Full Text CA-95-014

MULTI-INSTITUTIONAL COOPERATIVE GROUP FOR CLINICAL EVALUATION OF
MAGNETIC RESONANCE IMAGING IN BREAST CANCER

NIH GUIDE, Volume 24, Number 13, April 7, 1995

RFA:  CA-95-014

P.T.  34

Keywords: 
  Medical/Diagnostic Imaging 
  Clinical Medicine, General 


National Cancer Institute

Letter of Intent Receipt Date:  May 9, 1995
Application Receipt Date:  June 9, 1995

PURPOSE

The Diagnostic Imaging Research Branch (DIRB), Division of Cancer
Treatment (DCT) of the National Cancer Institute (NCI), invites
applications from consortia of institutions for Cooperative
Agreements (U01) to study the role of Magnetic Resonance Imaging
(MRI) in improved detection and staging of breast cancer.  The NCI is
seeking talented scientists from academic, non-profit and for-profit
research organizations who will interact with other members of the
Consortium, and with DIRB in a concerted way to evaluate and optimize
new approaches to breast cancer diagnosis.  One consortium of
multiple institutions, called "Multi-Institutional Cooperative Group
for Clinical Evaluation of MRI in Breast Cancer", will be funded by
the NCI.  Scientific approaches taken by the Cooperative Group will
be broad and will reflect the creativity and capabilities of
consortium participants.  The purpose of this Request for
Applications (RFA) is to stimulate cooperative efforts through phase
II clinical trials for facilitated evaluation of sensitivity,
specificity and local staging accuracy of breast MRI compared to
conventional radiologic approaches in women with abnormal or
non-diagnostic x-ray mammograms for whom biopsy is required.

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,
Multi-Institutional Cooperative Group For Clinical Evaluation of
Magnetic Resonance Imaging In Breast 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 domestic and foreign non-profit and
for-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and Local
governments, and eligible agencies of the Federal government.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Each application must be submitted from a single consortium
consisting of several participating institutions to ensure accrual of
about 3,000 women over a period of four years.

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 a substantial
involvement between NIH program staff and the awardee is anticipated
during performance of the activity.  Under the cooperative agreement,
the NCI purpose is to support and/or stimulate the recipient's
activity by involvement in and otherwise working jointly with the
award recipient in a partner role, but it is not to assume direction,
prime responsibility, or a dominant role in the activity.  Details of
the responsibilities, relationships and governance of the study to be
funded under cooperative agreement(s) are discussed later in this
document under the section "Terms and Conditions of Award".

The total project period for an application submitted in response to
this RFA may not exceed four years.  The anticipated award date is
September 30, 1995.

Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of the award will
vary also.  Award and level of support depend on receipt of
applications of high scientific merit.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all
investigator-initiated R01 applications and be reviewed according to
the customary peer review procedures.

FUNDS AVAILABLE

It is anticipated that one award will be made for approximately
$1,500,000 total costs per year for four years to a single consortium
consisting of several participating institutions.  Although this
program is provided for in the financial plans of the NCI, the award
of a Cooperative Agreement pursuant to this RFA is contingent upon
the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Breast cancer is second only to lung cancer as the cause of cancer-
related deaths in women in the United States.  Conventional x-ray
mammography has been shown to play an important role in detection and
staging of breast cancer in women older than 50 years of age.
However, younger women frequently have "radiodense" breast tissue,
rendering breast cancer diagnosis with conventional mammography
problematic. This scenario created a strong incentive for the
Diagnostic Imaging Research Branch to support development and
evaluation of novel breast imaging technologies.  Over the last few
years, contrast-enhanced MRI of the breast has emerged as one of the
most promising clinical tools for detection of breast cancer and
delineation of its anatomic local extent.  Preliminary results in
phase I, or exploratory clinical trials indicate that breast MRI may
be more sensitive than conventional x-ray mammography in detecting
small lesions.  Breast MRI also appears to be particularly useful for
detection of breast cancer in women with essentially uninterpretable
x-ray mammograms (e.g., when breast tissue is "radiodense" or
"radio-opaque" due to silicon implants).

