Full Text CA-96-012
 
MULTI-INSTITUTIONAL COOPERATIVE AGREEMENTS FOR CLINICAL EVALUATION OF
MAGNETIC RESONANCE IMAGING IN BREAST CANCER
 
NIH GUIDE, Volume 25, Number 12, April 19, 1996
 
RFA:  CA-96-012
 
P.T. 34

Keywords: 
  0715036 
  Medical/Diagnostic Imaging 
  Instrumentation, Medical 

 
National Cancer Institute
 
Letter of Intent Receipt Date:  May 15, 1996
Application Receipt Date:  July 30, 1996
 
PURPOSE
 
The Radiation Research Program (RRP) of the Division of Cancer
Treatment, Diagnosis and Centers (DCTDC) of the National Cancer
Institute (NCI), invites applications for cooperative agreements
(U01) to study the sensitivity, specificity and local staging
accuracy of breast MRI (BMRI) compared to conventional radiologic
approaches in about 3,000 women with abnormal x-ray mammograms and/or
abnormal physical examination (e.g., palpable mass).  The NCI is
seeking scientists from academic, non-profit and for-profit research
organizations who will interact with other members in a Cooperative
Consortium (called the Consortium throughout this Request for
Applications (RFA)), and with the RRP in a concerted way to evaluate
and optimize new approaches to breast cancer diagnosis.
 
One Consortium, consisting of multiple collaborating institutions and
called "Multi Institutional Consortium for Clinical Evaluation of MRI
in Breast Cancer", will be funded by the NCI.  The Consortium will
consist of two separately funded organizational components (or
awardees):  (1) Headquarters institution, responsible for the
identification and coordination of patient- accruing Clinical Sites;
and (2) Data and Statistics Center.
 
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 Agreements 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 202-512-1800).
 
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 package 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 (see APPLICATION
PROCEDURES).  Applications for the Headquarters and for the Data and
Statistics Center should be submitted together but as separate
applications; these two applications will be funded as separate
awards.
 
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 NCI program staff and the awardees 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 applications submitted in response to
this RFA may not exceed four years.  The anticipated award date is
April 1, 1997.
 
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.  If it is determined 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 in Review Considerations.
 
Although this program is provided for in the financial plans of the
NCI, the award of Cooperative Agreements pursuant to this RFA is
contingent upon the availability of funds for this purpose.
 
FUNDS AVAILABLE
 
It is anticipated that two awards will be made at approximately
$1,500,000 total  costs per year for four years.  The Consortium will
consist of two organizational components (or awardees): (1)
Headquarters institution, responsible for recruitment of
patient-accruing Clinical Sites; and (2) Data and Statistics Center.
The application for the Data and Statistics Center shall be separate
from the application for the Headquarters component, but both
applications should be planned and submitted together.
 
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 to
support development and evaluation of novel breast imaging
technologies.
 
Over the last few years, contrast-enhanced MRI of the breast (BMRI)
has emerged as one of the most promising clinical tools for detection
of early breast cancer and delineation of its anatomic local extent.
Exploratory clinical trials indicate that BMRI may be more sensitive
than conventional x-ray mammography in detecting small lesions.  BMRI
may 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.  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).  However, it is expected that the
applicants will present in their applications a specific range of
standards for performing BMRI that will be accepted by all main
member institutions.  While the sensitivity of BMRI 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 RRP, 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 BMRI is, with the
availability of breast-dedicated MR imaging coils and introduction of
MRI-guided biopsy capability, both feasible and timely.
 
A.  Objectives and Scope
 
The purpose of this RFA is to facilitate evaluation of sensitivity,
specificity and local staging accuracy of BMRI compared to
conventional imaging approaches in about 3,000 women with abnormal
x-ray mammograms and/or abnormal physical examination. BMRI data in
detection and staging of breast cancer may be compared to that of
conventional x-ray mammography, ultrasound (US) and other imaging
modalities.  Histopathologic correlation of and/or follow up studies
will be required for all patients.
 
A sufficient number of patients must be available in each
participating institution for successful completion of the proposed
clinical trial.  Each participating institution must demonstrate
experience with clinical studies in BMRI (at least 100 previous
examinations) and must adopt and participate in the Consortiums plan
for histopathologic evaluation and/or follow up of MRI-detected
lesions.
 
