From: kristoff@NET.BIO.NET (Dave Kristofferson)
Newsgroups: bionet.sci-resources
Subject: NIH Guide, vol. 21, no. 41, pt. 4, 13 November 1992
Date: 12 Nov 92 18:15:01 GMT
Distribution: bionet


$$XID RFA CA9303 CA-93-03 P1O1 *****************************************

THERAPEUTIC STUDIES OF PRIMARY CENTRAL NERVOUS SYSTEM MALIGNANCIES IN
ADULTS

NIH GUIDE, Volume 21, Number 41, November 13, 1992

RFA:  CA-93-03

P.T. 34; K.W. 0715035, 0705055, 0740015, 0740020

National Cancer Institute

Letter of Intent Receipt Date:  January 15, 1993
Application Receipt Date:  March 10, 1993

PURPOSE

The Cancer Therapy Evaluation Program (CTEP) and the Radiation Research
Program (RRP) of the Division of Cancer Treatment (DCT) at the National
Cancer Institute (NCI) invite applications for cooperative agreements
(U01) from consortia of institutions to perform Phase I and II clinical
evaluations of promising new chemotherapeutic or biologic agents for
the treatment of primary central nervous system (CNS) malignancies and
to perform ancillary laboratory studies of aspects of CNS tumor biology
with potential clinical implications.  Integrated packages of
individual applications are encouraged, with the lead institution of a
proposed consortium indicating which participating institutions will
provide organizational support, scientific leadership, laboratory
capabilities, and/or patient resources.  Each consortium of
institutions will be referred to as a CNS Consortium (CNSC) for the
purpose of this RFA.

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,
Therapeutic Studies of Primary Central Nervous System Malignancies in
Adults, 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

Applications may be submitted by North American non-profit and
for-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, DCT clinical trials cooperative groups, and eligible
agencies of the Federal government.  Applications from minority
individuals and women are encouraged.

It is essential that applications be submitted as an integrated package
from a team or consortium (CNSC) of medical institutions (a minimum of
three) that agree to work together with a single Project Leader and a
single administration, and submit applications that will be reviewed in
relation to the consortium. Together, the institutions in the
consortium would encompass experience in investigational drug clinical
trials, access to sufficient numbers of primary CNS tumor patients to
enter a minimum of 60-80 fully evaluable cases per year onto Phase I
and II protocols, expertise in laboratory investigation of the biology
of human gliomas, and access to a Central Operations Office for
coordination of research activities and data analysis.  Except under
unusual circumstances, the Central Operations Office/Coordinating
Center would be expected to reside at the Project Leader's institution.
Detailed requirements are listed below in Terms of Cooperation,
Responsibilities of Awardees.

The members of each proposed consortium should together fulfill the
criteria listed below.

A.  Requirements for the Consortium (CNSC) as a whole:

1.  A commitment to participate in multi-institutional protocols and
documentation of facilities and professional personnel available,
committed, and expert in conducting brain tumor clinical trials.  This
includes assignment of appropriate specialist collaborators including,
but not limited to, medical oncologists, radiation therapists,
neurologists, neurosurgeons, neuroradiologists, and neuropathologists.

2.  A Central Operations Office/Coordinating Center for biostatistical
support, collection, analysis, reporting, and quality control of data
from Phase I and II trials and related laboratory investigations.
Detailed requirements will be found in RESEARCH OBJECTIVES,
DEFINITIONS.

3.  The applicant CNSC and each of its participating clinical
institutions must have adequate central data collection and processing
capabilities and the capability to meet FDA and HHS requirements for
the conduct of research using investigational agents.

4.  Each CNSC, a minimum of three institutions, must have the
demonstrated capability of accruing a minimum of 60 fully evaluable,
histologically confirmed high-grade glioma patients per year who would
be appropriate candidates for Phase I or Phase II clinical trials, and
who have acceptable performance status and organ function to enter such
trials.  In the case of a consortium (CNSC) with more than three
clinical member institutions, a minimum of 20 such evaluable patients
per institution per year will be required.

5.  The CNSC (consortium) must demonstrate an active laboratory program
at one or more of its participant institutions that utilizes human
glioma specimens or cell lines and would be able to take advantage of
additional clinical specimens (and accompanying clinical data) to
perform correlative studies bearing on the clinical behavior of CNS
tumors and/or their response to therapeutic interventions.  Experience
with gliomas and/or other human CNS tumors must be documented by a
record of publications or peer-reviewed grant support.