Contrast enhanced MRI is thus a promising adjunctive diagnostic tool
and may be of particular value in the early detection of breast
cancer in women with "radiodense" and "radio-opaque" breasts and, by
virtue of its ability to improve local tumor anatomic delineation, in
clinical staging of local disease in women with apparent early-stage
breast cancer.  On the other hand, whereas current reported results
appear promising, they are preliminary in nature and based on a
limited patient sample in individual institutions.  It is not known
at this time what MRI technical approach is optimal (e.g. two- vs.
three-dimensional acquisition, fat suppression vs. subtraction,
trade-off between spatial and temporal resolution).  While the
sensitivity of breast MRI appears promising, specificity of this
technology has been reported to be low.  However, recent development
of specialized imaging coils and MRI-guided biopsy is expected to
have an important impact on tissue characterization of the
MRI-detected lesions.

The DIRB, NCI, with the advice of experts from academia and industry
in the fields of diagnostic imaging and breast cancer treatment, has
determined that a clinical trial to evaluate the sensitivity,
specificity and local staging accuracy of breast MRI is, with the
availability of breast-dedicated MR imaging coils and introduction of
MRI-guided biopsy capability, both feasible and timely.  Information
from this trial may suggest future trials aimed at more clearly
defining the role of MRI in breast cancer screening or clinical
evaluation of women with early breast cancer.

Objectives and Scope

The purpose of this RFA is to facilitate cooperative efforts to
evaluate MRI as a tool for improved breast cancer diagnosis through
centrally coordinated multi-institutional clinical trials, with
participation of multiple clinical centers for rapid patient accrual.
This RFA is expected to serve a public purpose by advancing the
current state-of-the-art knowledge regarding early detection and
staging of breast cancer.  The RFA proposes to achieve these goals
through formation of one Consortium to perform phase II clinical
evaluation of a new promising imaging modality and its role in breast
cancer diagnosis, including sensitivity, specificity and local
staging accuracy of breast MRI compared to conventional x-ray
mammography, ultrasound and other related technologies in about 3,000
women in whom biopsy will be performed.  The investigators will
develop a clinical protocol and its modifications, if necessary,
taking into account evolving scientific evidence related to the
current state -of-the-art in breast MRI and its new approaches not
previously mentioned in the application.  Pilot studies may be
performed during the initial period of this award before the phase II
study protocol will be finalized.

Histopathologic evaluation of MRI-detected lesions will be done for
every patient, either by MRI-guided biopsies in combination with
follow up imaging studies in patients with probable benign disease
and/or women with breast cancer selecting breast conservation therapy
(e.g. when some of the detected lesions may not be found in the
lumpectomy tissue samples), or by examination of mastectomy
specimens.  A sufficient number of patients must be available in each
participating institution for successful completion of the proposed
clinical trial.  Each participating institution must have experience
with clinical studies in breast MRI (at least 100 previous
examinations) and must demonstrate the plan for histopathologic
evaluation of MRI-detected lesions.

In addition, it is expected that the study participants will
establish a database that would enable the Group to address vital
questions such as:  Can MRI reduce the number of breast biopsies,
repeated lumpectomies, and/or other potentially avoidable diagnostic
and therapeutic procedures?  Particular emphasis will be placed on
the accrual of women younger than 50 years of age and/or minority
women with "radiodense" breast tissue.

It is anticipated that this phase II trial, focused on evaluation of
diagnostic value of MRI and its role in optimization of breast cancer
detection and staging in women undergoing biopsy, may, at its
completion suggest the need for phase III clinical trials to
validate:  (a) the impact of MRI data (e.g., improved staging
accuracy through improved definition of local anatomic tumor extent)
on cost-effectiveness of breast cancer management in women with
early-stage disease.  Particular emphasis will be placed on the
accrual of women younger than 50 years of age and/or minority women
with "radiodense" breast tissue as well as, (b) the role of MRI as a
screening tool in reducing mortality of general (asymptomatic)
population of women with "radiodense" breast tissue and patients at
high genetic risk for breast cancer.

