Full Text CA-95-007

COOPERATIVE NETWORK FOR EVALUATION OF MARKERS OF URINARY BLADDER
CANCER

NIH GUIDE, Volume 24, Number 7, February 24, 1995

RFA:  CA-95-007

P.T. 34

Keywords: 
  Urogenital System 
  Cancer/Carcinogenesis 
  Biochemical Markers 
  Pathophysiology 


National Cancer Institute

Letter of Intent Receipt Date:  April 21, 1995
Application Receipt Date:  June 23, 1995

PURPOSE

The Cancer Diagnosis Branch of the Division of Cancer Biology,
Diagnosis and Centers at the National Cancer Institute (NCI) invites
applications for cooperative agreements from institutions capable of
and interested in participating in the Cooperative Network for
Evaluation of Markers of Urinary Bladder Cancer.  The goal of the
network is to evaluate biochemical, immunologic, genetic, and other
quantifiable markers for diagnosis and prognosis of urinary bladder
cancer.  The network will perform collaborative studies requiring
expertise in urology, pathology and/or basic cancer biology to
evaluate appropriate quantifiable markers of urinary bladder cancer
and to define relevant clinical applications.  This network will
develop and carry out new studies and continue the collaborative
studies of bladder cancer markers currently being carried out by the
existing Marker Network for Bladder Cancer.

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,
Cooperative Network for Evaluation of Markers of Urinary Bladder
Cancer, is related to the priority area of cancer.  Potential
applicants may obtain a copy of "Healthy People 2000," (Full Report:
Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202 783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by for-profit and non-profit
organizations, public and private, located in the United States,
Canada, or Mexico.  These include universities, colleges, hospitals,
laboratories, units of state and local governments, and eligible
agencies of the Federal government among others.  Racial/ethnic
minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01) (an assistance mechanism rather
than an acquisition mechanism) in which substantial NCI scientific
and/or programmatic involvement with the awardee is anticipated
during the performance of the activity.  Under this mechanism, the
NCI purpose is to support and/or stimulate the recipient's activity
by working jointly with the award recipients in a partnership, but
not leadership role.  Details of the responsibilities, relationships,
and governance of the project are discussed later under the section
"Terms and Conditions of Award."

The NCI anticipates six awards at an average direct cost of about
$150,000.  However, since the nature and scope of the proposed
research may vary, the requested budget should reflect the
anticipated cost of the research.

This RFA is a one-time solicitation.  Generally future unsolicited
competitive continuation applications will compete as research
project applications with all other investigator initiated
applications and be reviewed by the Division of Research Grants
(DRG).  However, if the NCI determines that there is a sufficient
continuing program need, the NCI will invite recipients of awards
under this RFA to submit competitive continuation cooperative
agreement applications for review according to the procedures
described under REVIEW CONSIDERATIONS.

FUNDS AVAILABLE

The NCI anticipates making up to six awards for project periods of
four years.  A total cost of $1,300,000 is expected to be set aside
for funding these activities in the initial year.  Although this
project is provided for in the financial plans of the NCI, the award
of cooperative agreements pursuant to this RFA is contingent on the
availability of funds appropriated in fiscal year 1996.  The earliest
feasible start date for the initial awards will be April 1, 1996.

RESEARCH OBJECTIVES

Background

There is a need to improve diagnostic accuracy, more adequately
predict prognosis, and more effectively monitor response to therapy
in bladder cancer.  Advances in immunology, molecular biology and
genetics have opened new possibilities for developing cell or tissue
markers to detect cancer and to predict recurrence, invasion, and
metastasis.  These advances have led to new and more effective
approaches to diagnosis and prediction.  A number of potential
markers exist and there is a need for organized efforts to
effectively evaluate their utility.  The development of additional
quantitative cell or tissue markers will expand the repertoire of
diagnostic and prognostic measurements available to the clinician.

Different cell markers appear to correlate with particular biological
behaviors of urinary bladder tumors.  Separate markers may be useful
for predicting recurrence, progression or metastasis in early stage
disease (Ta, T1) or for detecting carcinoma in situ.  Markers for
prediction of treatment response may prove useful in selecting the
most appropriate treatment.  DNA ploidy studies of exfoliated tumor
cells have demonstrated some utility in predicting tumor behavior.
The addition of other quantitative markers will expand the range of
diagnostic measurements and may add to the accuracy and range of
diagnostic information available to the clinician.

A variety of immunological, biochemical and genetic markers are
currently being evaluated by the Marker Network for Bladder Cancer,
which was funded in April 1992 and will end in March, 1996.  While
these activities are expected to continue, activities of the proposed
network need not be confined to markers currently under study.
Investigators are encouraged to propose promising markers and
appropriate studies for their evaluation.  Individual proposals by
successful applicants will be evaluated by the Coordinating
Committee, which will determine which should be pursued as network
studies.