In addition, it is expected that study participants will establish a
database that would enable the Consortium to address vital questions
such as:  Can MRI reduce the number of diagnostic procedures, such as
breast biopsies, in women with benign conditions? Can and/or should
MRI data on local tumor staging make an impact on therapeutic
decisions in women with early stage disease?
 
It is anticipated that this non-randomized trial, focused on
evaluation of diagnostic value of MRI and its role in optimization of
breast cancer detection and staging, may, at its completion suggest
the need for randomized clinical trials to validate: a) the impact of
MRI data (e.g. improved staging accuracy through improved definition
of local anatomic tumor extent) on therapeutic decisions in women
with early-stage disease 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.  Particular emphasis will be
placed on the accrual of women younger than 50 years of age and
minority women with "radiodense" breast tissue.
 
B.  Organization
 
The Consortium will consist of two major operational components: 1)
Headquarters institution, responsible for recruitment and performance
of patient-accruing Clinical Sites; and 2) the Data and Statistics
Center.  Each component has general responsibilities in meeting the
objectives outlined above or in completing tasks necessary to
accomplish these goals.  The Headquarters of the Consortium should
describe membership criteria for inclusion and exclusion, procedures
for selecting members of the Executive Committee and other details of
governance, and will be led by a Chairperson who is ultimately
responsible to NCI for the contents and conduct of the Consortium's
research program. Beyond this requirement, the structure and
management of the Consortium should be clearly described in the
applications, including the identification of participating Clinical
Sites and the criteria for their selection.
 
The following sections describe the responsibilities and functions of
two organizational components:
 
1.  Headquarters and Chairperson.
 
The Headquarters component of the Consortium is the direct
responsibility of the Chairperson.  It provides executive leadership
and day-to-day administrative management of the Consortium.  Through
this office, the Chairperson implements Consortium's scientific and
organizational policies.  Specific roles and responsibilities include
the following:
 
a.  Provide general scientific oversight, assuring development of a
research plan and its priorities.
 
b.  Develop and provide to the Consortium membership and to NCI an
administrative plan specifying Consortium structure and management,
procedures and criteria for the selection of patient- accruing
Clinical Sites, establishment of the Quality Assurance Committee and
selecting its Coordinator, establishment and selection of the
Executive Committee membership, and other details of governance.
 
c.  Foster and monitor the inclusion of women younger than 50 years
of age, ethnic minorities and women with "radiodense" breast tissue
in the Consortium's clinical trial.
 
d.  Verify that all Clinical Sites and other members have an approved
Cooperative Project Assurance, or Multiple Project Assurance as
required on file with the Office of Protection from Research Risks,
Department of Health and Human Services.
 
e.  Monitor and maintain appropriate records of protocols, informed
consents, assurances and annual certifications of Institutional
Review Board (IRB) review and approval (HHS Optional Form 310) for
all Clinical Sites and other members of the Consortium.
 
f.  Subcontract and monitor performance of the leading investigators
at patient-accruing Clinical Sites, including but not limited to the
following:
 
i.  active participation in the Consortium's scientific and
administrative committees and meetings;
ii.  contribution of their independent clinical and research
experience to the Consortium;
iii.  patient accrual to the Consortium's protocol;
iv.  submission of accurate and timely patient data to the Data and
Statistics Center;
v.  participation in the Consortium's on-site audit program;
vi.  assumption of responsibility for all Consortium activities
conducted at their institutions.
 
2.  Data and Statistics Center:
 
The Data and Statistics Center has primary responsibilities for:
 
Development and establishment methods 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 Center to the Chairperson of the
Consortium who will be responsible for the submission of the audit
reports to the NCI Project Scientist within 10 weeks of their
completion.  The Director of the Data and Statistics Center will be
the Principal Investigator (PI) of the data and statistical center
component and an individual other than the Chairperson of the
Consortium.
 
Submission of the 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 non-competing continuation
applications.
 
SPECIAL REQUIREMENTS
 
To promote the development of a collaborative program among the award
participants, a number of issues need to be addressed in their
applications as discussed below (See Application Procedures).
Applicants should discuss the rationale for their choice of a
standard imaging technique and plan for histopathologic correlation.
They should document their ability to recruit a sufficient number of
participants, should be able to develop a plan for effective
administrative management, should discuss their capability to
participate in clinical trials involving BMRI, conventional x-ray
mammography and other technologies, and should state their
willingness to follow the uniform protocol.
 
