Full Text CA-93-038


NIH GUIDE, Volume 22, Number 32, September 3, 1993

RFA:  CA-93-038

P.T. 34

  Biological Markers 

National Cancer Institute

Letter of Intent Receipt Date:  October 6, 1993
Application Receipt Date:  December 7, 1993


The Cancer Diagnosis Branch of the Division of Cancer Biology,
Diagnosis and Centers, National Cancer Institute (NCI) invites
applications for cooperative agreements from institutions to identify
and evaluate tissue markers for improving the pathological
classification of human gliomas.  Precise pathologic diagnosis and/or
classification of gliomas is often difficult.  Since the incidence and
mortality of brain tumors are increasing, and gliomas constitute the
most common class of these important tumors, improved classification
would be beneficial to clinicians making decisions about patient
management.  For the purposes of this RFA, gliomas are meant to include
astrocytomas, mixed astrocytomas/oligodendrogliomas, and
oligodendrogliomas.  The purpose of the proposed awards is to extend
and expand the ongoing inter-institutional studies of the Glioma Marker
Network to increase the availability of patient resources and enhance
the technical capabilities of the Network to efficiently test clinical
correlative hypotheses.  The Network will carry out collaborative
studies designed to continue the evaluation of a variety of glioma
markers, identify additional promising markers, and correlate the
markers with clinical parameters.  The cooperative studies funded by
this RFA will optimize the use of rare tissue resources.  This RFA will
also provide funding for coordinated management and statistical
analyses of data collected by Network investigators.  These studies
will take advantage of the synergy resulting from collaborations among
neuropathologists, clinicians, cancer biologists, and statisticians.


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 Applications (RFA), Identification and Evaluation of Tissue Markers
for Pathological Classification of Human Gliomas, 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).


Applicant organizations must be located in the United States, Canada,
or Mexico.  Non-profit organizations and institutions, and government
agencies are eligible to apply. For-profit organizations are also
eligible.  Applications from minority individuals and women are


The administrative and funding mechanism to be used to support the
Glioma Network is the cooperative agreement (U01), an assistance
mechanism in which substantial NCI program staff involvement with the
recipient during performance of the planned activities is anticipated.
Under the cooperative agreement, the NCI purpose is to support and/or
stimulate the recipient's activities by collaborating and otherwise
working jointly with the award recipient in a partner role.  Details of
the responsibilities, relationships, and governance of the study to be
funded under cooperative agreements are discussed later in this
document under the section Terms and Conditions of Award.  The awardees
retain full responsibility for planning and direction of the projects
within the guidelines of the RFA and for performance of the proposed
studies.  There is no intent, real or implied, for NCI staff to direct
awardee activities or limit the freedom of the funded investigators.
Awards will be administered under PHS grants policy as stated in the
Public Health Service Grants Policy statement, DHHS Publication No.
(OASH) 90-50,000, revised October 1, 1990.

This RFA is a one-time solicitation.  However, if it is determined that
there is 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.


The NCI anticipates making four to six awards for project periods up to
four years and anticipates a total of $1,200,000 will be set aside for
the initial year's funding.  Because of the nature and scope of the
research proposed in response to this RFA may vary, it is anticipated
that the sizes of awards will vary also.  Funding in response to this
RFA is dependent on the receipt of a sufficient number of applications
of high scientific merit.  The earliest feasible start date for the
initial awards will be September 1, 1994.  Although the program is
provided for in the financial plans of the NCI, the award of
cooperative agreements pursuant to this RFA is contingent on the
availability of funds appropriated for fiscal year 1994.



Gliomas, the most common CNS tumors in adults, are divided into three
major classes that are characterized by differences in clinical
behavior.  The highly malignant glioblastoma multiform are uniformly
fatal with no effective therapy available.  Well differentiated
astrocytomas and oligodendrogliomas are least malignant and are
generally amenable to surgery and radiation therapy.  Overall
oligodendrogliomas have a better prognosis than comparable
astrocytomas.  Anaplastic astrocytomas, a diverse group of tumors with
intermediate malignancy, have a variable clinical outcome.
Approximately half the patients with anaplastic astrocytomas respond
well to a combination of radiotherapy and chemotherapy.  The
histological classifications currently in use do not identify the
subset of patients who will have a better clinical outcome or who will
respond to specific therapy.  The identification of these patients
would enable clinicians to design more effective treatment regimens.