Objectives and Scope

The objective of this RFA is to invite applications for cooperative
agreements to support a network of laboratories to evaluate promising
diagnostic and prognostic markers of urinary bladder cancer.  The
existing network has already demonstrated the feasibility of an
inter-institutional network for collaborative clinical studies of
urinary bladder cancer markers.  Important clinical questions
include, but are not limited to: Are there markers that can predict
recurrence in patients with superficial (Ta/T1) transitional cell
carcinoma of the bladder?  Can methods be developed to identify
patients whose disease will progress from carcinoma in situ to
invasive cancer?  Are there ways to predict metastatic potential and
or response to therapy in patients with invasive cancer?  Can
effective non-invasive techniques be developed to replace cystoscopy
in monitoring tumor recurrence.  Potential activities include, among
others:  (1) evaluation of additional genetic, biochemical and
immunological markers of urinary bladder cancer; (2) development of
techniques for quantitatively assaying those markers; and (3)
development of tumor classification systems useful in patient
management.  The collaborative approach will optimize the research
opportunities and build on the strengths of the participating
institutions by facilitating sharing of clinical material and
reagents.  This will expand the available patient resources, improve
the evaluation of potentially useful markers and allow comparison of
their utility in different clinical and laboratory settings.

SPECIAL REQUIREMENTS

The instructions for the "Specific Aims" section of the application
are modified as follows:  Specific aims must be listed in priority
order based on the best judgement of the applicants.  A paragraph
describing the rationale for the order selected must also be
provided.

Specific issues related to cooperative agreements must be addressed
in the application as follows: Travel funds for Coordinating
Committee meetings are to be set aside as a budget line item in each
project budget.  Applicants should include travel expenses to attend
three Coordinating Committee meetings in the first year and two in
each future year.  For planning purposes it should be assumed that
meetings will alternate between the East and the West coast.
Applicants must include in the Research Plans section of the
application specific plans for responding to the "Terms and
Conditions of Award" section.  Applicants should also state their
willingness to collaborate with the other awardees and to participate
as a member of the Coordinating Committee and be bound by its
decisions.  Applicants should also describe how they will comply with
the involvement of the NCI representative and how they will fulfill
the responsibilities of awardees to work together cooperatively.
Applications should propose collaborative network studies as well as
proposing individual laboratory studies to provide a basis for future
collaborative network activities.  Applicants should detail their
access to patients and to clinical and outcome data since clinical
studies are a critical part of network activities.  It is also
critical that each application completely describe the composition of
patient populations in terms of gender and minority status as
discussed in detail below.  For competing renewal applications, a
complete discussion of progress and a description of past
collaborative efforts should be included in the progress report
section of the application.

The following terms and conditions will be incorporated into the
award statement and provided to the institutional official at the
time of award.

Terms and Conditions of Award

These special terms of award are in addition to, and not in lieu of,
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR Parts 74 and 92 and other HHS,
PHS, and NIH Grant Administration policy statements.

The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01) an assistance mechanism (rather
than an acquisition mechanism) in which substantial NCI scientific
and/or programmatic involvement with the awardee is anticipated
during the performance of the activity.  Under this mechanism, the
NCI purpose is to support and/or stimulate the recipients activity by
working jointly with the award recipients in a partnership, but not
leadership role.

The Cooperative Agreement mechanism will require cooperation between
an NCI representative and the principal investigators of the
individual projects in order to assure smooth interactions among the
cooperating institutions.  The NCI representative will assist in
coordinating the activities of the research groups, and in
facilitating exchange of information.  Awardees will retain custody
and primary rights to their data developed under these awards,
subject to government, e.g., NCI, NIH or PHS, rights of access,
consistent with current DHHS, PHS and NIH policies.

1.  Awardee Rights and Responsibilities

Awardees are responsible for developing individual research projects
to facilitate the activities of the network and participating in the
development of clinical protocols for network studies.  All
collaborative studies conducted under this RFA by members of the
network must be approved by the Coordinating Committee.  Awardees
will be required to accept and implement the common protocols and
procedures approved by the Coordinating Committee.  Responsibility
for specific aspects of collaborative network studies (e.g.,
statistical design and analysis) will be determined by the Committee
at the time each study is planned.  Two members of each research
group are required to attend meetings of the Committee (as detailed
below), to help formulate the Committee's policies and protocols
(which will be submitted to the NCI representative for approval), and
to implement those policies.  Awardees are required to have access to
appropriate tumor tissue and normal tissue.  They are required to
submit progress reports at each meeting of the Coordinating
Committee.