SPECIAL REQUIREMENTS

To promote the development of a collaborative program among the award
participants, a number of issues need to be addressed in the
applications, as discussed below (See APPLICATION PROCEDURES).
Applicants must discuss the rationale for their choice of imaging
techniques and plan for histopathologic correlation, must document
their ability to recruit a sufficient number of participants, must be
able to develop a plan for effective administrative management, must
discuss their capability to participate in clinical trials involving
breast MRI, conventional x-ray mammography and other technologies,
and must state their willingness to follow the common protocol.

Definitions

AWARDEE - The organization to which a cooperative agreement is
awarded which is responsible and accountable to NCI for the use of
funds provided and for performance of the cooperative
agreement-supported project.  Each awardee will organize a consortium
that will consist of multiple participating institutions, including
Clinical Sites for patient accrual.

PRINCIPAL INVESTIGATOR (PI) -- The single individual designated by
the awardee institution who is responsible for the scientific and
administrative operations of the Cooperative Group consortium
(Group).

NCI PROJECT SCIENTIST - The Diagnostic Imaging Research Branch
Program Director, who will have scientific/programmatic involvement,
and who will also coordinate NCI interactions and administer and
provide guidance for the overall program within the NCI.  He/she is
available for duration of research conducted through this cooperative
agreement.

EXECUTIVE COMMITTEE - The committee chaired by the PI and responsible
for main study oversight, including protocol development and progress
monitoring.  In addition to the Principal Investigator and the NCI
Project Scientist, the Executive Committee will be composed at the
minimum of the following voting members:  Director of the Data and
Statistics (Coordinating) Center, Chairperson of the Quality
Assurance Committee and one clinical investigator from each Clinical
Site.  PI may select other voting members of the Executive Committee
deemed necessary for successful completion of the study.

DATA AND STATISTICS (COORDINATING CENTER) responsible for development
of procedures for statistical data collection, management, analysis
and onsite monitoring, including audits and audit reports.  Director
of the Center is an individual other than the Principal Investigator.

QUALITY ASSURANCE (QA) COMMITTEE - The committee, selected by the PI
from among the Group members, is responsible for the development of
procedures for centralized supply and quality control of contrast
agents, imaging devices and approaches required by the experimental
protocol.  Chairperson of the Quality Assurance Committee will be
selected by the Principal Investigator.

IMAGING SUBCOMMITTEE of the Protocol Review Committee of the Clinical
Therapy Evaluation Program will review and approve the protocol and
its proposed amendments to ensure that they are within the scope of
peer review and for safety considerations before implementation.  The
Imaging Subcommittee will consist at the minimum of the clinical
radiologist, medical oncologist and surgical oncologist who will
select its Chair.  Other members deemed necessary for review and
approval of the protocol and its amendments may be appointed by the
Chair of the Imaging Subcommittee.

Terms and Conditions of Award

A.  Applicability.  These special Terms and Conditions of Award are
in addition to and not in lieu of otherwise applicable OMB
administrative guidelines, HHS grant administration regulations in 45
CFR Parts 74 and 92, and other HHS, PHS and NIH grant administration
policy statements.

The administrative and funding instrument used for this program is a
cooperative agreement, an "assistance" mechanism (rather than an
"acquisition" mechanism) in which substantial NCI scientific and/or
programmatic involvement with the awardee is anticipated during
performance of the activity.  Under the cooperative agreement, the
NCI 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 reside with the awardee for the project as a whole, although
specific tasks and activities in carrying out the studies will be
shared among the awardees and the NCI.  The NCI shall be represented
in the Group by an extramural Project Scientist selected from the
Diagnostic Imaging Research Branch. This representative will be
referred to as the NCI Project Scientist.

B.  Awardee Rights and Responsibilities

The Awardee will have primary rights and responsibilities to define
study objectives and approaches, and to plan, conduct, analyze and
publish results, interpretations, and conclusions of their studies.

The Awardee will have primary and lead responsibilities for the
project as a whole, including research design and protocol
development, participant recruitment and follow up, data collection,
quality control, interim data and safety monitoring, final data
analysis and interpretation, preparation of publications, with
assistance from the NCI Project Scientist.

