB will be held.

Phase II (Months 7 - 79):  Patient recruitment, intervention, and follow-up:

It is anticipated that there will be a 24-month period of recruitment.  
Participants will be randomized and follow-up data collection 
initiated.  The minimum period of follow-up for randomized participants 
will be 48 months.  The Steering Committee will meet every 6 months in 
the Washington, D.C. area during this Phase.  The DSMB will meet once 
per year in Phase II.

Phase III (Months 79 – 84):  Final Data Analysis and Close-out:

The major activities during this phase will be close-out of the CETCs 
and final data analysis.  Results will be presented at major scientific 
meetings and publications prepared for publication in the peer-reviewed 
scientific literature.  A final meeting of the Steering and Planning 
Committee will be held in the Washington, D.C. area to review the 
results of the trial.  The DSMB will meet once in Phase III.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  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.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: 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 time of submission, two additional copies of the application and any 
appendix material must be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard
Rm. 752 MSC 5452
Bethesda, MD  20892-5452
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
(for express/courier service: Bethesda, MD  20817)

APPLICATION PROCESSING: Applications must be received by the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review.
 
The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  The CSR will not accept any application that is 
essentially the same as one already reviewed. This does not preclude 
the submission of substantial revisions of applications already 
reviewed, but such applications must include an Introduction addressing 
the previous critique.

PEER REVIEW PROCESS

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

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by NIDDK, NCCAM, and ODS in accordance with the 
review criteria stated below.  As part of the initial merit review, all 
applications will:

o Receive a written critique
o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications 
under review, will be discussed and assigned a priority score
o Receive a second level review by the NIDDK National Advisory Council or Board.
 
REVIEW CRITERIA

Applicants are expected to address issues identified under SUBMITTING 
AN APPLICATION/SUPPLEMENTAL INSTRUCTIONS as well as the RESEARCH SCOPE. 
All applications will be reviewed according to the criteria listed 
below.  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.

Review Criteria for Clinical Evaluation and Treatment Centers (CETC) 
are as follows.

o Significance:  The application should address the problem outlined in 
the RFA.  The application should demonstrate how the clinical trial 
will advance scientific and/or medical knowledge.

o Approach:  The adequacy of the proposed conceptual framework and 
details of the trial design.

o Recruitment and Retention Capabilities:  This is the most critical 
review criterion.  Applicants must demonstrate the ability to recruit a 
large number of men who are candidates for the non-surgical treatment 
of BPH and follow them prospectively. Recruitment of racial and ethnic 
minority men should be described in detail with regards to racial and 
ethnic make-up of the study population.  The importance of complete 
follow-up of study participants 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 patients 
treated with non-surgical therapy over the past three years must be 
included in the application. 

o Investigators:  The Principal Investigator should be appropriately 
trained and well suited to carry out this clinical trial.  The roles 
and responsibilities of other key personnel should be identified in the 
application and their experience in clinical trials clearly noted.  

o Environment:  The environment in which the work will be done should 
contribute to the probability of success.  There should be evidence of 
institutional support.

o Resources:  Documented adequacy of the proposed facility and space 
is necessary.

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

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 the final protocol developed 
collaboratively by the Steering and Planning Committee must be included 
in the grant application.

o Collaboration between institutions in a single CETC application: For 
those applications proposing collaborative efforts between one or more 
applicants from different institutions to form a single CETC additional 
factors to be considered include cost, recruitment capabilities, and 
the utilization of support personnel, and logistics of participant 
follow-up and adherence promotion.  An administrative plan for such 
arrangements needs to be clearly delineated.

Review Criteria for the Data Coordinating Center (DCC) are as follows.

o Significance:  The application should address the problem outlined in 
the RFA.  The application should demonstrate how the clinical trial 
will advance scientific and/or medical knowledge.    

o Approach:  The applicant must include the conceptual framework, 
design, methods, and analyses to support the goals of the program?  
Potential problem areas and approaches to solve problems must be 
included in the application.  

o Potential problems specific to conducting a large simple trial:  It 
is anticipated that there will be few data collection forms and a 
simple intervention administered to the men participating in this 
clinical trial (the format of a large simple trial).  Applications for 
the DCC should address potential problems in such a study design.

o Proposed Plans for Data Analysis:  Plans been established for 
analyzing (interim and final data analysis) the data from the proposed 
trial, including plans for interim monitoring of results for the Data 
and Safety Monitoring Board must be included in the application.

o Investigators:  The Principal Investigator should be appropriately 
trained and well suited to carry out this clinical trial.  The roles 
and responsibilities of other key personnel should be identified in the 
application and their experience in clinical trials clearly noted.  

o Environment:  The environment in which the work will be done should 
contribute to the probability of success. There should be evidence of 
institutional support.

o Data Management and Quality Control: Adequacy of plans to ensure 
complete, reliable, and timely transmission of the study data by the CETCs. 

o Web-based data transmission:  It is expected that the DCC will 
implement a web-based data transmission system.  A plan for data 
transmission via the worldwide 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 stopping guidelines, reporting the 
results of the trial, including adverse events and safety of the interventions?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  The adequacy of the proposed protection for humans, 
animals, or the environment, to the extent they may be adversely 
affected by the project proposed in the application.

o INCLUSION:  The adequacy of plans to include subjects from both 
genders, all racial and ethnic groups (and subgroups), and children as 
appropriate for the scientific goals of the research.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, below).

o DATA SHARING:  The adequacy of the proposed plan to share data.

o BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:    March 15, 2002
Application Receipt Date:         April 15, 2002
Peer Review Date:                 June/July 2002
Council Review:                   September 18-19, 2002
Earliest Anticipated Start Date:  September 30, 2002

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 Programmatic priorities
o Geographic distribution (applies only to CETCs)
o Potential for recruitment of racial and ethnic minorities (applies to 
CETCs only)
o Success in the recruitment and retention of trial participants, and 
the promotion of medication adherence in previous NIH funded clinical 
trials (applies to CETCs only).

REQUIRED FEDERAL CITATIONS

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research 
components involving Phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the 
policy of the NIH that women and members of minority groups and their 
sub-populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating that inclusion is inappropriate with respect to the health 
of the subjects or the purpose of the research. This policy results 
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates: the use of an NIH 
definition of clinical research, updated racial and ethnic categories 
in compliance with the new OMB standards, clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398, and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must 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) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

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.   Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet site.

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 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.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.848 and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284 and administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.

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


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