URINARY INCONTINENCE TREATMENT NETWORK

Release Date:  July 8, 1999

RFA:  DK-99-001 (Limited competition, see RFA-DK-06-501)

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Child Health and Human Development

Applicant Information Forum Date:  July 23, 1999
Letter of Intent Receipt Date:  September 24, 1999
Application Receipt Date:  October 20, 1999

PURPOSE

The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of the
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and
the National Institute of Child Health and Human Development (NICHD) have a
substantial and longstanding interest in research on the urinary bladder and
urinary continence disorders.  Surgery is one of the most common therapeutic
interventions for urinary incontinence, but long-term outcomes have not been
systematically evaluated.  To clarify the benefits of the different surgical
interventions for treatment of patients with urinary incontinence, the NIDDK
and the NICHD invite cooperative agreement applications for investigators to
design and implement a multicenter, prospective cohort study.  This study will
assess the long-term outcomes of the most commonly utilized surgical
interventions to correct urinary incontinence in adult women and the
utilization of concomitant medical and behavioral therapy.  These cooperative
agreements will support a collaborative network of Continence Treatment
Centers (CTCs) and a Biostatistical Coordinating Center (BCC) that will
prospectively assess the outcomes of different surgical interventions for the
treatment of urinary incontinence in women over an approximately 3-year to 4-
year period.  Prior to initiation of these collaborative, prospective
observations, this group of investigators, known as the Urinary Incontinence
Treatment Network (UITN), will develop standardized diagnostic and outcome
measures that can be applied uniformly to all of the different surgical
cohorts to be evaluated by this initiative.  This includes the establishment
of diagnostic entry criteria, identification of clinically and patient-
relevant outcomes, and the development of questionnaires to measure quality of
life and other patient-reported factors.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This RFA, Urinary Incontinence Treatment
Network, relates to the priority areas of chronic disabling conditions and
prevention services.  Potential applicants may obtain a copy of "Healthy
People 2000" (Full Report Stock No. 017-001-00474-0 or Summary Report: Stock
No. 017-001-00473-1) through Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone 202-512-1800).  Applicants may
also obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit,
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 CTC and the BCC, however, separate applications are required and a
specific plan of how 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 July 1, 2000.  At
this time, the NIDDK has not determined whether or how this solicitation will
be continued beyond the present RFA.

FUNDS AVAILABLE

The NIDDK and NICHD plan to make five awards for CTCs and one award for a BCC. 
Approximately $2,000,000 total cost (direct plus indirect costs) is expected
to be available per year of support under this RFA.  It is anticipated that
the award for each CTC will be about $250,000 total cost per year and the
award for the BCC will be about $750,000 total cost per year.

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 and
the NICHD, 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

Background

Urinary incontinence is a complex condition that affects females and males of
all ages.  The factors influencing a patient"s decision to seek care and the
criteria by which the clinician selects therapy are not uniform.  In addition,
diagnostic criteria that define the categories and subcategories of urinary
incontinence are neither well-defined nor utilized by many physicians.  There
are numerous options available for the treatment of urinary incontinence,
including surgery, pharmaceuticals, behavioral modification, and prostheses. 
Frequently, a combination of these therapies is utilized.  Most of the
literature on surgical intervention supports the conclusion that there is
marked improvement for continence during the immediate and short-term post-
operative period.  There are, however, very few well-designed, long-term
observational studies that document the outcomes of invasive interventions
over a longer period.  The clinical studies reported to date suffer from a
number of methodological shortcomings, including brief follow-up, inadequate
sample size (and thus low statistical power), uncertain diagnostic criteria
for patient selection and outcome assessment, inadequate measurement of
quality of life, uncertainty about the relevance of reported clinical and
patient-related outcomes, absence of documentation of complications, and large
numbers of patients lost to follow-up (thus introducing possible bias into
results).

Despite the frequent use of surgery for urinary incontinence, there is no
consensus on which procedure(s) offers the most improvement and patient
satisfaction.  No rigorously conducted long-term, prospective cohort studies
have been performed to date that evaluate the most commonly performed surgical
procedures.  In addition, the pharmacological and behavioral therapy after
surgery for urinary incontinence is common and use of these interventions are
rarely standardized or reported in prospective studies.  Therefore, well-
designed prospective cohort studies of surgical treatments for urinary
incontinence are needed to provide both physicians and patients with the
information necessary to make well-informed decisions about treatment options
for specific types of urinary incontinence.

