Full Text CA-93-01

RADIOLOGIC DIAGNOSTIC ONCOLOGY GROUP V:  STEREOTACTIC BIOPSY FOR
NON-PALPABLE BREAST LESION CHARACTERIZATION

NIH GUIDE, Volume 21, Number 44, December 11, 1992

RFA:  CA-93-01

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Medical/Diagnostic Imaging 
  Diagnosis, Medical 


National Cancer Institute

Letter of Intent Receipt Date:  January 12, 1993
Application Receipt Date:  March 12, 1993

PURPOSE

The Radiation Research Program (RRP), Division of Cancer Treatment
(DCT) of the National Cancer Institute (NCI), invites applications for
cooperative agreements to establish a multi-institutional scientific
group to optimize a clinical algorithm for subclinical, non-palpable
breast lesion characterization.

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 Request
for Application (RFA), Radiologic Diagnostic Oncology Group V:
Stereotactic Breast Biopsy for Non-Palpable Lesion Characterization, 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 "Healthy People 2000" (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

Non-profit and for-profit organizations and institutions, governments
and their agencies, and foreign and domestic institutions are eligible
to apply.  Applications from minority individuals and women are
encouraged.  Applications may be submitted from institutions that
desire to be a participating Clinical Institution in a consortium
and/or as a headquarters institution.  The same institution may serve
in both capacities within this cooperative agreement.

MECHANISM OF SUPPORT

Support of this program will be through the cooperative agreement
(U01), an assistance mechanism in which substantial NCI programmatic
involvement with the recipient during performance of the planned
activity is anticipated.  The nature of NCI staff involvement is
described in the Terms of Cooperation section.  Applicants will be
responsible for the planning, direction, and execution of the proposed
project.  Except as otherwise stated in this RFA, awards will be
administered under PHS grants policy as stated in the PHS Grants Policy
Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1,
1990.

This RFA is a one-time solicitation.  Future unsolicited competitive
continuation applications will compete as research project applications
with all other investigator-initiated applications and be reviewed by
the Division of Research Grants (DRG).  If the NCI determine 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 below.

FUNDS AVAILABLE

Approximately $1,500,000 in total costs per year for four years will be
committed to fund applications that are submitted in response to this
RFA.  It is anticipated that a consortium of about ten clinical
institutions and the headquarters component will be funded to establish
the RDOG V.  It is anticipated that approximately one-fourth of the
total funds expended each year will be devoted to the headquarters
function, and approximately three-quarters will be awarded to the
participating Clinical Institutions.  This funding level is dependent
on the receipt of a sufficient number of applications of high
scientific merit.  The total project period for applications submitted
in response to the present RFA may not exceed four years.

RESEARCH OBJECTIVES

Background

The Radiologic Diagnostic Oncology Group (RDOG) was formed in September
1987, in response to an RFA.  The RDOG objective is timely evaluation
of current and emerging imaging modalities in the management of
patients with cancer.  The development of multi-institutional clinical
trial groups allows for rapid patient accrual within a short period of
time.  This in turn assures rapid evaluation and optimization of
imaging techniques for diagnosis, staging and serial monitoring of
cancer, with early dissemination to the public of proven new methods.

Since the time of its establishment, RDOG clinical research has been
important for the development of optimal imaging algorithms for
prostate and lung cancer (RDOG I), pancreatic and colon cancer (RDOG
II), and musculoskeletal and head and neck cancer (RDOG III).  Five
protocols are currently underway in fourteen academic centers in this
country.  Recently, a new RFA (RDOG IV) has been issued to study
ovarian and pediatric solid tumor imaging, and six to eight new
institutions are expected to be funded.  RDOG has had significant
impact on clinical research in radiology.  This is the first time that
multi-institutional clinical trials in diagnostic imaging have been
conducted in a centrally coordinated fashion with strict quality
control and analysis of cost-effectiveness.  Ultimately, RDOG study
findings would be useful for design of therapeutic protocols, in
formulating clinical and reimbursement policy.