2.  NCI Staff Responsibilities

The Program Director for Bladder Cancer of the Cancer Diagnosis
Branch (hereafter referred to as the NCI representative) will
coordinate and facilitate the programs supported by these Cooperative
Agreements, will attend and participate in all meetings as a member
of the Coordinating Committee, and will provide liaison between the
Coordinating Committee, the Protocol Review Committee of the Cancer
Therapy Evaluation Program, and participating research groups.  The
NCI representative will assist the Coordinating Committee in
developing operating policies, quality control procedures and
consistent policies for dealing with recurring situations that
require coordinated action.  The NCI representative may review the
operations of individual laboratories for compliance with protocols
and other operating policies developed by the Coordinating Committee.
The NCI representative may recommend withholding of support,
suspension or termination of an award for lack of progress or failure
to adhere to policies established by the Coordinating Committee.  To
assure consistency and quality, the Chief, Cancer Diagnosis Branch,
DCBDC, NCI must concur in operating policies and clinical protocols
prior to their implementation.

3.  Collaborative Responsibilities

The NCI representative and the participating research groups will be
responsible for forming a Coordinating Committee as defined below.
Operating policies developed by the Coordinating Committee will be
submitted by the NCI representative to the Branch Chief, Cancer
Diagnosis Branch, NCI for concurrence prior to implementation.  The
NCI will facilitate the review of operating policies and clinical
research protocols.  Results of the review will be discussed with the
Coordinating Committee and an arbitration system, as detailed below
will be available to resolve disagreements between the NCI
representative and the other members of the Coordinating Committee.

The Coordinating Committee will review the plans proposed in their
applications by the individual research groups to insure that they
are compatible with the overall goals of the RFA.  Members of the
Coordinating Committee will be responsible for redefining research
objectives and defining strategies for network studies to optimize
progress and efficient use of patient and tissue resources.  The
Coordinating Committee will also be responsible for coordinating
activities such as plans for statistical design and analyses,
developing forms, distributing reagents and biological samples, data
collection and data analysis, monitoring the progress of the network
and maintaining quality assurance.

The Coordinating Committee will consist of the NCI representative and
two members from each cooperating institution, one of whom is the
principal investigator.  The NCI representative will be appointed by
the Chief of the Cancer Diagnosis Branch, Division of Cancer Biology,
Diagnosis and Centers.  The Coordinating Committee will be
responsible for electing a chairperson (who may not be the NCI
representative).  The Chairperson of the Coordinating Committee will
be responsible for coordinating the Committee activities, for
preparing meeting agendas, and for scheduling and chairing meetings.
The NCI representative will attend and participate in all meetings of
the Coordinating Committee and should be informed of major
inter-group interactions. The Coordinating Committee members will
evaluate progress reports from each participating research group;
each group is responsible for timely preparation and presentation of
its report.

The Coordinating Committee will meet initially to map strategies and
set up operating procedures.  The Coordinating Committee will meet at
least twice a year thereafter (for a total of three meetings in the
first year and two per year thereafter).  Meetings may be held at any
of the participating institutions or at another convenient location.
These meetings are aimed at coordinating the activities of the
participating laboratories, establishing new policies and priorities,
and reviewing progress.  The NCI representative will participate in
the discussions at these meetings.

4.  Arbitration

Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between award recipients and the NCI
may be brought to arbitration.  An arbitration panel will be
composed of three members -- one selected by the Coordinating
Committee (with the NCI member not voting), one selected by the NCI,
and the third chosen by the two previously 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 PHS regulations at 42 CFR part 50, subpart D and HHS
regulations 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 subpopulations must be included in all NIH supported
biomedical and behavioral research involving human subjects, unless a
clear and compelling rationale and justification is provided that
inclusion is inappropriate with respect to the health of the subjects
or the purpose of the research.  This new policy results from the NIH
revitalization Act of 1993 (Section 492B of Public Law 103-43) and
supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations) which have been in effect since
1990.  The new policy contains some new provisions that are
substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guide for Inclusion of Women and Minorities in Clinical
Research", which have been published in the Federal Register of March
28, 1994 (FR 59 14508-14513) and reprinted the NIH Guide for Grants
and Contracts, Volume 23, Number 11, March 18, 1994.

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

LETTER OF INTENT

Prospective applicants are asked to submit, by April 21, 1995, a
letter of intent that includes a descriptive title of the proposed
project, the name, address and telephone number of the principal
investigator, the names of other key personnel, the participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.  Although a letter of intent
is not required, is not binding and does not enter into the review of
subsequent applications, the information allows NCI staff to estimate
the potential workload and to avoid conflict of interest in the
review.