The Awardee has primary responsibilities for:

1.  Establishment of procedures for all participating institutions to
comply with FDA regulations for studies involving investigational
drugs (e.g., contrast agents) or devices (e.g., MRI-guided biopsy
equipment) and to comply with the requirements of 45 CFR Part 46 for
the protection of human subjects.

2.  Establishment of the Executive Committee, chaired by the
Principal Investigator, responsible for research design and protocol
development, progress monitoring and project administrative
oversight, including definition of objectives and approaches,
planning, implementation, participant recruitment and follow-up,
approval of procedures for data collection, analysis, interpretation,
and publication of results, and approval of methods for
instrumentation supply and quality assurance.  The Executive
Committee is responsible for ensuring accurate and timely assessment
of the progress of each study, including establishment of procedures
to ensure that data collection and management are:  (l) adequate for
quality control and analysis; (2) as simple as appropriate in order
to encourage maximum participation of physicians and patients and to
avoid unnecessary expense; and (3) sufficiently staffed across the
participating institutions.

The Principal Investigator will define the final composition of the
Executive Committee, with assistance from the NCI Project Scientist
who will serve as a voting member.  In addition to the Principal
Investigator and the NCI Project Scientist, the Executive Committee
will be composed at the minimum of the following voting members:
Director of the Data and Statistics (Coordinating) Center,
Chairperson of the Quality Assurance Committee and one clinical
investigator from each Clinical Site.  PI may select other voting
members of the Executive Committee deemed necessary for successful
completion of the study.  Principal Investigator of the Group
functions as the scientific coordinator for the protocol and shall
assume responsibility for administrative operations of the Group.  A
degree of flexibility in the clinical trial proposed in the initial
stages of the MRI evaluation may be needed.  The investigators will
develop a clinical protocol and its modifications, if necessary,
taking into account evolving scientific evidence related to the
current state-of-the-art in breast MRI and its new approaches not
previously mentioned in the application.  Pilot studies may be
performed during the initial period of this award before the phase II
study protocol will be finalized.  Under the leadership of the
Principal Investigator and with assistance of the NCI staff, the
Executive Committee will develop a clinical protocol (and its
modifications, if necessary).  The proposed protocol and all
modifications will be submitted by the Principal Investigator of the
Group to the NCI Project Scientist in compliance with the NCI
protocol approval procedure described below (see section C, part 3c
of these Terms and Conditions of Award).

3.  Establishment and implementation of methods developed by the Data
and Statistics (Coordinating) Center and approved by the Executive
Committee for statistical data collection, management, analysis and
monitoring, including on-site audits and audit reports.  Audit
reports should be submitted by the Director of the Data and
Statistics (Coordinating) Center to the Principal Investigator who
will be responsible for the submission of the audit reports to the
NCI Project Scientist within 10 weeks of their completion.  Director
of the Data and Statistics (Coordinating) Center, selected by the
Principal Investigator, will be an individual other than the
Principal Investigator of the Group.

In the multi-institutional Group, it is the responsibility of
individual Clinical Sites to accrue patients and to ensure that data
will be submitted in a timely way to the central Data and Statistics
(Coordinating) Center.

4.  Establishment and implementation of mechanisms developed by the
Quality Assurance Committee and approved by the Executive Committee
for coordinated supply of contrast agents and instrumentation
required by the experimental protocol, development of methods and
protocols for acquisition and review of images, preparation of
pathologic specimens, plan for histopathologic correlation any other
relevant correlative studies, and centralized standardization of
instrumentation quality control, including technical requirements and
performance standards for hardware and software instrumentation.
Chairperson of the Quality Assurance Committee will be selected by
the Principal Investigator from among the Group participants.

5.  Submission of semiannual interim progress reports to the NCI
Project Scientist including as a minimum, summary data on protocol
performance and accrual.  Such reports are in addition to the annual
progress report submitted in the noncompeting continuation
applications.