The specific focus of this RFA is to expand RDOG in order to study
imaging-guided stereotactic breast lesion biopsy as a minimally
invasive alternative to an open surgical biopsy.  This RFA is based on
the recommendations of the NCI workshop organized by the Diagnostic
Imaging Research Branch of the Division of Cancer Treatment in
collaboration with the Early Detection Branch of the Division of Cancer
Prevention and Control.

The majority of patients (about 80 percent) undergoing open surgical
biopsy of the breast lesions do not have cancer.  Recently,
imaging-guided stereotactic breast biopsy has emerged as a minimally
invasive novel tool with the potential to replace open surgical biopsy
in a significant fraction of patients.  There are two potential
advantages of stereotactic breast biopsies compared to surgery:  (1)
minimization of tissue damage (and thus improvement in cosmetic
results) and (2) cost effectiveness.  In addition, recent reports
indicate that stereotactic technique, which allows for precise,
quantitative, pinpoint localization of breast lesions, improves
diagnostic yield of conventional free-handed approaches to
imaging-guided biopsy of breast lesions; indeed, stereotactic
methodology may decrease the insufficient sample rate when fine needle
biopsy is performed (Schmidt R., University of Chicago, Presented at
the NCI Workshop, September 5, 1991).

Two approaches to imaging-guided stereotactic breast tissue diagnosis
are employed:  (1) Stereotactic Fine Needle Aspiration (SFNA) and (2)
Stereotactic Core Needle Biopsy (SCNB).  SFNA produces aspiration
cytology, and SCNB produces tissue samples comparable to open surgery.
The sensitivity of SFNA compared to open surgery ranges from 79 to 100
percent (depending on the clinical center), while the insufficient
sample rate ranges from zero to 25 percent (Schmidt R., University of
Chicago, Presented at the NCI Workshop, September 5, 1991).  The
sensitivity for SCNB, on the other hand, was reported at 95 percent of
the sensitivity of open surgical biopsy---with no insufficient samples
(Parker et al. Radiology 1991; 180:403-407; Parker et al. Radiology
1990; 176:741-747).  SCNB and in particular SFNA are less traumatic
than open surgery, and the cost of stereotactic tissue diagnosis is
about 28 percent of that for surgical procedures.

In summary, these preliminary clinical data indicate patient benefit
and cost-effectiveness of imaging-guided stereotactic breast biopsy
compared to open surgical biopsy.  However, indications for
stereotactic (SFNA or SCNB) compared to open surgical biopsy have not
been defined, and a number of questions remain to be addressed (e.g.,
false negative rate--missed lesions, the quality of samples).

Research Goals

The goal of this RFA is to stimulate multi-center evaluation of
imaging- guided stereotactic breast lesion biopsy and its impact on
patient management and cost-effectiveness compared to open surgical
biopsy.  Major clinical questions can be answered by such a study:

o  what specific stereotactic technique is most appropriate?
o  can stereotactic breast biopsy replace open surgery?
o  in what specific clinical situations?
o  in what percentage of patients?
o  what gain in patient management and health care cost management can
be achieved?

In order to address these questions, a centrally-coordinated,
cooperative, multi-institutional study, with consensus-based
experimental design development and data analysis should be performed.

SPECIAL REQUIREMENTS

Terms of Cooperation

A.  Nature of Participation by NCI Staff

All RRP staff assistance, advice, and support, as described throughout
these Terms of Cooperation, will be communicated to awardees by the
Associate Director, RRP (ADRRP), or the designated Program Coordinator
(from RRP staff), who will act as deputy for the ADRRP in his absence
or when directed.  In all cases, the role of the NCI is to assist and
facilitate but not to direct research activities.  Thus the ADRRP and
Program Coordinator, even in cases where review of protocols or other
decisions are undertaken, will be serving as facilitators to aid the
awardees in arriving at optimal protocols, mutually suitable methods of
operation and communication, efficient use of NCI-referred assistance
when needed, compliance with established NIH and/or FDA regulations,
and achievement of the research goals of this cooperative agreement.
If objective differences of opinion should arise, the arbitration panel
described below will be available to assist in their resolution.