DEFINITIONS
 
The following definitions will be used throughout the enclosed Terms
and Conditions of Award:
 
AWARDEES - The organizations to which a cooperative agreement is
awarded which are responsible and accountable to NCI for the use of
funds provided and for performance of the cooperative
agreement-supported project.
 
CHAIRPERSON OF THE CONSORTIUM-- The person who submits the
application for the Headquarters awardee institution as a Principal
Investigator (PI) and who is responsible for the Consortium as a
whole, including but not limited to: 1) selecting and coordinating
activities of patient-accruing Clinical Sites; and 2) establishing
the Quality Assurance Committee and selecting its Coordinator.  The
Chairperson is responsible for scientific and administrative
operations of the Consortium.  The participating institutions must
agree to work together with the Chairperson of the Consortium.  The
Chairperson of the Consortium is a voting member and the Chair of the
Executive Committee.
 
COOPERATIVE AGREEMENT - An assistance mechanism in which substantial
NCI programmatic involvement with the grant awardees is anticipated
during performance of the planned activity.
 
CONSORTIUM- The association of institutions who are submitting
research grant applications together to conduct the planned clinical
trial.
 
DATA AND SAFETY MONITORING COMMITTEE (DSMC) - A NCI mandated
committee with responsibilities described below (see DSMC, below) and
geared towards protection of patient safety, ethics (e.g. conflict of
interest)) and data impartiality.
 
DATA AND STATISTICS CENTER -- The awardee institution responsible for
development of procedures for statistical data collection,
management, analysis and on-site monitoring, including audits and
audit reports.  The Director of the Data and Statistics Center is a
person who submits a grant application on behalf of the Center as its
Principal Investigator (PI).  The Director of the Data and Statistics
Center must be an individual other than the Chairperson of the
Consortium.
 
EXECUTIVE COMMITTEE  - The committee chaired by the Chairperson of
the Consortium and responsible for the main study oversight,
including protocol development and progress monitoring.  In addition
to the Chairperson of the Consortium 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 Center,
Coordinator of the Quality Assurance Committee and one clinical
investigator from each Clinical Site. The Chairperson may select
other voting members of the Executive Committee deemed necessary for
successful completion of the study.
 
NCI PROJECT SCIENTIST -  The staff member from the Radiation Research
Program (RRP), Division of Cancer Treatment, Diagnosis and Centers
(DCTDC) (cited in the INQUIRIES SECTION), who is the Associate
Director of RRP or designatee to coordinate NCI interactions with the
Consortium, administer and provide guidance for the overall program
within the NCI.  He/she is available for the duration of research
conducted through this cooperative agreement and will be a voting
member of the Executive Committee.
 
 QUALITY ASSURANCE (QA) COMMITTEE - The committee selected by the
Chairperson of the Consortium from among the Consortium members and
responsible for the development of procedures for centralized supply
and quality control of instrumentation and approaches required by the
experimental protocol.  The Quality Assurance Committee is headed by
its Coordinator, who is selected by the Chairperson of the
Consortium.
 
THE  CANCER THERAPY EVALUATION PROGRAM (CTEP) PROTOCOL REVIEW
COMMITTEE.  The NCI committee that will review and approve the
protocol and its amendments as proposed by the Consortium to ensure
that they are within the scope of peer review and for safety
considerations before implementation.
 
TERMS AND CONDITIONS OF AWARD
 
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 awardees 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 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 NCI.  The NCI shall be
represented in the Consortium by a Project Scientist selected from
the Radiation Research Program.  This representative will be referred
to as the NCI Project Scientist.
 
1.  Awardees' Rights and Responsibilities
 
General
 
The Awardees 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 Awardees 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.
 
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 awardees 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.
 
Headquarters
 
The Headquarters Awardees have primary responsibilities for:
 
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.
 
Establishment of the Executive Committee, chaired by the Chairperson
of the Consortium and 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.
 
Implementation of methods developed by the Data and Statistics 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 Center to the Chairperson of the
Consortium who will be responsible for the submission of the audit
reports to the NCI Project Scientist within 10 weeks of their
completion.
 