6.  Cooperation in the reporting of the study findings.  The NCI will
have access to and may periodically review all data generated under
an award.  Where warranted by appropriate participation, plans for
joint publication with NCI of pooled data and conclusions are to be
developed by the Principal Investigator or Executive Committee, as
applicable.  NIH policies governing possible co-authorship of
publications with NCI staff will apply in all cases.  In general, to
warrant co-authorship, NCI staff must have contributed to the
following:  (a) significant intellectual contribution to the concept
or experiments being tested; (b) performance of significant portions
of the research activity; and, (c) preparation of pertinent
manuscripts.  The awardee will retain custody of and the primary
rights to the data developed under these awards, subject to
Government rights to access consistent with current HHS, PHS, and NIH
policies.

C. NCI Staff Responsibilities

The NCI Project Scientist will have substantial scientific
programmatic involvement during conduct of this activity, through
technical assistance, advice and coordination above and beyond normal
program stewardship for grants, as described below.

It is expected that the dominant role and prime responsibility for
the activity will reside with the awardee for the project as a whole,
although specific tasks and activities in carrying out the studies
will be shared between the awardee and the NCI Project Scientist who
will serve as the contact point for all facets of scientific
interaction with the awardee.

The NCI Project Scientist responsibilities will include:

1.  Interacting with the Principal Investigator of the Group on a
regular basis to monitor study progress, to participate in the
Executive Committee meetings and related activities.  The NCI Project
Scientist will be a voting member of the Executive Committee and, if
applicable, subcommittees.  The NCI retains, as an option, periodic
external review of progress.

2.  Serving as a resource with respect to other ongoing NCI
activities that may be relevant to the protocol to facilitate
compatibility and avoid unnecessary duplication of effort.

3.  Substantial involvement in the design and coordination of
research activities for awardees as elaborated below:

a. Providing advice in the management and technical performance of
the investigations, coordinating clearances for investigational drugs
(e.g. contrast agents) and devices (e.g. MRI-guided biopsy equipment)
to ensure that the proposed study is in accord with FDA requirements
for investigational agent and device trials.

b. Assisting, through participation in the Executive Committee, in
the design, development, and coordination of a common research or
clinical protocol and statistical evaluations of data in the
preparation of questionnaires and other data recording forms and in
the publication of results.  c. Submitting the experimental protocol
and its revisions for review by the Imaging Subcommittee of the
Protocol Review Committee of the Clinical Therapy Evaluation Program
(see Special Requirements, under Definitions) that will review and
approve the protocol and its amendments proposed by the Group to
insure they are within the scope of peer review and for safety
considerations before implementation, as required by Federal
regulations.  The decision of the Imaging Subcommittee will be
communicated to the awardee by the NCI Project Scientist within 30
days of the Imaging Subcommittee meeting. The NCI Project Scientist
will monitor protocol progress, and may request that a protocol study
be closed to accrual for reasons including:  (i) accrual rate
insufficient to complete study in a timely fashion; (ii) accrual
goals met early; (iii) poor protocol performance; (iv) patient safety
and regulatory concerns; (v) study results that are conclusive before
completion of full accrual; and, (vi) emergence of new information
that diminishes the scientific importance of the original study
question.  The NCI will not permit further expenditures of NCI funds
for a study after requesting closure (except for patients already on
study).  If disagreements develop over NCI recommended protocol
closure for reasons other than patient safety or regulatory concerns
NCI will establish an arbitration procedure to resolve differences
between the awardee and the NCI as described below (see section E of
these Terms and Conditions of Award).  No expenditures of NCI funds
will be allowed for protocols disapproved by NCI unless disapproval
has been modified by arbitration panel.

7.  Reviewing and providing advice regarding methods established by
the Group for statistical data collection, management, analysis and
monitoring, including audits, in accordance with the procedures
approved by the Executive Committee.

8.  Reviewing and providing advice regarding procedures established
by the Group for coordinated supply and centralized quality control
of contrast agents and instrumentation.