B.  Research Goals and Scope of the Activity

The intent of the RFA is to solicit applications from investigators proposing
to serve as CTCs and/or BCC to develop and conduct a multicenter, prospective
cohort study of women who have undergone surgical treatment of urinary
incontinence.  Investigators will cooperate in a collaborative manner to
develop a protocol to evaluate the effect of different surgical techniques on
patient- and physician-reported outcomes. The cooperative group of
investigators will also develop objective diagnostic and outcome measures to
evaluate individual surgical interventions.  We anticipate that the CTC will
require expertise in urology and urogynecology as related to the surgical
treatment of urinary incontinence in women.  The BCC must have expertise in
biostatistics, data management, database development and computer programming
as well as experience in coordinating multicenter epidemiological studies.

The specific goals of this solicitation are as follows:

1.  to determine the long-term effects and outcomes, including complications,
of the most commonly used surgical procedures for women with urinary
incontinence,

2.  to document the use and evaluate the effects of adjuvant therapy,
including behavioral and medical treatment, in women who have undergone
surgery for urinary incontinence,

3.  to determine which surgical procedure(s) provides the most beneficial
outcome and fewest complications for different categories of urinary
incontinence patients defined at baseline (prior to surgery),

4.  to develop uniform clinical definitions for the various categories of
urinary incontinence patients,

5.  to develop standardized outcome measures, including questionnaires, to
evaluate quality of life and patient satisfaction,

6.  to determine the influence of race/ethnicity and co-morbid medical
conditions such as diabetes, obesity, and child-bearing, on treatment outcomes
and complications, and

7.  to determine the prognostic utility of urodynamic testing for surgical
success and as a measure of outcome.

We anticipate that the procedures and survey instruments developed in the
study will be utilized, with modification when necessary, in all the clinical
studies conducted under this RFA.

Because the prevalence of urinary incontinence is substantially greater in
women than in men, and since the surgical procedures for urinary incontinence
are markedly different for women and men, the study population for this RFA is
restricted to women.

Study Phases

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 the Prospective Surgical Cohort Study.

This phase will include planning and developing the protocol for a prospective
cohort study of surgery, establishing indices for measurement of quality of
life and patient satisfaction, writing the protocol and manual of operations,
and creating data collection forms.  The protocol for urodynamic studies will
also be developed.  The BCC will develop the database for the study and
implement procedures for data collection by the CTCs.  Upon completion of the
protocol and manual of operations, centralized training of the study
coordinators will be conducted.  Subsequently, a small number of patients will
be enrolled by each CTC during the last two months of Phase I to test
recruitment procedures and methods for data collection and transmission. 
Prior to implementation of the cohort study, a group of external advisors,
selected by the NIDDK, will review the protocol.

Phase II (Months 13-54) Surgical Intervention/Recruitment of the Full Study
Cohort, Follow-up of Study Participants and Interim 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 cohort study will be
carried out.  It is anticipated that the follow-up of patients from the
surgery cohort will be completed in month 42 of Phase II (month 54 of total
project period).  Data from the urodynamic studies will also be collected and
analyzed.  Interim data analysis and reporting of selected findings will occur
throughout this Phase.

Phase III: (Months 55-60) Final Data Analysis and Close out of Continence
Treatment Centers.

Final analysis of results from the prospective surgical cohort study and the
urodynamic studies will be performed during a six-month period and manuscripts
will be prepared suitable for publication in peer-reviewed scientific
journals.  The CTCs will also be closed out.