6.  The CNSC must demonstrate laboratory capabilities among one or more
of its participant institutions sufficient to perform at least two
comprehensive pharmacokinetic studies per year of selected Phase I or
Phase II drugs being evaluated by the consortium.  Experience with
pharmacokinetic data analysis and correlation of these data with
clinical drug response must be documented, as must familiarity with the
latest technology for the detection and quantitation of drugs and their
metabolites in physiological fluids and tissues. (see RESEARCH
OBJECTIVES, RESEARCH GOALS AND SCOPE below)

B.  Each participant institution in the CNSC must have a mechanism to
collect and ship patient specimens to other members of the CNSC and
other consortia under the guidelines established for the individual
studies.  Institutions involved in laboratory studies must have the
capability to receive and conduct research studies on patient specimens
not only from within their own centers, but also from other members of
the CNSC and other consortia funded by this U01.  There must also be a
mechanism in place for the collection and transfer of patient and
laboratory data to the Central Operations Office/Coordinating Center
for analysis.

C.  Each institution participating in the clinical trials of the
consortium must meet the following requirements:

1.  Experienced full-time physician investigators associated with the
project who have demonstrated expertise in Phase I/II studies.

2.  A multi-disciplinary neuro-oncology team with clinician members
representing expertise in the disciplines of medical and radiation
oncology, neurology/neurosurgery, neuropathology and neuroradiology.

3.  Adequate physician, nursing and data management resources to comply
with all data reporting requirements of NCI-sponsored Phase I and II
trials.

4.  Patient populations to support adequate patient accrual (criteria
determined by the consortium) with annual monitoring to assure
continued enrollment of patients on Phase I and II trials.

5.  Availability of state-of-the-art instrumentation for neurologic
magnetic resonance imaging and for radiation therapy.

6.  Appropriate drug control procedures as required for utilization of
NCI-supplied experimental agents.

7.  Capability of meeting FDA requirements in A3 above.

MECHANISM OF SUPPORT

Awards will be made as cooperative agreements, which create an
assistance relationship with substantial NCI programmatic involvement
with the recipients during the performance of the project, as outlined
in this RFA.  The cooperative agreement mechanism is used when the NCI
wishes to stimulate investigator interest and proposes to advise or
assist in an important and opportune area of research.

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 Terms of Cooperation, Nature of Participation by NCI
Staff.  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 Public Health Service Grants Policy Statement, DHHS Publication No.
(OASH) 90-50,000, revised October 1, 1990.

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, Part A.

FUNDS AVAILABLE

Approximately $1,500,000 in total costs per year for four years will be
committed to specifically fund applications submitted in response to
this RFA.  It is anticipated that six to nine individual awards will be
made to the members of one to three consortia.  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.  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 continuing availability of funds for this purpose.

RESEARCH OBJECTIVES

A.  Background

Primary malignant brain tumors are responsible for approximately 12,000
deaths annually in the US.  Astrocytomas of various histologic grades
make up 65-70 percent of all primary, central nervous system (CNS)
tumors.  Other malignant histologies such as medulloblastomas,
ependymomas, oligodendrogliomas, and CNS lymphomas make up an
additional 15-20 percent of all cases.  Standard treatment with
surgery, radiation therapy, and chemotherapy has been shown to improve
short term survival by two- to threefold, but in spite of aggressive,
multimodality therapy and despite the fact that the majority of these
cancers rarely metastasize, high-grade gliomas are nearly 100 percent
lethal, and average survival usually ranges between 9-18 months.

Surgery, radiation therapy, chemotherapy, and immunotherapy are limited
in their effectiveness by the susceptibility of adjacent, normal brain
to the adverse effects of treatment and by extensively infiltrating
and/or resistant nests of malignant cells, and perhaps by other
phenomena such as relative incapacity of the immune effector system and
the brain's poor capacity for repair.  In addition, clinical trials
have been hampered by the fact that tumor status, the adverse sequelae
of therapy, and the effects of ancillary treatments (such as steroids)
are very difficult to segregate when assessed either by clinical
examination or conventional diagnostic imaging.

Clinical investigations of new means to treat such tumors are needed.
Collaborative interactions between clinicians and laboratory scientists
and between clinicians and diagnostic imagers are essential features of
these investigations.  The special skills of experienced tumor
neurosurgeons, neuro-oncologists, radiation therapists, and
neuroradiologists with access to the latest generation of imaging
equipment will be required.  NCI is therefore seeking multidisciplinary
and multiinstitutional teams of talented scientists from non-profit and
for-profit research organizations who will interact with the Cancer
Therapy Evaluation Program (CTEP) and Radiation Research Program (RRP)
in a concerted way to conceive, create, and evaluate new approaches to
therapy of CNS malignancies. Scientific approaches should be broad and
reflect the creativity and capabilities of team participants, including
surgical, medical, radiotherapeutic, diagnostic imaging, laboratory and
statistical skills.