The inability of classification schemes to predict outcome and response
to therapy suggests that there are biologically distinct subsets of
tumors that cannot be distinguished morphologically.  Significant
variation in tumor classification can result from using different
histological classification schemes.  In addition, classification of
anaplastic astrocytomas using any single classification scheme fails
because the clinical behavior of these tumors is highly variable.
Neuropathologists from the current Glioma Marker Network have focused
on identifying histological features that contribute to differences in
classification.  Mixed astrocytomas/oligodendrogliomas, which appear to
have a favorable prognosis, have been identified as being particularly
difficult to classify using the current classification schemes.

The application of molecular genetic, cytogenetic, and
immunohistological techniques to the study of CNS tumor markers is
being reported more frequently in the literature.  Common chromosomal
alterations, mutations in tumor suppressor genes and gene
overexpression or amplification have been reported in gliomas.
Correlation of chromosomal alterations and molecular markers with tumor
initiation and progression and with clinical parameters may aid in the
classification of the tumors and the identification of a subset of
gliomas with high malignant potential and poor clinical outcome.
Promising prognostic markers need to be evaluated in larger scale
clinical trials before they can be used by clinicians for patient

Research Goals and Scope

The objective of this RFA is to invite applications for cooperative
agreements to extend and expand the Glioma Marker Network currently
carrying out studies to identify and evaluate molecular markers for
improving the pathological classification of human gliomas.  Applicants
should propose studies with hypotheses designed to evaluate tumor
markers and to correlate markers with clinical parameters.
Applications should discuss the use of molecular genetic, cytogenetic,
immunohistological, and/or biochemical techniques in studies of glial
tumor markers that will be useful in tumor classification.
Collaborations among neuropathologists, clinicians, cancer biologists,
and statisticians are critical to these types of studies and are
specifically encouraged.

Applicants should address approaches to establishing correlations
between tumor markers and clinical parameters.  The hypotheses to be
tested by the proposed studies should be clearly stated and the
rationale for the study design and experimental techniques selected
thoroughly discussed.  Sufficient preliminary data should be provided
to support the feasibility of the proposed studies.  Applications
should include a discussion of the statistical issues related to study
design and data analysis.

A goal of the RFA is to promote collaborative studies to optimize the
use of rare tissue resources.  The cooperative agreement mechanism was
chosen to facilitate the coordinated management of tissue resources
with associated clinical data and the statistical analyses of data
generated in collaborative studies.  Applicants should discuss their
anticipated contribution to collaborative studies carried out by the


The Cooperative Agreements (U01) will require cooperation between an
NCI representative (Program Administrator) and the Principal
Investigators (PIs) of the individual funded projects in order to
facilitate effective interactions among the cooperating institutions.
The Program Administrator will assist in coordinating the activities of
the research groups and in the exchange of information.

The following terms and conditions will be incorporated into the award
statement and provided to the Principal Investigator(s) and the
institutional officials at the time of award.

Awardee Rights and Responsibilities

Awardees are responsible for proposing research projects to advance the
goals set forth in the RFA and for participating in the development and
conduct of Network studies.  All studies approved by the Coordinating
Committee will be conducted by the members of the Network with
responsibilities for specific aspects of the study determined by the
Committee at the time the study is developed.  The PI and one other
member of each cooperating institution are required to attend meetings
of the Coordinating Committee to help formulate policies and protocols
for the Network, to facilitate implementation of these policies and to
participate in the analysis of data submitted by the participating
research groups.  Awardees will retain custody and primary rights to
their data developed under these awards, subject to Government rights
of access consistent with current DHHS, PHS and NIH policies.

NCI Staff Responsibilities

The Program Administrator (identified under INQUIRIES) has two areas of
responsibility, administration of the program and collaboration with
funded investigators.  The Program Administrator will coordinate and
facilitate the programs supported by these Cooperative Agreements, but
will not direct activities of the Research Network.  As a voting member
of the Coordinating Committee, the Program Administrator will attend
and participate in all meetings and assist in developing operating
policies, quality control procedures and consistent polices for dealing
with recurring situations that require coordinated action.  The Program
Administrator will communicate NCI policies and priorities to the
Coordinating Committee.  The Program Administrator will monitor
research progress and may review the activities of individual
laboratories for compliance with the protocols, quality control
procedures and policies established by the Coordinating Committee.  The
Program Administrator can recommend withholding of support, suspension
or termination of an award for failure to comply with Network or NCI

Collaborative Responsibilities

The NCI Program Administrator and the awardees are responsible for
establishing a Coordinating Committee as defined below.  The
Coordinating Committee will develop operating policies and research
protocols which will be submitted to the Program Administrator for
review of concurrence to NCI policies prior to implementation.  The
Program Administrator will facilitate the review of the policies and
protocols and discuss the results of the review with the Coordinating
Committee.  An arbitration system, as detailed below, will be available
to resolve differences between the Program Administrator and the
members of the Coordinating Committee.