D.  Study Outline

It is envisioned that over the five-year period a cooperative, multicenter,
prospective cohort study of the outcomes of the surgical treatment of urinary
incontinence in adult women will be designed and implemented by the UITN. 
Prior to initiation of enrollment for the cohort study, standard diagnostic
criteria, inclusion and exclusion criteria, and outcome measures, and tools to
assess quality of life and patient satisfaction will also be developed.  It is
anticipated that the prospective cohort study will evaluate the outcomes of
the most commonly utilized surgical procedures in the United States for women
with urinary incontinence.  Participants will be recruited and enrolled into
the cohort study over a period of approximately twelve months.  All patients
will be periodically and uniformly assessed during follow-up clinic visits for
the duration of the study.  A study to evaluate the prognostic significance of
urodynamic testing and its utility in evaluating patients during the course of
follow-up will also be designed and implemented.

It is not expected that each CTC will have experience in all of the currently
utilized surgical procedures for urinary incontinence nor is it required that
CTCs alter their current clinical practice patterns to participate in this
study.

The design for the prospective cohort study protocol will be established and
implemented by the UITN.  Essential elements of the design including patient
eligibility criteria, outcome measurements, and the specific surgical
interventions to be evaluated will be decided by the Steering and Planning
Committee and approved by a group of external advisors, as described below.

STUDY COMPONENTS

1.  Continence Treatment Center

A Continence Treatment Center is an institution that is actively involved in
the recruitment, evaluation, treatment, and follow-up of study participants. 
It should consist of an interdisciplinary team of clinical investigators and
appropriate personnel, such as a research coordinator and clerical staff.  The
clinical investigators must include a urologist and a urogynecologist with
demonstrated training and experience in the diagnosis and surgical treatment
of female urinary incontinence.  It is assumed that either a urologist or a
urogynecologist will serve as the principal investigator of a CTC. Other
clinicians with similar training and experience may also be included as
investigators.

CTC investigators must be capable of recruiting and retaining a sufficient
number of women for the proposed cohort study.  CTCs should have an available
target population from which the required number of study participants can be
recruited, including a sufficient number of women of racial/ethnic minority. 
The principal investigator and co-investigators in each CTC should be skilled
in collaborative clinical investigation since they will be required to submit
protocol data to the BCC expeditiously.  CTCs 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.

2.  Biostatistical Coordinating Center

The BCC will assist investigators in developing the design and protocol for
the prospective cohort study, including determination of the final sample size
and power calculations for comparison of surgical treatment groups.  The BCC
will also have primary responsibility for collecting, editing, storing, and
analyzing data generated by the CTC.  It should be prepared to assume a key
role in overseeing implementation and adherence to the study protocol, and
assuring quality control of the data collected.  Staff required for a BCC
should include biostatisticians, project managers, computer programmers, and
study coordinators.  The BCC also will 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 meeting of these committees
and their subcommittees.  The BCC will play a key role in analyzing data to
support the efforts of the CTCs in writing manuscripts suitable for
publication in peer-reviewed scientific journals.

3.  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 CTCs and the
BCC, the Chairperson of the Steering and Planning Committee, and the NIDDK and
NICHD Project Scientists (described in detail under Terms and Conditions). 
The Steering and Planning Committee will develop the design of the cohort
study, propose interim and final data analysis plans, and along with their
staff at the CTCs, recruit, perform surgery, and follow-up study participants.

Executive Committee

An Executive Committee, including the Chairperson of the Steering and Planing
Committee, the principal investigator of the BCC, NIDDK and NICHD 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.

5. Group of External Advisors

An independent group of experts in urology, urogynecology, biostatistics,
clinical trials, and ethics who are not otherwise involved in the study will
be recruited by the NIDDK to review periodically the progress of the study
(described in detail under Terms and Conditions).  This group will also be
responsible for reviewing the acceptability of plans to monitor data quality
established by the Steering and Planning Committee and the subsequent
monitoring of data quality by means of reports prepared by the BCC.

6.  Project Scientists

The NIDDK will identify two project scientists for the study.  The project
scientists will assist the Steering and Planning Committee and a group of
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.

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 protocol
development, patient recruitment and follow-up, data collection, quality
control, final data analysis and interpretation, and preparation of
publications.  The awardees agree to work cooperatively with the other CTCs
and the BCC and agree to follow the common protocol and Manual of Operations
developed by the Steering and Planning Committee.  The awardees agree also to
transmit all study data to a central 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 urinary
incontinence and the other will have experience in the development and conduct
of multicenter 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 external advisors.