1.  RRP as a Scientific Resource for NCI-supported Clinical
Investigations

The ADRRP, or designee, will serve as a resource available to awardees
for specific scientific information with respect to clinical trial
design.  The staff will assist the RDOG V institutions as appropriate
in developing information concerning the scientific basis for specific
research protocols and also will be responsible for advising the group
of the nature and results of relevant studies being carried out
nationally or internationally.  The ADRRP, or designee, will
participate in planning and strategy meetings of the RDOG V
institutions.  At these meetings, RDOG V institutions, assisted by the
ADRRP, or designee, will review relevant information and establish and
prioritize the outstanding research questions.

2.  RRP Assistance in Protocol Development

The protocol must be a study document mutually acceptable to the RDOG
V and to the ADRRP.  Communication at the various stages of protocol
development is encouraged.  The ADRRP, or designee, will be available
to assist the group in developing a mutually acceptable protocol,
consistent with the research interests, abilities, and strategic plans
of the group and of the NCI.  The ADRRP will assist the RDOG V
institutions in protocol design as may be appropriate by providing
information regarding:  (a) the existence and nature of concurrent
clinical trials in the area of RDOG V research, pointing out possible
duplication of effort, and (b) relevant data concerning imaging
research.  The ADRRP, or designee, will also comment on the scientific
rationale and value of the proposed study, the design, the statistical
requirements, and the implementation of the study, if indicated.  All
protocols for submission to the NCI must be preceded by a letter from
the RDOG V Chairperson to the ADRRP describing the hypothesis
investigated, the general design of the contemplated trial, and
relevant information on accrual capabilities to document feasibility.
The ADRRP will then formally review and provide a program response to
these concepts, commenting on study originality and programmatic
interest.  This preliminary review will expedite protocol development
and implementation and facilitate agreement on study priority and
design.

3.  RRP Review of Proposed Protocols

All the RDOG V scientific protocols will be reviewed by the ADRRP.  For
all protocols, the ADRRP, or designee, will provide the RDOG V
Chairperson with a written consensus review that describes recommended
modifications and other suggestions as appropriate.

The major considerations relevant to protocol review by the NCI
include: (a) the strength of the scientific rationale supporting the
study, (b) the medical importance of the question being posed, (c) the
avoidance of undesirable duplication with other ongoing studies, (d)
the appropriateness of study design, (e) a satisfactory projected
accrual rate and follow-up period, (f) patient safety, (g) compliance
with federal regulatory requirements, (h) adequacy of data management,
and (i) appropriateness of patient selection and follow-up, evaluation,
and assessment of complications/toxicity.

If a proposed protocol is disapproved by the NCI, the specific reasons
for lack of approval will be communicated by the ADRRP to the RDOG V
Chairperson as a consensus review within 45 days of receipt of the
proposed protocol.

Disagreements arising pursuant to protocol disapproval may be submitted
to an arbitration panel.  An arbitration panel composed of one RDOG V
nominee, one ADRRP nominee, and a third member with clinical trials
expertise chosen by the other two will be formed to review the NCI
decision and recommend an appropriate course of action to the ADRRP.
These special arbitration procedures in no way affect the awardee's
right to appeal an adverse determination in accordance with PHS
regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR
Part 16.

The RDOG V will not expend NCI funds to conduct any study not approved
by the NCI unless the disapproval has been modified by the arbitration
process outlined above.

4.  RRP Study Monitoring

The ADRRP, or designee, will review RDOG V mechanisms for study
monitoring (see Responsibilities of Awardees, RDOG V Headquarters).

5.  RRP Review of Data Management and Analysis

The ADRRP, or designee, will review RDOG V mechanisms established by
the RDOG V Headquarters for data management and analysis (see
Responsibilities of Awardees, RDOG V Headquarters).  The ADRRP, or
designee will make recommendations to the RDOG V Group Chairperson for
assuring that data collection and management procedures are adequate
for quality control and analysis and sufficiently uniform across the
RDOG V participating institutions.  Any disagreements between NCI and
RDOG V members relating to data management and analysis that cannot be
resolved by bilateral discussions will be submitted to the same
arbitration process previously outlined.