The Coordinating Committee will review the plans for Network studies
and operating procedures proposed by the individual research groups to
insure overall compatibility with the goals of the RFA.  Members of the
Coordinating Committee will be responsible for redefining research
goals and for defining strategies for Network studies in order to
optimize progress and the efficient use of tissue resources.  The
Coordinating Committee will also be responsible for coordinating
Network activities such as the design and implementation of a central
data base for tissue samples and associated clinical data, design of
required forms, distribution of reagents and tissue samples,
pathological review of tissue samples, monitoring research progress,
data collection, statistical design for data analysis and maintaining
quality assurance.

The Coordinating Committee will consist of the NCI Program
Administrator and two members from each cooperating institution,
preferably a clinician or neuropathologist and a basic scientist or
statistician.  One of the two members must be the Principal
Investigator.  The Coordinating Committee will be responsible for
electing a chairperson, who will not be the Program Administrator.
This may be a rotating position.  The Chairperson of the Coordinating
Committee will be responsible for coordinating the Committee
activities, for preparing agendas for meetings and conference calls,
for scheduling and chairing meetings.  The Program Administrator will
attend and participate in all meetings of the Coordinating Committee
and should be kept informed of interactions between research groups.
The Coordinating Committee will prepare an annual report of Network
activities which will include reports from each participating research
group.  Each Principal Investigator is responsible for the timely
preparation of a report of individual group activities.

The Coordinating Committee will meet three times the first year; first,
shortly after the cooperative agreements are awarded to plan basic
operating procedures and to initiate integration of the participating
programs and twice more to monitor Network progress, and will meet
twice yearly thereafter.  The meetings may be held at any of the
participating institutions or at any other convenient location with
concurrence of the NCI.  The meetings will be used to plan research
activities, coordinate tissue utilization, establish priorities,
monitor progress, and address administrative issues.

Arbitration Procedures

An arbitration panel of external consultants will be created to resolve
any irreconcilable differences of opinion related to
scientific/programmatic matters between the Program Administrator and
the members of the Coordinating Committee with respect to
implementation of a proposed operating policy.  The panel will include
one member selected by the Coordinating Committee without participation
of the Program Administrator, one member selected by the NCI and a
third member selected by the other two members of the arbitration
panel.  The NCI arbitration process for the Cooperative Agreement in no
way affects the rights of awardees to appeal selected postaward
administrative decisions in accordance with PHS regulation at 42 CFR
part 50, subpart D and HHS regulations at 45 CFR part 16.



NIH policy is that applications for NIH clinical research grants and
cooperative agreements are 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 or 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
populations-based studies, a clear compelling rationale must be

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 (rev. 9/91) in
Sections 1-4 of the Research Plan and summarized in Section 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 American
[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 is defined as 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

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

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.


Prospective applicants are ask to submit, by October 6, 1993, a letter
of intent that includes a descriptive title of the proposed project,
the name, address, and telephone number of the Principal Investigator,
the names of key personnel, any collaborating 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 the applications to be reviewed.  This information allows NCI
staff to estimate potential workload and to avoid conflict of interest
in the review.

The letter of intent is to be sent to Dr. James W. Jacobson at the
address listed under INQUIRES below.


The grant application form PHS 398 (rev. 9/91) is to be used for the
cooperative agreement application.  These forms are available from most
offices of sponsored research; from the Office of Grants Information,
Division of Research Grants, National Institutes of Health, Westwood
Building, Room 449, Bethesda, MD 20892-4500, telephone 301/584-7248;
and from Dr. James W. Jacobson at the address and telephone number
listed under INQUIRIES below.

The RFA label available in the application form PHS 398 (rev. 9/91)
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 to be reviewed.  The RFA
number and title must be typed on line 2a of the face page of the
application form as well.