The NIDDK reserves the right to terminate or curtail the study (or an
individual award) in the event of substantial shortfall in participant
recruitment, follow-up, data reporting, quality control, or other major breach
of the protocol, reaching a major study endpoint substantially before schedule
with persuasive statistical significance 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 CTCs, 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, facilitating the
conduct and monitoring of the cohort study, and reporting the study results. 
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 urinary incontinence who are not
participating directly in the study.  Subcommittees that are appointed by the
Steering and Planning Committee and comprised of Principal Investigators and
appropriate staff from the CTCs and the BCC will be involved in the design of
the protocol and the manual of operations.  The subcommittees will also
involved in ongoing functions of the prospective cohort study, such as review
of ancillary studies and preparation of publications.  Not all CTCs will
necessarily be represented on all subcommittees.

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 Planing Committee meetings, as needed for efficient
progress of the cohort study.  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 held in the Washington, D.C. area or by conference call.

c) An independent group of external advisors, selected by the Director, NIDDK,
will review periodically the progress of the cohort study.  This group will
include experts in the relevant medical, statistical, psychological, and
ethics fields who are not otherwise involved in the study.  The external
advisors will review participant safety, evaluate results, monitor data
quality, and provide operational and policy advice to the Steering and
Planning Committee and to the NIDDK regarding the status of the study. One of
the NIDDK Project Scientists will serve as Executive Secretary of the group. 
The members of the group will review progress and report to the NIDDK and
NICHD at least once each year, or more often if necessary.

5) Arbitration

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

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their sub-populations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 1003-43).  All investigators proposing research
involving human subjects should read the "NIH Guidelines for Inclusion of
Women and Minorities as Subjects in Clinical Research" which have been
published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number
11, available on the web at:
http://grants.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html

Because the prevalence of urinary incontinence in women is substantially
greater than in men and because treatment of urinary incontinence is markedly
different in men and women, participation in the prospective cohort study
planned under this initiative will be restricted to women.

OPEN INFORMATION FORUM FOR PROSPECTIVE APPLICANTS

A one-day open information forum will be held for prospective applicants on
July 23, 1999, from 12 noon to 4 p.m. in Conference Room 6 on the sixth floor
of Building 31C on the NIH reservation in Bethesda, MD.  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 to either of the two NIDDK program staff listed under INQUIRIES at
least one week in advance of the forum.  A list of the questions asked during
the information forum and a written summary of the responses from DKUHD staff
will be provided to persons who request it and were unable to attend the
meeting.

LETTER OF INTENT

Prospective applicants are asked to submit, by September 24, 1999, 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 45 Center
Drive, Room 6AS-37F, MSC 6600
Bethesda, MD 20892-6600
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 available in the form PHS 398 must be affixed to the bottom of
the face page.  Failure to use this label could result in delayed processing
of the application such that it may not reach the review committee in time for
review.  For purposes of identification and processing, item 2 of the face
page of the application must be marked "YES" and the RFA number and the words
"Urinary Incontinence Treatment Network" 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 this 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
45 Center Drive, Room 6AS-37F, MSC 6600
BETHESDA, MD 20892-6600

Applications must be received by October 20, 1999.  If an application is
received after this date it will be returned to the applicant without review. 
The Center for Scientific Review  (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The
CSR will not accept any application that is essentially the same as one
already reviewed. This does not preclude the submission of a substantial
revision of an application already reviewed, but such an application must
follow the guidance in the PHS 398 applications instructions for the
preparation of revised applications, including an introduction addressing the
previous critique.

Information to be Included in Applications

Details of the Proposed Cohort Study Protocol:  Applicants for both the CTC
and the BCC should respond with a research protocol involving multi-center
participation to address the objectives of the study and to reach the study
goals.  Applicants should outline the rationale and background of the proposed
cohort study, study design and protocol, eligibility criteria, and initial
sample size and power analyses in their applications.  An application for a
CTC should provide evidence that the investigators are capable of recruiting a
sufficient number of participants for the proposed study, including plans for
recruitment of minority/ethnic women. Applications for the BCC should also
include information about plans for data collection, data transmission
(including distributed data entry), and overall quality control of the study. 
Information on proposed plans for data analysis and sample size and power
calculations should also be provided by applicants for the BCC.