6.  Access to Data

The NCI will have access to all data generated under this cooperative
agreement and may periodically review the data.  Data must also be
available for external monitoring as required by agreement between the
NCI and the Food and Drug Administration (FDA) with respect to the
responsibility of the NCI as a study sponsor.  The awardee will retain
custody and primary rights to the data consistent with current HHS,
PHS, and NIH policies.

7.  RRP Involvement in Protocol Closure

The ADRRP, or designee, will review RDOG V mechanisms for interim
monitoring of results and will monitor protocol progress.  The ADRRP
may request that a protocol study be closed to accrual for reasons
including:  (a) insufficient accrual rate; (b) achievement of the
original accrual goal; (c) poor protocol performance; (d) patient
safety; (e) conclusive study results; and (f) emergence of new
information that diminishes the scientific importance of the study.
The NCI will not permit expenditures of NCI funds for a study after
requesting closure (except for patients already on-study).  For any
study closure, the NCI will establish an arbitration process for
institutions that wish to appeal protocol closure.  This process will
be identical to that described above for protocol disapproval.

If the RDOG V wishes to close accrual to a study prior to meeting the
initially established accrual goal, the RDOG V Chairperson must submit
the interim results and written justification to NCI staff for review
and approval.  Unresolved disagreements between NCI staff and the RDOG
V institutions regarding the appropriateness of early study closure
will be arbitrated by the process outlined above.

8.  RRP Involvement in Investigational Device and Agent Management

a.  If applicable, RRP staff will advise the RDOG V institutions of
specific requirements and changes in requirements concerning
investigational device and/or agent management that the FDA may
mandate. Investigators performing trials under RDOG V cooperative
agreements will be expected, with RRP assistance, to comply with all
FDA monitoring and reporting requirements for investigational devices,
if applicable.

b.  Investigators performing NCI funded clinical trials will be advised
by NCI staff of potential studies that will be relevant to new avenues
of cancer diagnosis.  When this involves an investigational device
and/or agent, the clinical information must be acceptable to the FDA.
With ADRRP assistance, the RDOG V institutions will develop protocols
to obtain such information needed, if applicable, for the projects.

9.  RRP Review of Procedures for Compliance with Federally Mandated
Regulations

RRP staff will review procedures established by the RDOG V headquarters
for monitoring of compliance and assurance to meet FDA regulatory
requirements for studies involving investigational devices/agents, if
applicable, and Office for Protection from Research Risks (OPRR)
requirements for the protection of human subjects by all RDOG V
institutions (see Responsibilities of Awardees, RDOG V headquarters).

10.  RRP Review of Progress

Performance of each RDOG V member and affiliate will be reviewed
annually by the ADRRP, or designee, on the basis of the information
provided at the progress review meetings, annual and semi-annual
reports.  Each RDOG V institution must submit an annual progress
report. Annual and semi-annual reports submitted to the NCI will
contain highlights of progress made during that period and will
include, at a minimum, summary data on protocol performance by each
RDOG V member and affiliate and other relevant data.  In addition,
periodic accrual information may be requested by the NCI for all active
studies whenever deemed appropriate.  A system for providing such
information in a timely manner must be in place.

Support recommended for the remainder of the project will be contingent
upon favorable review by the ADRRP, or designee, of the progress of the
project and sufficient patient accrual.  Insufficient patient accrual,
or noncompliance with the terms of award, including these Terms of
Cooperation, may result in a reduction of budget, withholding of
support, or termination of the award.

B.  Responsibilities of Awardees

It is the responsibility of the awardee to develop the details of the
research design including definition of objectives and approaches,
planning, implementation, analysis, and publication of results,
interpretations and conclusions of studies.  The awardee, with ADRRP or
designee assistance, shall develop RDOG V research goals, develop
protocols for clinical cancer research in accord with the awardee's
research interests, abilities and goals, and submit to the NCI for
review and approval prior to implementation.