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 and any other
relevant correlative studies, and centralized  standardization of
instrumentation quality control, including technical requirements and
performance standards for hardware and software instrumentation.
Coordinator of the Quality Assurance Committee will be selected by
the Chairperson of the Consortium from among the Consortium
participants.
 
Establishment of the DSMC that is independent of study leadership, is
clearly free of conflict of interest, and have formally documented
policies and procedures which are approved by NCI.  The main
objectives of the DSMC are to:
 
i.  Ensure that patients in the trial are protected and that their
interests are not made secondary to the interests of scientific
investigations.
 
ii.  Ensure that evaluation of interim results and decision making
about continuation, modification, termination of accrual and
reporting of results are made competently based on thorough
evaluation.
 
iii.  Ensure that the credibility of trial reports and ethics of
trial conduct are above reproach with no possible appearance of
professional or financial conflicts of interest.
 
iv. a.  Enable physicians entering patients to remain free of
knowledge of interim efficacy data.  This permits physicians to
continue to approach their patients honestly and avoids the need to
modify informed consent based on non-statistically significant
interim results.
 
b.  Enable study leadership to remain free of knowledge of interim
efficacy data so that they may deal honestly with their peers in
encouraging them to enter patients in the study and so that they do
not put themselves, or the study, at risk by indirectly divulging
interim results.
 
The Chairperson
 
The Chairperson of the Consortium is responsible for:
 
The establishment of the Executive Committee.
 
The definition of the final composition of the Executive Committee,
with assistance from the NCI Project Scientist who will serve as a
non-voting member.  In addition to the Chairperson of the Consortium
and the NCI Project Scientist, the Executive Committee will be
composed at the minimum of the following voting members: The Director
of the Data and Statistics Center, the Coordinator of the Quality
Assurance Committee and one clinical investigator from each Clinical
Site.  The Chairperson of the Consortium may select other voting
members of the Executive Committee deemed necessary for successful
completion of the study.
 
The scientific coordination for the protocol and the administrative
operations of the Consortium.  Under the leadership and coordination
of the Chairperson, the investigators will be in charge of the
development of a clinical protocol and of its modifications, if
necessary, taking into account evolving scientific evidence related
to the current state-of-the-art in BMRI and its new approaches not
previously mentioned in the application. Under the leadership of the
Chairperson of the Consortium and with assistance of the NCI Project
Scientist, the Executive Committee will review the model clinical
protocol proposed in the grant application, introduce modifications
if necessary, finalize protocol development and monitor its
implementation. The proposed protocol and all modifications will be
submitted by the Chairperson of the Consortium to the NCI Project
Scientist in compliance with the NCI protocol approval procedure that
requires the review and approval of all protocols by the CTEP
Protocol Review Committee.
 
The accrual of patients. Although under the supervision of the
Chairperson and Headquarters, 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 Center.
 
Data and Statistics Center
 
The Data and Statistics Center staff are integral collaborators in
all stages of study development, conduct, analysis, and reporting. In
addition, the Data and Statistics Center funded by this RFA is
responsible for data monitoring, including on-site audits.  The
general responsibilities assumed by this component will include:
 
a.  Ensure study feasibility and appropriateness of study design with
respect to stated research objectives.
 
b.  Ensure that there are clear and consistent definitions of study
objectives, eligibility criteria, primary analysis endpoints,
evaluation criteria and guidelines for removal of patients from
experimental protocol.
 
c.  Take primary responsibility for establishment and implementation
of data monitoring, including on-site audits.
 
d.  Assume responsibility for planned interim analyses of clinical
research and their timely reporting to DSMC.
 
e.  Prepare semi-annual progress reports, including patient accrual,
eligibility, evaluability, and adverse effects (when applicable), in
coordination with the Chairperson of the Consortium.
 
f.  Implement appropriate registration and accrual tracking
procedures.
 
g.  Design, develop and implement forms required to collect
Consortium data.
 
h.  Provide for all aspects of the collection and management of
Consortium study data, especially timeliness and quality of data
submission.
 
i.  Contribute to all decisions regarding the conduct of Consortium
studies.
 
j.  Perform statistical analyses that use state-of-the-art
methodology and provide unbiased results.
 