Participation in a Collaborative Program:  To promote the development of a
collaborative program among the awardees, the applicant should present
evidence of experience in working cooperatively with other institutions
serving as a patient recruitment/surgical treatment/follow-up center
("Continence Treatment Centers") and/or a Biostatistical Coordinating Center. 
The applicants must also indicate their ability to follow common protocols
that are collaboratively developed.  CTCs also will be expected to communicate
with the BCC and the NIDDK and NICHD Project Scientists on a regular basis.

Institutional Support:  There should be evidence of strong institutional
support for the study, including adequate space in which to conduct clinic
(for a CTC) or data analysis/management (for the BCC) activities. An
organizational structure for the study should be set forth in the application,
delineating lines of authority and responsibility for dealing with problems in
all general areas as well as stated willingness to follow the commonly agreed
upon protocol.

Previous Experience:  The applicant should include a succinct discussion of
previous relevant research efforts in collaborative clinical studies,
including epidemiological studies and randomized clinical trials.  Research on
urinary incontinence and urological disorders in women is especially relevant.

Suggested Personnel Requirements:  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.  Overall, the staff of a CTC should include urologists and
urogynecologists with demonstrated expertise in female incontinence surgery. 
The study 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 following suggested roles are intended
to be illustrative, not prescriptive:

o  Principal Investigator to provide overall scientific guidance.

o  Physician(s) with expertise in the surgical, pharmacological and behavioral
management of patients with urinary incontinence.  Experience in urodynamic
testing of patients is also important.

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

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

The expertise required for the BCC includes statistics, data management,
computer programming and data base development, and project management.
Clinical consultants for the surgical, pharmacological and behavioral therapy
of urinary incontinence are also required.

The following personnel requirements are suggested:

o  Principal Investigator to provide overall scientific guidance.

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

o  Project Coordinator who can provide full-time attention to the statistical,
administrative, and management aspects of the cohort study.

o  Computer programmers to develop the necessary database.
Individuals for clerical and technical support.

o  Part-time medical consultants with expertise in the treatment of urinary
incontinence patients.

Budget Preparation by Year

Applications for the CTCs and the BCC must include an adequately justified
year-by-year budget, reflecting the major changes in proposed activities as
the cohort study progresses through its various phases.

During Phase I (Year 1), the budget will be for development of the protocol,
manual of procedures, and data collection forms for the prospective surgical
cohort study. The database will also be created by the BCC.  During the last
two months of Phase I, a small number of patients will be recruited by each
CTC and enrolled into the cohort study to evaluate recruitment procedures and
methods for data collection and transmission. The urodynamic studies will also
be developed.  The travel budget for Phase I should be estimated based on
travel for two key investigators to attend two day, bimonthly meetings of the
Steering and Planing Committee in the Washington, D.C. area.

During Phase II (Years 2, 3, 4, and the first six months of year 5), the
budget should reflect recruitment of a full complement participants for the
cohort study in year 2 and follow-up of these participants in years 3 and 4
and in the first half of year 5. Urodynamic studies will also be carried out
during Phase II.  Interim data analysis and preparation of reports to the
Steering and Planning Committee, the Executive Committee, a group of external
advisors and writing of papers for publication will also be performed in Phase
II.  This phase of the program will require meeting approximately every four
months in the Washington, D.C. area.  The travel budget for Phase II should be
estimated based on travel for the Principal Investigator and the Study
Coordinator.

During Phase III (final six months of year 5), final data analyses of the
cohort study and the urodynamic evaluations will be performed by the BCC in
collaboration with UITN investigators to support the writing of manuscripts
for submission to peer-reviewed, scientific journals.  The CTC will also be
closed out.

For a CTC, the budget should request support for the minimum number of full
and/or part-time staff to successfully carry out the proposed trials.  A CTC
personnel list could include a principal investigator, co-Investigator, study
coordinator, and data entry clerk.  Travel for centralized training of the
study coordinator and data entry clerk must also be budgeted (assume central
training to be held in the Washington, D.C. annually during years 2 through
4).  A meeting of study coordinators will be held in the Washington, D. C area
during the first six months of year 5 to plan study close out.