1.  RDOG V Headquarters

The Principal Investigator of the headquarters institution will serve
as the RDOG V Chairperson.  The RDOG V Headquarters, under the
leadership of the RDOG V Chairperson, will be responsible for the
coordination of protocol development, quality control and study
monitoring, data management and analysis, adherence to requirements
regarding investigational device management (when applicable) and
federally mandated regulations, protocol and performance reporting, and
recommendations for resource adjustments.  All the scientific and
administrative decisions related to the RDOG V-funded activities and
made by the RDOG V institutions or affiliates will be communicated to
the ADRRP or designee by the RDOG V Chairperson.  The RDOG V
Chairperson will communicate the results of the NCI protocol reviews to
the RDOG V institutions.

a.  Study Monitoring

The RDOG V Headquarters, under the leadership of the RDOG V
Chairperson, is responsible for establishing a mechanism for study
monitoring to ensure accurate and timely knowledge of the progress of
each study through:

o  tracking and reporting of patient accrual and adherence to defined
accrual goals;

o  ongoing assessment of case eligibility and evaluability;

o  timely review and assessment of patient data;

o  if applicable, rapid reporting of procedure-related morbidity and
measures to ensure communication of this information to all parties;

o  if applicable, interim evaluation and consideration of measures of
outcome, as consistent with patient safety and good clinical trials
practice;

o  timely communication of results of studies; and

o  a method of providing, upon NCI request, summary of the imaging
methodology sensitivity/specificity and, when appropriate, morbidity
data.

b.  Data Management and Analysis

The RDOG V Headquarters, under the leadership of the RDOG V
Chairperson, will develop procedures to ensure that data collection and
management are:  (a) adequate for quality control and analysis; (b) as
simple as appropriate in order to encourage maximum participation of
physicians entering patients and to avoid unnecessary expense; and (c)
standardized among the RDOG V participating institutions.  Any
disagreements between RRP and RDOG V members relating to data
management and analysis that cannot be resolved by bilateral
discussions will be submitted to the same arbitration process
previously outlined.

c.  RDOG V Compliance with Federally Mandated Regulations

The RDOG V Headquarters, under the leadership of the RDOG V
Chairperson, is responsible for establishing procedures for all RDOG V
institutions to comply with DHHS and FDA regulatory requirements for
studies involving investigational devices/agents, if applicable, and
the OPRR requirements for the protection of human subjects.  These
procedures include:

o  methods for ensuring that each protocol is reviewed by the
responsible Institutional Review Board (IRB) prior to patient entry,
and that each protocol is reviewed at least annually by the IRB while
the protocol is active in accordance with 45 CFR 46, Protection of
Human Subjects.

o  a system for ensuring timely reporting of all serious and unexpected
complications to the ADRRP, or designee.

d.  Progress Review

The RDOG V Headquarters, under the leadership of the RDOG V
Chairperson, will have a mechanism in place for assessing performance
of its members, with particular attention to accrual of an adequate
number of eligible patients onto group trials, timely submission of
required data, conscientious observance of protocol requirements,
authorship, and participation in group leadership.  This mechanism will
include a procedure for the RDOG V Chairperson to recommend to the NCI
an adjustment of funds within the group as appropriate for the level of
participation in group activities including, but not limited to,
accrual.  Financial adjustments may be made by NCI at the time a
non-competing continuation [Type 5] award is negotiated.  The RDOG V
Chairperson, Principal Investigator from each RDOG V institution, and
the ADRRP, or designee, shall meet jointly twice a year to review RDOG
V progress, establish priorities, and plan future activities. The
frequency of such meetings may be increased if it is deemed necessary.

2.  Membership in RDOG V

NCI funding is contingent upon the institution remaining a member of
the RDOG V.

3.  Planning Procedures

It is anticipated that decisions on all RDOG V activities will be
reached by consensus of the group under the leadership of the RDOG V
Chairperson who will be responsible for communication with the ADRRP or
designee.