2.  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 awardees for the project as a
whole, although specific tasks and activities in carrying out the
studies will be shared between the awardees and the NCI Project
Scientist who will serve as the contact point for all facets of
scientific interaction with the awardees.
 
The NCI Project Scientist responsibilities will include:
 
Interacting with the Chairperson of the Consortium  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 non-voting member of the Executive Committee and, if
applicable, subcommittees.  The NCI retains, as an option, periodic
external review of progress.
 
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.
 
Being substantially involved 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, finalization, and coordination of a uniform
standardized 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 Protocol Review Committee of the CTEP that will review and
approve the protocol and its amendments proposed by the Executive
Committee of the Consortium to insure:
 
i) That they are within the scope of peer reviewed research
 
ii) That the plans to accrue sufficient women and/or minorities and
are within regulations (see below under Inclusion of Women and
minorities in Research Involving Human Subjects)
 
iii) That there are sufficient safety considerations before
implementation, as required by Federal regulations.  The decision of
the CTEP Protocol Review Committee will be communicated to the
awardees by the NCI Project Scientist within 30 days of the Committee
meeting.
 
The NCI Project Scientist will monitor protocol progress, and may
request that the Consortium DSMC consider closing a protocol to
accrual for reasons including: (i) insufficient accrual rate; (ii)
poor protocol performance; (iii) patient safety and regulatory
concerns;  (iv) study results that are conclusive before completion
of full accrual;  and,  (v) 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 recommended protocol closure for
reasons other than patient safety or regulatory concerns NCI will
establish an arbitration procedure to resolve differences between the
awardees and the NCI as described below under Arbitration (Section
4).  No expenditures of NCI funds will be allowed for protocols
disapproved by NCI unless disapproval has been modified by
arbitration panel.
 
Reviewing and providing advice regarding methods established by the
Consortium for statistical data collection, management, analysis and
monitoring, including audits, in accordance with the procedures
approved by the Executive Committee.
 
Reviewing and providing advice regarding procedures established by
the Consortium for coordinated supply and centralized quality control
of contrast agents and instrumentation.
 
Assessing Consortium compliance with the NCI established policies on
DSMCs.  NCI Project Scientist will serve as an observer during the
DSMC meetings.
 
3. Collaborative Responsibilities
 
In addition to the interactions defined above, NCI staff and the
Consortium shall share responsibility for the following activities:
 
a.  The Chairperson of the Consortium functions as the scientific
coordinator for the protocol and shall assume responsibility for
administrative operations of the Consortium.  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 BMRI and its new approaches not
previously mentioned in the application.  Under the leadership of the
Chairperson of the Consortium and with assistance of the NCI staff,
the Executive Committee will review the model clinical protocol
proposed in the grant application, introduce modifications if
necessary, finalize protocol development and monitor its
implementation.  The proposed protocol and all modifications will be
submitted by the Chairperson of the Consortium to the NCI  Project
Scientist in compliance with the NCI protocol approval procedure that
requires the review and approval of all protocols by the CTEP
Protocol Review Committee.
 
b.  Executive Committee.  An Executive Committee chaired by the
Chairperson of the Consortium will be the main oversight body of the
study.  NCI Project Scientist will serve as a non-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 Chairperson of the Consortium 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 Center, Coordinator of the Quality Assurance
Committee and one clinical investigator from each Clinical Site.
Chairperson of the Consortium 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.
 
With assistance of the NCI staff, the Executive Committee will
finalize a model clinical protocol proposed in the grant application
(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 Chairperson of the Consortium in coordination with
the NCI Project Scientist.  The Chairperson of the Consortium is
responsible for coordinating the Executive Committee's activities,
for preparing meeting agendas, and for scheduling and chairing
meetings.  The Executive Committee, under the leadership of the
Chairperson of the Consortium, will document progress in written
semiannual reports to the NCI Project Scientist, and will provide
supplementary reports to designated NCI staff upon request.
 
c.  Data and Safety Monitoring Committee (DSMC).  The DSMC is a NCI
mandated committee with responsibilities described below (see DSMC,
above) and geared towards protection of patient safety, ethics and
data impartiality.  The appropriate conduct of the Consortium DSMC
procedures is a collaborative responsibility of the Consortium and
the RRP/NCI program staff.
 