For applications for the BCC, the budget should also include the time and
effort of key personnel needed to conduct the cohort study and the required
number and cost of computers to be used at the CTCs for distributed data
entry.  Travel by BCC staff to Washington, D.C. for the following meetings
should be budgeted: group of external advisors (one meeting per year for each
of the 5 years) and the Steering and Planing Committee (six in Year 1-Phase I
and three meetings annually during Years 2-4, and two meetings in Year 5). 
The budget must also include five site visits each year during years 2-4).

The following is a list of yearly major activities to assist in the
preparation of budget for each of the five years of the program.

Year 1: Development of the study protocol and manual of operations for the
surgical cohort study and urodynamic studies.  Forms and database created. 
Recruitment of a small number of patients to evaluate recruitment procedures
and data collection and transmission methods.

Year 2: Recruitment/perform surgery on participants to reach individual CTC
and study-wide recruitment goals, and follow-up of all participants.  Initiate
urodynamic studies.

Year 3: Continued follow-up of surgical cohort study with emphasis on
retention of participants and tracking adjuvant medication and/or behavioral
therapy treatments.  Preparation of manuscripts (interim findings).  Continue
urodynamic studies.

Year 4: Continued follow-up of cohort participants with emphasis on retention
of participants in study and tracking medication use and/or behavioral
interventions.  Preparation of manuscripts (interim findings).  Continue
urodynamic studies.

Year 5: At the end of the first six months of year 5, follow-up of the cohort
will be completed and final urodynamic studies performed.  During the final
six months of year 5, final data analyses will be performed.  Close out of the
CTCs will be completed.  Preparation of manuscripts reporting final results.

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 encouraged to submit and describe their own ideas about how
best to meet the goals of the cooperative study as outlined in this RFA, and
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 pursuit of these
goals.  Each of these 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 Continence Treatment Centers

o  Significance:  Does this study address an important problem?  If the aims
of the applications are achieved, how will scientific knowledge by advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?

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

The final study design will be developed collaboratively by the Steering and
Planing Committee.  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.  Justification for the proposed sample size is
required.

o  Investigator:  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the Principal Investigator and other researchers?

For the urinary incontinence prospective cohort study described in this RFA,
this criterion will focus on the following questions: Is there documented
evidence of the investigatorþs training experience, and specific competence
relevant to the operation of a CTC?  Is there evidence of successful
collaborative interactions with other investigators under a common protocol in
multi-center clinical trials?

o  Environment:  Does the scientific 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?

Review of applications for Continence Treatment Center awards also will focus
on the following specific criteria:

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

o  Documented experience in surgical, pharmacological and behavioral treatment
for urinary incontinence is required.  Demonstrated knowledge of clinical
aspects of urinary incontinence is also required.

o  Recruitment Capability: Evidence of successful experience and/or realistic
plans for the recruitment and retention of subjects in multi-center clinical
trials and/or cohort studies as well as experience in the recruitment of
minority participants to studies of urinary incontinence to achieve the
necessary sample size is required.  Documentation of the number of adult women
undergoing surgery (procedure-specific) for urinary incontinence over the past
three years is necessary.

o  Retention Capabilities: Plans and/or experience in achieving high rates of
clinic follow-up visits (exceeding 90% during the course of the study) and
adherence in prospective studies are essential.

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.

o  Knowledge of Problems: Demonstrable knowledge of the problems associated
with the conduct of the cohort study and possible solutions is necessary.

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  Collaboration between Centers: For those applications proposing
collaborative efforts between two applicants from different institutions to
form a single CTC additional factors to be considered would include the
advantages of collaboration in terms of cost and recruitment capabilities. 
The organizational/administrative plan for such arrangements needs to be
clearly delineated.

In addition to the above criteria, 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 and 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.

Review Criteria for a Biostatistical Coordinating Center are as follows:

o  Significance:  Does this study address an important problem?  If the aims
of the applications are achieved, how will scientific knowledge by advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?