4.  Attendance Requirements

It is required that a Principal Investigator, or designee, from all
RDOG V members participate at all meetings and workshops relevant to
their protocol(s).

5.  Protocol Development

All RDOG V institutions are expected to participate in the development
of new and revised protocols under the leadership of the RDOG V
Chairperson.  The RDOG V Chairperson will submit such protocols in a
timely fashion for review and approval by NCI.

6.  Conduct of Research and Patient Accrual

Awardees are expected to conduct pertinent clinical imaging studies
consistent with approved applications and post-award procedures.
Awardees also are expected to provide timely results from sufficient
numbers of patients.  All new and revised protocols must be submitted
by the RDOG V investigators to the appropriate IRB within 30 days of
the date of the written approval from the RDOG V Chairperson.  Patients
may not be entered into new or revised protocols until the protocol has
been reviewed and approved by the IRB in accordance with 45 CFR 46,
Protection of Human Subjects.

7.  Progress Review

The RDOG V Chairperson, the Principal Investigator from each RDOG V
institution and the ADRRP, or designee, shall meet twice a year to
review RDOG V progress, establish priorities, and plan future
activities.  The frequency of such meetings may be increased if it is
deemed necessary.

8.  Reporting Requirements

Annual and semi-annual progress reports will be submitted to the NCI
and will include at a minimum summary data on protocol performance by
each awardee.  Interim reports of each activated and ongoing study
shall appear in the minutes of each RDOG V meeting and shall include
specific data on patient accrual and, whenever appropriate, detailed
reports of device/agent-associated morbidity.  Awardees should have a
system in place for providing semi-annual accrual information, if
requested by the ADRRP, or designee, for all active studies.

9.  Publication of Data

Timely publication of major findings is encouraged.  Publication and
oral presentation of work done under this agreement will require
appropriate acknowledgement of NCI support.  The NCI will have access
to all data generated under this cooperative agreement and may
periodically review the data.  The awardee will retain custody of and
primary rights to the data consistent with current DHHS, PHS, and NIH
policies.

C.  These Terms of Cooperation are in addition to and not in lieu of
otherwise applicable OMB administrative guidelines, HHS grant
administration regulations at 45 CFR Part 74, and DHHS, PHS, and NIH
grants administration policies.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and women
in study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis must be placed on the need for inclusion of minorities
and women in studies of diseases, disorders and conditions which
disproportionately affect them.  This policy is intended to apply to
males and females of all ages.  If women or minorities are excluded or
inadequately represented in clinical research, particularly in proposed
population-based studies, a clear compelling rationale should be
provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale for
its choice.  In addition, gender and racial/ethnic issues should be
addressed in developing a research design and sample size appropriate
for the scientific objectives of the study.  This information should be
included in the form PHS 398 (rev. 9/91) in the Research Plan, 1-4, AND
summarized in 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However, NIH
recognizes that it may not be feasible or appropriate in all research
projects to include representation of the full array of United States
racial/ethnic minority populations (i.e., Native Americans [including
American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks,
Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.

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.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 12, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name and address of the Principal Investigator, the names
of other key personnel, the participating institutions, and the number
and title of the RFA in response to which the application may be
submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, it is requested
in order to provide an indication of the number and scope of
applications to be reviewed.

The letter of intent is to be sent to:

Dr. Faina Shtern
Chief, Diagnostic Imaging Research Branch
Radiation Research Program
National Cancer Institute
Executive Plaza North, Suite 800
Bethesda, MD  20892
Telephone:  (301) 496-9531

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for cooperative agreements.  These forms are available at
most institutional offices of sponsored research; from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 496-7441; and from the NCI program director named below.

The RFA label available in the application form PHS 398 must be affixed
to the bottom of the face page.  Failure to use this label could result
in delayed processing of the application such that it may not reach the
review committee in time for review.  In addition, the RFA number and
title must be typed on line 2a of the face page of the application
form.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed, exact photocopies, in one package to the
address below.  The photocopies must be clear and single sided.