D. Collaborative Responsibilities

In addition to the interactions defined above, NCI staff and the
Awardee shall share responsibility for the following activities:

Executive Committee.  An Executive Committee chaired by the Principal
Investigator of the Group will be the main oversight body of the
study.  NCI Project Scientist will serve as a voting member of the
Executive Committee.  An initial meeting of the Executive Committee
will be convened by the Principal Investigator early after the award
in coordination with the NCI Project Scientist.  In addition to the
Principal Investigator and the NCI Project Scientist, as mentioned
above, the Executive Committee will be composed at the minimum of the
following voting members:  Director of the Data and Statistics
(Coordinating) Center, Chairperson of the Quality Assurance Committee
and one clinical investigator from each Clinical Site.  PI may select
other voting members of the Executive Committee deemed necessary for
successful completion of the study.  The final structure and
composition of the Executive Committee will be established at the
first meeting by the Principal Investigator, with assistance from the
NCI Project Scientist.

A degree of flexibility in the clinical trial proposed in the initial
stages of the MRI evaluation may be needed.  The investigators will
develop a clinical protocol and its modifications, if necessary,
taking into account evolving scientific evidence and unanticipated
developments in MRI contrast agents, technologies and methodologies.
Pilot studies may be performed during the initial period of this
award before the phase II study protocol will be finalized.  With
assistance of the NCI staff, the Executive Committee will develop a
clinical protocol (and its modifications, if necessary), determine
which correlative studies are appropriate and develop long term
sequential planning, including prioritization of study goals.

The Executive Committee will meet at least twice yearly under usual
circumstances.  Semiannual meetings of the Executive Committee will
be convened by the Principal Investigator in coordination with the
NCI Project Scientist.  The Principal Investigator of the Group is
responsible for coordinating the Executive Committee's activities,
for preparing meeting agendas, and for scheduling and chairing
meetings.  It is suggested that applicants be advised to include
plans for meetings in the budget requests.  The Executive Committee,
under the leadership of the Principal Investigator, will document
progress in written semiannual reports to the NCI Project Scientist,
and will provide supplementary reports to designated NCI staff upon
request.

E. Arbitration

Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between the awardee and the NCI may
be brought to arbitration.  An arbitration panel will be composed of
three members -- one selected by the awardee, a second member
selected by the NCI, and the third member elected by the two prior
selected members.  This special arbitration procedures in no way
affect 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
biochemical and behavioral research projects involving human
subjects, unless a clear and compelling rationale and justification
is provided that inclusion is inappropriate with respect to the
health of the subjects or the purpose of the research.  This new
policy results from the NIH Revitalization Act of 1993 (Section 492B
of Public Law 103-43) and supersedes and strengthens the previous
policies (Concerning the Inclusion of Minorities in Study
Populations, and Concerning the Inclusion of Women in Study
Populations), which have been in effect since 1990.  The new policy
contains some provisions that are substantially different from the
1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which was reprinted in the Federal
Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting
errors in the earlier publication, and reprinted in the NIH GUIDE FOR
GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.

Investigators may also obtain copies of the policy from the program
staff listed under Inquiries.  Program staff may also provide
additional relevant information concerning the policy.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

For this study, all research subjects will be women, although a
particular emphasis will be placed on recruitment of women younger
than 50 years of age and minority women with "radiodense breast
tissue".

LETTER OF INTENT

Prospective applicants are asked to submit, by May 9, 1995, a letter
of intent that includes a descriptive title of the proposed research,
name, address and telephone number of the Principal Investigator, the
identities of other key personnel and participating institutions, and
the number and title of the RFA in response to which the application
is being 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 NCI staff to estimate the
potential review workload and to avoid conflict of interest in the
review.

The letter of intent is to be sent to Dr. Faina Shtern at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

Special Instructions for Preparation of Cooperative Agreement
Applications

General instructions are contained in the grant application form PHS
398 (rev. 9/91), which is to be used in applying for these grants.
These forms are available at most institutional offices of sponsored
research and from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, Westwood Building,
Room 449, Bethesda, MD 20892, telephone 301-435-0714; and from the
NIH program administrator listed under INQUIRIES.

Additional Materials to Include in the Application

Any special information that is required as a result of the use of
the cooperative agreement mechanism should be provided, such as
special meetings and budgetary requirements, special instructions for
multi-center or multistudy projects, etc.