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

The final study design will be developed collaboratively by the Steering and
Planing Committee.  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  Investigator:  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the Principal Investigator?

o  Environment:  Does the scientific environment in which the work will be
done contribute to the probability of success?  Is there evidence of
institutional support?

Review of applications for the Biostatistical Coordinating Center will also be
based on the following specific criteria:

o  The proposed design, including sample size estimates and power
calculations, for a prospective cohort study of the major surgical procedures
for urinary incontinence in women is required.

o  Scientific and technical merit of the proposed approach to managing the
requirements of the study as outlined in the RFA.

o  Staff Qualifications: Documented specific competence and relevant
experience of professional, technical, and administrative staff pertinent to
the operation of a BCC for a prospective, collaborative cohort study.  Prior
experience collecting data from multiple clinical sites, monitoring the data
quality and developing and utilizing statistical methods to analysis of data
should be demonstrated.

o  Experience of BCC personnel in utilizing procedures that insure the safety
and confidentiality of all records should be documented.

o  Data and Sample Management: Adequacy of the proposed plans and experience
relating to data collection, management, editing, processing, analysis, and
reporting.

o  Centralized Support Functions: Demonstrated ability to identify, enlist,
and coordinate the efforts of central laboratories and clinical facilities to
carry out centralized support functions for the CTCs.  Adequacy of plans to
recruit central laboratories, clinical facilities, and/or other central
support functions.

o  Resources:  Adequacy of the proposed facility, technical hardware, and
space.  Appropriateness of the organizational and administrative structure of
the proposed BCC.  Evidence of institutional support and commitment for the
proposed program should be provided.

o  Knowledge of Problems: Demonstrable knowledge of the potential problems
associated with the conduct of this study and approaches to their solution.

o  Cooperative Experience and Approach: Adequacy of the approach to developing
a cooperative relationship among the participating CTCs and exercising
appropriate leadership in matters of study design, data acquisition, data
management, data quality, and data analysis.  Evidence of experience in and
willingness to participate appropriately in a collaboratively study as
described in this RFA.

In addition to the above criteria, in accordance with NIH policy, all
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 human subjects and the
environment, to the extent they may be adversely affected by the project
proposed in the application.  The initial review group will also examine the
safety of the research environment.

Schedule

Applicant Information Forum Date:  July 23, 1999
Letter of Intent Receipt Date:     September 24, 1999
Application Receipt Date:          October 20, 1999
Special Review Committee:          January/February 2000
NIDDK Advisory Council:            May 2000
Anticipated Award Date:            July 1, 2000

AWARD CRITERIA

Award 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 of centers
o  The frequency and type of surgical procedures exhibited by a CTC
o  Recruitment of racial and ethnic minorities

INQUIRIES

Written and telephone inquiries concerning this RFA are strongly encouraged. 
The opportunity to clarify any issues or questions from potential applicants
is welcome.

For information relating to the NIDDK, programmatic inquiries may be made 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
45 CENTER DRIVE MSC 6600
BETHESDA, MD 20892-6600
Telephone: (301) 594-7717
Fax:  (301) 480-3510
Email: kusekj@extra.niddk.nih.gov
or nybergl@extra.niddk.gov

Fiscal and administrative inquiries may be directed to:

Trude Hilliard
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 CENTER DRIVE Room 6AN-44B MSC 6600
BETHESDA, MD 20892-6600
Telephone:  (301) 594-8859
FAX:  (301) 480-3504
Email: hilliardt@extra.niddk.nih.gov

For information related to NICHD, programmatic inquiries may be directed to:

H. Trent MacKay, M.D., M.P.H. or Anne M. Weber, M.D., M.S.
Center for Population Research
National Institute of Child Health and Human Development
6100 EXECUTIVE BOULEVARD 8B13
BETHESDA, MD  20892
Telephone: (301) 435-6972
Fax: (301) 496-0962
Email: mackayt@mail.nih.gov
or webera@mail.nih.gov

Fiscal and administrative inquiries related to NICHD may be directed to:

Melinda Nelson
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard
Suite 8A17K
Bethesda, MD 20892
Telephone:  (301) 496-5481
FAX:  (301) 496-0915
E-mail:  nelsonm@exchange.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.849 and 93.864.  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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