4. Arbitration
 
Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between the awardees and the NCI may
be brought to arbitration. An arbitration panel will be composed of
three members -- one selected by the Consortium, a second member
selected by the NCI, and the third member elected by the two prior
selected members. This arbitration panel will review the RRP decision
and recommend an appropriate course of action to the Director,
Division of Cancer Diagnosis, Treatment and Centers. This special
arbitration procedures in no way affect the awardees' right to appeal
an adverse action that is otherwise appealable in accordance with PHS
regulations at 42 CFR Part 5c, subpart D, and HHS regulations at 45
CFR Part 16.  The Consortium will not expend NCI funds to conduct any
study disapproved by RRP unless this disapproval has been modified by
the arbitration process described above.
 
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", 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 15, 1996 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
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 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. Carl Mansfield
Division of Cancer Treatment, Diagnosis, and Centers
National Cancer Institute
Executive Plaza North, Suite 800
6130 Executive Boulevard, MSC 7440
Bethesda, MD  20892-7440
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-6111
FAX:  (301) 480-5785
Email:  mansfieldc@dtpepn.nci.nih.gov
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (revised 5/95) is to be
used in applying for these grants.  Applications kits are available
at most institutional offices of sponsored research and may be
obtained from the Grants Information Office, Office of Extramural
Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/710-0267, email:  ASKNIH@odrockm1.od.nih.gov; and from the
program administrator listed under INQUIRIES.
 
The RFA label available in the PHS 398 (rev. 5/95) 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 2 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, high quality/one sided photocopies,
in one package to the address below.  The photocopies must be clear
and single sided.
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/express 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 (NCI)
Executive Plaza North, Room 636
6130 Executive Boulevard
Bethesda, MD  20892 USA
Telephone:  (301) 496-3428
 
Applications must be received by July 30, 1996.  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.
 
Special Instructions for the Preparation of Multiinstitutional
Consortium Cooperative Agreements Applications
 
Any special information should be provided which is required as a
result of the use of the cooperative agreement mechanism, such as
special meetings, budgetary requirements, special instructions for
multi-center or multi-study 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.  It is suggested that applicants be advised to
include planned meetings in the budget requests.  Plans must describe
how the applicant will comply with the program staff involvement and
how all the Awardees Responsibilities will be fulfilled.
 
Application Preparation
 
All applications must be submitted on the form PHS 398 (rev. 5/95).
Successful applications for each of the two components of the
Consortium (the Headquarters and the Data and Statistics Center) will
be submitted in together and awarded separately to the sponsoring
institutions.
 
Each individual application must contain a detailed budget for the
first 12 months period and a budget for the entire proposed project
period for direct costs.  The Headquarters and the Data and
Statistics Center applications, should describe the scientific and
administrative experience of key personnel and should include and
follow the PHS 398 (rev. 5/95, Office of Grant Inquiries/Information
Rockledge II/Rm. 6207 Bethesda, MD 20892 301-710-0267) instructions
for Biographical Sketches and Other Support information.
 
For each Consortium component, the specific application requirements
are listed below:
 
1.  Headquarters Application
 
The Headquarters Application should contain a model experimental
protocol for the multi-institutional evaluation of BMRI, which, in
turn, should outline the Consortium's scientific strategy, including
rationale and future plans; a clear sense of direction should be
evident.  In addition to its scientific proposal, the Headquarters
application should also contain information describing the
Consortium's organizational structure, including all the
participating Clinical Sites and the plan for the establishment of
the Quality Assurance Committee, and the operating procedures and
policies to accomplish major objectives and responsibilities.
 
The budget for the Headquarters should be presented in logical,
discrete units. Separate budgets should be provided for the Executive
Committee, Quality Assurance Committee, and each participating
Clinical Site, 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.
 