New clinical research opportunities exist with the development of novel
cytotoxic drugs, radiation sensitizers, differentiating agents, immune
modulators, monoclonal antibodies, and new approaches to gene therapy.
Among the agents and techniques currently under development that
appropriately might be studied by such a consortium are:  temozolomide,
the topoisomerase-1 inhibitors, taxol and its analogues, inhibitors of
cytokines such as suramin or the TNF-` inhibitor pentoxifylline,
differentiation-inducers, newer polyamine analogs, inhibitors of
O6-methylguanine-DNA methyltransferase or mdr-1/P-glycoprotein or other
drug resistance inhibitors, antisense oligonucleotides, monoclonal
antibodies to appropriate cellular targets such as gangliosides, the
novel bioreductive agent SR-4233, which is cytotoxic to hypoxic cells
preferentially, and others, alone and in potential combination with
sophisticated regional approaches such as brachytherapy, radiosurgery,
or other modalities.  Team objectives and approaches will be
investigator-originated but consistent with program aims of improving
the survival and quality of life for persons with primary CNS
malignancies and providing fundamental insights into the biology of
these tumors.

B.  Definitions

COOPERATIVE AGREEMENT - An assistance mechanism in which substantial
NCI programmatic  involvement with the recipient is anticipated during
performance of the planned activity.

CENTRAL NERVOUS SYSTEM CONSORTIUM (CNSC) - The consortium of
institutions (minimum of three members) who are submitting research
grant applications together to conduct Phase I/II clinical trials and
ancillary laboratory studies.  Each CNSC also contains an application
for a Central Operations Office/Coordinating Center.  Each consortium
will consist of talented and experienced individuals in multiple
disciplines (e.g. medical oncology, neurosurgery, neurology,
radiotherapy, radiobiology, pharmacology, molecular biology, pathology,
biostatistics).

CENTRAL OPERATIONS OFFICE/COORDINATING CENTER - An administrative unit
that coordinates all CNSC activities.  Responsibilities include
administrative management, coordination of protocol development and
submission, study conduct, quality control and protocol performance
monitoring, statistical analyses, adherence to requirements regarding
NCI drug accountability and FDA, OPRR and HHS regulations, and protocol
and institutional performance reporting.  Statistical responsibilities
include experimental design, participation in study planning and
coordination, collection and analysis of patient and laboratory data,
data management and analysis, data monitoring, and reporting of data.
The Central Operations Office/Coordinating Center may consist of a
consortium with the statistics center located at another institution.

PROJECT LEADER -  The person who submits the application for the
Central Operations Office/Coordinating Center and who is responsible
for the CNSC as a whole.  The consortium of participant institutions
must agree to work together with the Project Leader.  The Project
Leader is responsible for coordinating the CNSC activities
scientifically and administratively.  The Project Leader may be the
principal investigator on a participant institution application.

PARTICIPANT INSTITUTION - The individual research grant application
from an institution who is participating in the CNSC.  The participant
institution may conduct clinical trials and/or laboratory studies.

PRINCIPAL INVESTIGATOR - The person who submits the single application
for the participant institution and who is responsible for performance
of the key personnel of that application.  The Principal Investigator
provides the scientific leadership for the participant institution.

PROGRAM DIRECTOR - The staff member from the Cancer Therapy Evaluations
Program, Division of Cancer Treatment (cited in the INQUIRIES SECTION)
who coordinates NCI interactions, interacts scientifically with the
CNSC, and provides guidance for the overall program within the NCI.

C.  RESEARCH GOALS AND SCOPE

The primary goal of this initiative is to stimulate clinical research
in the treatment of primary CNS malignancies in adult patients by
providing support for consortia of institutions to perform Phase I and
II clinical evaluations of promising new chemotherapeutic or biologic
agents.  A secondary goal is to utilize the consortia as a mechanism
for sharing human brain tumor specimens among investigators conducting
laboratory studies relevant to the biology, clinical behavior, or
therapy of CNS tumors, particularly malignant gliomas.