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, send two additional copies of the
application to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 838
5333 Westbard Avenue
Bethesda, MD  20892

Applications must be received by March 12, 1993.  If an application is
received after that date, it will be returned without review.  If the
application submitted in response to this RFA is substantially similar
to a grant application already submitted to the NIH for review, but has
not yet been reviewed, the applicant will be asked to withdraw either
the pending application or the new one.  Simultaneous submission of
identical applications will not be allowed, nor will essentially
identical applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this RFA
that is essentially identical to one that has already been reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.

Special Instructions for Preparation of Cooperative Agreement
Applications

General instructions for the preparation of the cooperative agreement
application are contained in the grant application form PHS 398 (rev.
9/91).

Because the Terms of Cooperation, discussed above, will be included in
all awards issued as a result of this RFA, it is critical that each
applicant include specific plans for responding to these terms.  Plans
must describe how the applicant will comply with the program staff
involvement and how all the Responsibilities of Awardees will be
fulfilled.

Principal Technical Requirements for Membership:

A.  Requirements for a Consortium of Clinical Institutions

1.  A commitment to participate in multi-institutional protocols and
documentation of the facilities and professional personnel available to
conduct cooperative imaging trials.  This includes assignment of
appropriate specialists required by each protocol including, but not
limited to, radiologists, surgeons, and pathologists, in order to
ensure complete patient evaluation.

2.  Individual applicant institutions in a consortium must demonstrate
the availability of state-of-the-art instrumentation and the capacity
to perform stereotactic and surgical breast biopsy.  Each member
institution must have the instruments, facilities, and capabilities for
the proposed experimental protocol.  Applicant institutions must be
able to correlate mammographic imaging-guided stereotactic and surgical
biopsies as designed by the protocol.

3.  The presence of expertise for review and evaluation of the quality
of mammographic images, the existing procedures for quality control of
imaging equipment, imaging technique, and image interpretation must be
demonstrated.

4.  The availability of qualified support personnel to ensure timely
and accurate data retrieval and reporting is necessary.

5.  The availability of sufficient expertise and the potential for
adequate patient accrual (no less than 50 patients per year per
individual institution) must be demonstrated by a Consortium.
Applicants must show the ability to organize, conduct, and monitor
clinical trials in radiology.

6.  The organizational plan must be presented for personnel and
facilities capable of performing and supporting the administrative
functions of a cooperative group member conducting imaging trials in
cancer.

7.  Each proposed Consortium of Individual Clinical Institutions must
describe procedures by which they would perform their functions,
including protocols for accomplishing the clinical work and data
accrual.  The application should include a sample protocol for
correlation of image-guided stereotactic and surgical biopsies of
non-palpable breast lesions.

B.  Requirements for the Headquarters

1.  Expertise in the design and coordination of multi-institutional
cooperative clinical trials including interactions with participating
institutions.

2.  Capability to provide educational workshops and ongoing training
for group participants in order to ensure the development of
scientifically valid results in the most efficient manner.

3.  Capacity to develop and implement an administrative and management
structure for the RDOG V including criteria for membership, an
Executive Committee, a Quality Assurance Committee, a Protocol and a
Research Strategy Committee that will assume responsibility for
randomized studies and set the priorities for protocol development.

4.  Capacity for monitoring performance of studies and producing timely
reports on the quality of data, including, but not limited to, image
interpretation and related information, sensitivity and specificity of
various stereotactic and surgical approaches to minimal breast lesions
characterization.

5.  Expertise in the development of experimental design for
statistically valid multi-institutional imaging trials.

6.  Availability of facilities and professional personnel with
expertise in data management and analysis and the ability to
participate in cooperative clinical trials to provide centralized
statistical services.

7.  Headquarters applicants must describe procedures by which they
would perform their functions, including data management and analyses.