The letter of intent is to be sent to Dr. Roger L. Aamodt at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The grant application form PHS 398 (rev. 9/91) is to be used in
applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/435-0714; and from the NCI Program Director listed
under INQUIRIES.

The RFA label available in the PHS 398 application form must be
affixed at the bottom of the face page of the application.  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 2a of the face page of the application form and the YES box must
be marked.

Submit a signed typewritten original of the application, including
the checklist, and three signed photocopies, in one package to:

Division of Research Grants
National Institutes of Health
6701 Rockledge Drive - MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express mail)

At the time of submission two additional copies of the application
must also be sent to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636A
6130 Executive Boulevard
Rockville, MD  20892
Rockville, MD  20859 (for express mail)

Applications must be received by June 23, 1995.  If an application is
received after this date it will be returned to the applicant without
review.  The Division of Research Grants (DRG) will not accept any
application in response to this RFA that is the same as one currently
pending initial review, unless the applicant withdraws the pending
application.  The DRG 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 applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

General Considerations

All applications will be judged on the basis of the scientific merit
of the proposed project and the documented ability of the
investigators to meet the RESEARCH OBJECTIVES of the RFA.  Although
the technical merit of the proposed activities is important, it will
not be the sole criterion for evaluation of the application.  Other
considerations such as the importance and timeliness of the proposed
studies, access to patients, and appropriateness of proposed
collaborations are also part of the evaluation criteria.

Factors considered to be important for review include demonstrated
expertise in urology, pathology and/or basic cancer biology applied
to the diagnosis and treatment of urinary bladder cancer; expertise
and an active research program in cell marker studies; availability
of an appropriate population of patients for study; good interaction
among collaborating researchers; demonstration of adequate
facilities; and willingness to interact within the terms of a
Cooperative Agreement as outlined in this document.

Review Method

Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants (DRG) and for responsiveness by the NCI.
Incomplete and/or non-responsive applications will be returned to the
applicant without further consideration.

Applications that are complete and responsive will be evaluated for
scientific and technical merit by an appropriate peer review group
convened by the NCI in accordance with the review criteria stated
below.  As part of the initial merit review, all applications will
receive a written critique and may undergo a process in which only
those applications deemed to have the highest scientific merit will
be discussed, assigned a priority score, and receive a second level
of review by the National Cancer Advisory Board.

Review Criteria

Applicants are encouraged to submit and describe their own ideas
about how to best meet the goals of the cooperative network and to
propose their own protocols, and are expected to address the issues
identified under SPECIAL REQUIREMENTS.

The Review group will assess the scientific merit of the applications
and related factors, including:

1.  Feasibility and relevance of the proposed project to the overall
goals and objectives of the RFA.

2.  Demonstration of availability of and access to appropriate
patients (including representative numbers of women and minorities or
sufficient justification for their exclusion), tissue and appropriate
patient data.

3.  Proposed collaborations among urologists, pathologists, basic
cancer biologists and other key personnel.

4.  Qualifications, experience and proposed responsibilities of the
principal investigators and of key support personnel.

5.  Facilities and resources, and their availability for this
project.

6.  Plans for effective interaction and coordination among
cooperating projects and with the NCI, including a proposed
timetable.

7.  Plans to protect the rights of human subjects.

8.  For competing continuation applications, the reviewers will
consider, in addition to the above criteria, the degree of active
collaboration with the other members of the existing Network,
participation in the development of proposed future studies and
contributions to ongoing studies of the existing Network.

This criterion must not be applied to new applicants.

The review group will recommend an appropriate budget and period of
support for each approved application.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.

Inquiries regarding programmatic issues, including the activities of
the currently funded marker network or inquiries about whether or not
specific proposed research would be responsive may be directed to:

Roger L. Aamodt, Ph.D.
Division of Cancer Biology, Diagnosis, and Centers
National Cancer Institute
Executive Plaza North, Room 513
6130 Executive Boulevard
Rockville, MD  20892-9904
Rockville, MD  20852 (for express mail)
Telephone:  (301)-496-7147
FAX:  (301) 402-1037
Email:  ra32u@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Kathleen Shino
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
6120 Executive Boulevard
Rockville, MD  20892
Rockville, MD  20852 (for express mail)
Telephone:  (301) 496-7800
FAX:  (301) 496-8601
Email:  shinok@nihncigab.gov

AUTHORITY AND REGULATIONS

This program is described in the catalog of Federal Domestic
Assistance No 93.394, Cancer Detection and Diagnosis Research.
Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410 as amended: 42 USC 241 and 285)
and administered under PHS grants policies and Federal Regulations 42
CFR Part 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

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

.

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