Applicants must describe plans to accommodate stated program
requests, criteria and staff involvement.  It is critical that each
applicant include specific plans for responding to these Terms and
Conditions of Award.  Plans must describe how the applicant will
comply with the program staff involvement and how all the Awardee
Responsibilities will be fulfilled.

To promote the development of a collaborative program among the study
participants, a number of issues need to be addressed by the
Applicants as described below:

1.  Applicants should describe their rationale for their choice of
the experimental protocol.  The potential for the adequate patient
accrual necessary for the achievement of the proposed study goals
(and understanding of how the estimated ideal number is arrived to)
should be demonstrated.

2.  Applicants should present a plan for personnel and facilities
capable of performing and supporting the administrative functions of
a cooperative group conducting imaging trials in cancer.  Applicants
must demonstrate the ability to organize, conduct, and monitor
clinical trials in radiology.  Applicants must describe a plan for
qualified support personnel to ensure timely and accurate data
retrieval and reporting.  Applicants must describe procedures by
which institutions participating in a consortium would perform their
functions, including protocols for accomplishing the clinical work
and patient accrual and administrative project management. The
application should include the proposed protocol for correlation of
breast MRI with conventional x-ray mammography and, if applicable,
other technologies (e.g. US) with histopathologic findings.

3.  The PI of the Group should demonstrate expertise in the design
and coordination of clinical trials, capability to provide
educational workshops and ongoing training for Group participants,
capacity to develop and implement an administrative and management
structure for the Group, including an Executive Committee, a Quality
Assurance committee, and a Data and Statistics (Coordinating) Center
and Clinical Sites.  The PI will supervise the administrative and
scientific aspects of the Group's function.

4.  The Data and Statistics (Coordinating) Center Director and staff
should demonstrate experience in the management of data from
multicenter clinical trials and must have expertise in statistical
data collection, management, analysis, monitoring and other related
issues.

5.  The Quality Assurance Committee Chairperson and staff should
demonstrate experience in the development of review, evaluation and
quality control procedures for contrast agents, imaging devices,
imaging techniques, image interpretation and experimental approaches
required by the protocol.

6.  Individual Clinical Sites in a consortium should demonstrate
commitment to participate in multi-institutional protocols, including
their willingness to follow the common protocol, their ability to
participate in the study and their documentation of the facilities
and professional personnel available to conduct cooperative imaging
trials.  This includes assignment of appropriate specialists required
by the experimental protocol including, but not limited to,
radiologists, surgeons and pathologists, in order to ensure complete
patient evaluation.  Individual Clinical Sites in a consortium should
demonstrate the availability of the state-of-the-art instrumentation
in breast MRI, conventional x-ray mammography and other technologies
required by the protocol.  Each Clinical Site must have the
instruments, facilities, and capabilities for the proposed
experimental protocol.  Clinical Sites must be able to interact
effectively with the Executive Committee, Data and Statistics
(Coordinating) Center and Quality Assurance Committee.  Clinical
Sites must be able to correlate mammographic x-ray imaging, breast
MRI, and US data with pathologic findings.  Each Clinical Site must
have the capability for performing biopsies of small lesions
detectable only by MRI.  This may consist of (but not limited to) the
placement of appropriate markers with MRI guidance for surgical
biopsy, or direct MRI-guided needle biopsy.

Separate budgets should be provided for the Executive Committee, Data
and Statistics (Coordinating) Center, Quality Assurance Committee,
with detailed justification of each item; a separate budget should be
also prepared as a subcontract for each participating institution for
which funds are requested, including applicable indirect costs (see
NIH/DHHS Guidelines for Establishing and Operating Consortium Grants
of January 1989).  It is also suggested that applicants include plans
for meetings in the budget requests.