To promote the development of a collaborative program among the study
participants, a number of issues need to be addressed by the
applicants for the Headquarters as described below:
 
i.  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 revised)
should be demonstrated.
 
ii.  Applicants should present a plan for personnel and facilities
capable of performing and supporting the administrative functions of
a Consortium 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 the 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 BMRI with
conventional x-ray mammography and, if applicable, other technologies
(e.g., US) with histopathologic findings.
 
iii. The Chairperson of the Consortium should demonstrate expertise
in the design and coordination of clinical trials, capability to
provide educational workshops and ongoing training for Consortium
participants, with special emphasis on MRI-guided biopsy, capacity to
develop and implement an administrative and management structure for
the Consortium, including an Executive Committee, a Quality Assurance
committee, and Clinical Sites.  The Chairperson will supervise the
administrative and scientific aspects of the Consortium's function.
 
iv.  The Quality Assurance Committee Coordinator 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.
 
v.  Individual Clinical Sites in a Consortium should demonstrate
commitment to participate in multi-institutional protocols, including
their willingness to follow the uniform 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 the Consortium
should demonstrate the availability of the state-of-the-art
instrumentation in BMRI, 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 Center
and Quality Assurance Committee.  Clinical Sites must be able to
correlate x-ray mammography imaging, BMRI, 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.
 
2.  Data and Statistics Center Application
 
The Data and Statistics Center Director and staff should demonstrate
expertise in all areas of data collection, management and monitoring.
The applicants should describe in detail the proposed plan for the
management of data from multicenter clinical trials, including
statistical data collection, management, analysis, monitoring and
other related issues.  They should describe in detail the
Consortium's data management practices and procedures, its quality
control and study monitoring methodology, and its analytical
techniques and resources.
 
The budget for the Data and Statistics Center application should be
presented in logical, discrete units with specific budgets for each
unit as well as the total Center's request. Personnel, travel
expenses, and computer systems to accomplish the task of data
management, including on-site audits, should be carefully and fully
documented.
 
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 Request for
Applications will be reviewed for scientific and technical merit by
an appropriate peer review committee 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 (NCAB).
 
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 committee will assess the scientific and technical merit
of each of the two components of the Consortium, as summarized below:
 
A.  Consortium Headquarters
 
-Scientific, technical, or medical significance and originality of
proposed research plans;
 
-Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
 
-Qualifications and research experience of the Chairperson and key
personnel, particularly, but not exclusively in the area of the
proposed research;
 
-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;
 
-Appropriateness of the proposed budget and project duration in
relation to the proposed research;
 
The initial review committee 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:
 
-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:
 
-The overall qualifications of collaborating institutions in the
Consortium as stated under the Application Procedures for
participants (see Application Procedures);
 
-A record or evidence of willingness of the professional and support
personnel  to work as a team with other Consortium members and with
the NCI Project Scientist;
 
-Evidence of the ability and /or the potential of the Chairperson to
develop multicenter clinical trials of substantial scientific and
technical merit in BMRI;
 
-Evidence of the previous experience of the key professional
personnel of Clinical Sites with clinical BMRI studies of sound
scientific quality (at least 100 examinations) and their
histopathologic correlation;
 
-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;
 
-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.
 
B.  Data and Statistics Center
 
This portion of the evaluation involves multiple facets:
 
-The performance and capabilities of the Data and Statistics Center;
 
-The development and operation of the data quality control program
with on-site monitoring, including auditing;
 
-Evidence of the experience of the key personnel of the Data and
Statistics Center in biostatistical study design and data collection,
management, analysis and monitoring of multicenter clinical trials;
 
-Adequacy of the facilities and computing resources to assure smooth
and efficient function.
 
AWARD CRITERIA
 
Applications recommended by the National Cancer Advisory Board (NCAB)
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. Furthermore, the applicant
organization must indicate a commitment to accept provisions outlined
under the Terms and Conditions of Award in this RFA.
 
Application Receipt Date:  July 30, 1996
Review by the NCAB:        February 25, 1997
Anticipated Award Date:    April 1, 1997
 
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. Carl Mansfield
Division of Cancer Treatment, Diagnosis and Centers
National Cancer Institute
Executive Plaza North, Suite 800
6130 Executive Boulevard, MSC7440
Bethesda, MD  20892-7440
Telephone:  (301) 496-6111
FAX:  (301) 480-5785
Email:  mansfieldc@dtpepn.nci.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Ms. Eileen Natoli
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, Extension 256
FAX:  (301) 496-8601
Email:  natolie@gab.nci.nih.gov
 
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 recipients to provide a
smoke-free workplace and promote the non-use of 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 for 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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