REVIEW CONSIDERATIONS

A.  Review Procedure

Upon receipt, applications will be reviewed by the DRG for
completeness.  Incomplete applications will be returned to the
applicant without further consideration.  Evaluation for responsiveness
to the program requirements and criteria stated in the RFA is an NCI
program staff function.  Applications that are judged non-responsive
will be returned by the NCI, but may be submitted as
investigator-initiated research grants at the next receipt date.
Questions concerning the responsiveness of proposed research to the RFA
may be directed to program staff listed under INQUIRIES.

If the number of applications is large compared to the number of awards
to be made, the NCI may conduct a preliminary scientific peer review to
eliminate those that are clearly not competitive.  The NCI will remove
from competition those applications judged to be noncompetitive for
award and notify the applicant and institutional business official.

Those applications judged to be both competitive and responsive will be
further evaluated according to the review criteria stated below for
scientific and technical merit by an appropriate peer review group
convened by the Division of Extramural Activities, NCI.  The second
level of review will be by the National Cancer Advisory Board.

B.  Review Criteria

1.  Applications for the Headquarters will be reviewed on the basis of
the following criteria:

a.  Scientific merit and resources, appropriateness and adequacy of the
proposed approach to experimental protocol development and
biostatistical data processing.  The proposed methodology must exhibit
scientific soundness showing how the trials will be conducted to attain
the objectives.

b.  Qualifications and research experience of the Principal
Investigator and staff including, but not limited to, previous
experience with administration of multi-institutional clinical trials
in imaging science.  These should include the experience of the
proposed personnel (statisticians, programmers, and data management
staff) in the design, monitoring, analysis, and reporting of
cooperative multi-center clinical trials.

c.  Feasibility and merit of the proposed structure for RDOG V
administration and data management including, but not limited to,
interactions with the RDOG V participating institutions.

2.  Applications for a Consortium of Clinical Institutions will be
reviewed on the basis of the following criteria:

a.  The overall qualifications of applicant institutions in accordance
with the "Principal Technical Requirements for Membership" in the
collaborative group as stated above.

b.  Adequacy of professional and support personnel.  Record or evidence
of willingness to work as a team with other group members and to
participate in group-generated and program-monitored protocols
according to their capacity.

c.  Evidence of the ability to develop clinical trials in radiology.
Relevance and merit of sample typical protocols submitted with the
application will be considered.  Such suggested protocols may be
considered as logical bases for budget presentations and justifications

d.  Evidence of the ability of the applicant to complete imaging trials
of substantial scientific merit.  It is anticipated that different
institutions will have varying patterns of patient referral and
accession.  Applicants must show that they have the potential to
accomplish multi-center imaging trials of sound scientific quality in
a reasonable period of time.

e.  Evidence of the ability to accrue an adequate number of patients.

f.  Availability of appropriate facilities, equipment, instrumentation,
and other resources to ensure that each institution is capable of
performing innovative cooperative trials in cancer diagnosis.

g.  Appropriateness of the proposed budget and duration in relation to
the proposed research.

AWARD CRITERIA

The earliest feasible start date for the initial awards will be
September 30, 1993.  In making funding recommendations, the National
Cancer Advisory Board considers the special needs of the NCI and the
priorities of the National Cancer Program.  Although this program is
provided for in the financial plans of the NCI, the award of
cooperative agreements pursuant to this RFA is also contingent upon the
availability of funds for this purpose.

INQUIRIES

Written and telephone inquiries concerning the objectives and scope of
this RFA and inquiries about whether or not specific proposed research
would be responsive are encouraged and may be directed to Dr. Shtern at
the address below.  Dr. Shtern welcomes the opportunity to clarify any
issues or questions from potential applicants.

Direct inquiries regarding programmatic issues to:

Dr. Faina Shtern
Chief, Diagnostic Imaging Research Branch
Radiation Research Program
National Cancer Institute
Executive Plaza North, Suite 800
Bethesda, MD  20892
Telephone:  (301) 496-9531

Direct inquiries regarding fiscal matters to:

Ms. Barbara Fisher
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 242
Bethesda, MD  20892
Telephone:  (301) 496-7800, Extension 29
FAX:  (301) 496-8601

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 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.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

.

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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