Submit a signed typewritten original of the application, including a
checklist, and three signed, exact, clear, and single-sided photocopies
in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892-4500**

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

Ms. Toby Friedberg, Referral Officer
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard
Bethesda, MD  20892

Applications must be received by December 7, 1993.  Applications
received after this date will be returned.  The Division of Research
Grants (DRG) will not accept any application in response to this
announcement that is the same as one currently pending initial review,
unless the applicant withdraws the pending application.  The DRG will
not accept any application that is essentially the same as one already
reviewed.  This does not preclude the submission of substantial
revisions of applications already reviewed, but such application must
include an introduction addressing the previous critique.

Special Instructions for Preparation of Cooperative Agreement

Applicants must propose feasible scientific studies that address the
goals of the RFA with specific reference to the issues discussed in the
REVIEW CRITERIA section.  It is critical that each applicant address
issues relating to participation in a cooperative agreement research
network.  Each applicant should include specific plans for responding
to the "Terms and Conditions of Award" discussed above.  Applicants
should indicate their willingness to interact with the other awardees
and provide a clear description of the nature of proposed interactions.
They should also describe how they will comply with the involvement of
the NCI representative.

Each applicant should anticipate the participation of the Principal
Investigator and one other member of the research group on the
Coordinating Committee that meets three times in the first year and
twice yearly in each subsequent year.  Travel funds for attending the
Coordinating Committee meeting should be included as a budget line
item.  For planning purposes either three trips to Washington DC or one
trip each to the East Coast, West Coast, and Central U.S. may be
proposed for the first year.


Review Procedures

Upon receipt, applications will be reviewed (initially) by the DRG for
completeness.  Incomplete applications will be returned to the
applicant without further consideration.  Evaluation for responsiveness
to the RFA is an NCI program staff function.  An application judged
non-responsive will be returned by the NCI, but may be resubmitted as
an investigator-initiated regular research grant (R01) at the next
receipt date.  The application would require modification in accordance
with the R01 guidelines.  The new application would not be considered
an application for a cooperative agreement, nor would it be considered
a response to this RFA.

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
(triage) by an NCI peer review group to determine their relative
competitiveness.  The NIH will remove from further competition those
applications that are judged to be noncompetitive and notify the
applicant Principal Investigator and institutional official.  Those
applications judged to be competitive and responsive will be evaluated
for technical merit according to the review criteria stated below by an
appropriate peer review group convened by the Division of Extramural
Activities, NCI.  The second level of review by the National Cancer
Advisory Board considers the special needs of the Institute and the
priorities of the National Cancer Program.

Review Criteria

Reviewers will be asked to review the grant applications by considering
the following criteria:

1.  Scientific merit and feasibility of the proposed research and its
relevance to the goals and objectives of the RFA.

2.  The appropriateness of the proposed techniques and methodologies to
be used.

3.  Qualifications, experience and proposed responsibilities of the
Principal Investigator and other key personnel.

4.  Demonstration of access to appropriate patient populations or
access to frozen and/or fixed tumor tissue samples, with associated
clinical data.

5.  Adequacy of discussion of statistical issues related to study
design and data analysis.

6.  Adequacy of proposed collaboration between basic scientists and

7.  Plans for effective cooperation and coordination among
participating awardees and the NCI.

8.  Availability and quality of facilities and resources for the
proposed research.

9.  Adequacy of provisions for the protection of human subjects.

The review group will critically examine the submitted budget and will
recommend an appropriate budget and period of support for each
favorably recommended application.


The anticipated date of award is September 1, 1994.  Awards will be
based on the peer reviewed priority score and programmatic priorities.


Written and telephone inquiries concerning the objectives and scope of
this RFA are encouraged.  The Program Director welcomes the opportunity
to clarify any issues or questions from potential applicants.

Direct inquiries regarding programmatic issues to:

James W. Jacobson, Ph.D.
Division of Cancer Biology, Diagnosis and Centers
National Cancer Institute
Executive Plaza North, Room 513
6130 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-1591
FAX:  (301) 402-1037

Direct inquires regarding fiscal and administrative matters to:

Robert E. Hawkins, Jr.
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
6120 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7800 Ext. 13


This program is described in the Catalog of Federal Domestic Assistance
No. 93.394, Cancer Detection and Diagnostic Research.  Awards are made
under authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS grants policies and Federal Regulations
42 CFR 52 and 45 CFR Part 74.  This program is no subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.


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