The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page of the 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, clear, and single-sided photocopies,
in one package to:

Division of Research Grants
National Institutes of Health
6701 Rockledge Drive, Room 1040 MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for courier/overnight mail service)

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

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard
Bethesda, MD 20892
Telephone:  (301) 496-3428

Applications must be received by June 9, 1995.  If an application is
received after that 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 essentially
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
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

General Considerations

All applications will be judged on the basis of the scientific and
technical merit of the proposed project and the documented ability of
the investigators to meet the RESEARCH OBJECTIVES of this RFA.  Other
considerations, such as the importance and timeliness of the proposed
study, access to patients, and multidisciplinary nature of the
studies, will be part of the evaluation criteria.

Review Method

Upon receipt, applications will be reviewed for completeness by DRG
and for responsiveness by the NCI.  Incomplete applications will be
returned to the applicant without further consideration.  If NCI
staff find that the application is not responsive to the RFA, it will
be returned to the applicant without further consideration.

Applications that are complete and responsive to this RFA 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 and technical merit will be discussed, assigned a priority
score, and receive a second level review by the National Cancer
Advisory Board.

Review Criteria

Applicants are encouraged to submit and describe their own ideas
about how best to meet the goals of the cooperative study and their
specific protocols, and are expected to address issues identified
under APPLICATION PROCEDURES of this RFA.

The review group will assess the scientific and technical merit of
the proposed study and related factors, including:

o  Scientific, technical, or medical significance and originality of
proposed research;

o  Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  Qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively in the area
of the proposed research;

o  Availability of appropriate facilities, equipment, instrumentation
(including but not limited to the state-of-the-art conventional x-ray
mammography, dedicated breast MR imaging coils, MRI-guided biopsy
capability), and other resources to ensure that each institution
participating in the consortium is capable of performing innovative
cooperative trials in breast cancer diagnosis;

o  Appropriateness of the proposed budget and project duration in
relation to the proposed research;

The initial review group will also examine the provisions for the
protection of human subjects, the safety of research environment, and
conformance with the NIH Guidelines for the Inclusion of Women and
Minorities as Subjects in Clinical Research.

o  Adequacy of plans to include minorities and their subgroups as
appropriate for the scientific goals of the research.  Plans for
recruitment and retention of subjects will also be evaluated.  A
particular emphasis should be placed on the accrual of women younger
than 50 years of age and minority women with radiodense breast
tissue.

Specific attention will be given to:

o  The overall qualifications of applicant institutions in the
collaborative group as stated under the Eligibility Requirements for
participants (see ELIGIBILITY REQUIREMENTS);

o  A record or evidence of willingness of the professional and
support personnel to work as a team with other Group members and with
the NCI Project Scientist;

o  Evidence of the ability and /or the potential of the Principal
Investigator to develop multicenter clinical trials of substantial
scientific and technical merit in breast MRI;

o  Evidence of the previous experience of the key professional
personnel of Clinical Sites with clinical breast MRI studies of sound
scientific quality (at least 100 examinations) and their
histopathologic correlation;

o  Evidence of the potential of Clinical Sites for reaching the
adequate patient accrual necessary for the achievement of the
proposed study goal in a reasonable period of time;

o  Evidence of the experience of the participants of the Data and
Statistics (Coordinating) Center in biostatistical study design and
data collection, management, analysis and monitoring of multicenter
clinical trials;

o  Evidence of the experience of the key personnel of the Quality
Assurance Committee in the development of procedures for quality
control of contrast agents and imaging devices, including
standardization of instrumentation performance and technical
requirements.

AWARD CRITERIA

Applications recommended by the National Cancer Advisory Board will
be considered for award based upon (a) scientific and technical merit
as reflected by the priority score; (b) availability of funds; and
(c) programmatic priorities.

INQUIRIES

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

Direct inquiries regarding scientific and programmatic issues to:

Dr. Faina Shtern
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Suite 800
Bethesda, MD  20892
Telephone:  (301) 496-9531
FAX:  (301) 480-5785
Email:  shternf@rrp.nci.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Joy McCauley
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, Ext. 253
FAX:  (301) 496-8601

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance Number 93.395, Cancer Treatment Research.  Awards are made
under the 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 PHS grants policies and Federal
Regulations 42 CFR Part 52 and 45 CFR Part 74 and 45 CFR Part 92.
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 and contract recipients to
provide a smoke-free workplace 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 routing 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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