Clinical trials will take advantage of new developments in drug and
radiation resistance, radiation sensitization, biological response
modification, immune modulation, induction of apoptosis,
differentiation induction, therapeutic irradiation techniques,
induction or suppression of specific gene function, or other innovative
approaches.  Each CNSC will be formed for the purpose of:  (1) sharing
expertise of researchers in multiple disciplines; (2) conducting joint
phase I and II clinical trials to provide adequate patient populations
and timely completion; and (3) sharing of tumor specimens and data
useful in the conduct of clinical pharmacologic and correlative
laboratory studies.  Participant institutions in the proposed
consortium may be involved in clinical trials and/or laboratory
studies.

It is anticipated that one to three consortia will be established,
comprising three to nine institutions.  Each CNSC will select the
specific agents to be tested in accord with their scientific interest
and expertise and will develop a series of appropriate Phase II or
Phase I trials with supporting protocol documents.  Each applicant CNSC
should submit as examples one or more draft clinical protocols as
supplements to the Central Operations Office/Coordinating Center
(Project Leader) and the participant institution applications.  The
CNSC, along with the assistance of the NCI Program Director, will
develop a plan for prioritization of investigational trials.  The NCI
may provide NCI-sponsored IND agents or provide assistance to the
awardee(s) by sponsoring or cross-referencing INDs for selected agents.
Each CNSC must have documented numbers of patients with CNS tumors and
a history of accrual of patients to clinical trials adequate for
two-six phase I or II trials (60- 180 patients) per year.  It is
expected that all of the CNSC institutions together will be able to
complete approximately six phase I or phase II trials (180 patients)
per year.  In addition, proposed consortia must have: (1) adequate
radiotherapy support for clinical trials utilizing radiation in
combination with other modalities; (2) adequate central data collection
and processing capabilities as well as biostatistical expertise; (3)
adequate pathology support for both institutional tumor classification
and central neuropathology review and for banking and distribution of
tumor tissues for concurrent and future laboratory studies; (4)
mechanisms to collect and store patient specimens for laboratory
studies being conducted by institutions in the CNSC; (5) expertise in
antineoplastic drug pharmacology/pharmacokinetics.

The correlative laboratory research program in a CNSC should address at
least one field of research into the biology of human malignant gliomas
with some potential for future clinical relevance.  Examples of
research fields for laboratory studies include:  molecular genetics and
cytogenetics, gene function and expression, signal transduction
pathways, radiobiology, growth regulation, metabolism, differentiation
and gene modulation by investigational agents, intracellular
metabolism, mechanisms of drug resistance in tumor cells, CNS
pharmacokinetics, invasion and spread, cytokine production or
interactions, immune function and antigen expression, or other aspects
that may have clinical implications or lead to new therapeutic
approaches.  Investigators are not limited to the above areas of
laboratory experimentation.

Correlative laboratory studies need not be directly related to
individual clinical Phase I/II trials but should attempt to utilize the
large clinical database that will be generated by the consortium to
identify potential correlates of tumor behavior, and laboratory studies
should be based on strong and testable hypotheses.  A clear rationale
should be given for the experimental design and technological
methodologies selected.  Preliminary data from appropriate tumor models
or analysis of patient specimens should be provided to support the
feasibility of each study.  The laboratory assays must utilize tumor
specimens from patients and there should be an established plan for
prioritization of specimen distribution to collaborating laboratories.

Participating institutions primarily involved in laboratory studies may
accrue patients on CNSC clinical trials if the minimum clinical
resources are in place (See Eligibility Requirements).

The cooperative approach outlined in this RFA allows for interactions
among successful applicants, with the assistance of NCI extramural
staff, to perform Phase I and Phase II trials of anticancer agents and
ancillary laboratory studies.  This mechanism retains the
decision-making prerogatives of the Principal Investigator and his/her
colleagues, but at the same time, permits the active participation of
NCI in research activities.  (See Terms of Cooperation)

SPECIAL REQUIREMENTS

A.  Terms of Cooperation

The cooperative agreements will require cooperation between an NCI
Program Director and the Project Leader(s) of the CNSC(s). The NCI
Program Director will assist in coordinating the activities of the CNSC
as defined below and in facilitating exchange of information.

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 other HHS, PHS and
NIH grant administration policy statements.

Nature of Participation by NCI Staff

The role of the CTEP and RRP staff as described throughout these terms
of cooperation is to assist and facilitate but not to direct research
activities.  This cooperative agreement is part of a larger program of
investigational agent development in the NCI.  Each of the CTEP staff
listed below has very specific and well defined responsibilities in
terms of investigational agent development and the role of DCT as a
drug sponsor as defined in 21 CFR Part 312.

1.  CTEP and RRP as a Scientific Resource for NCI-supported Phase I and
II Clinical Trials Investigations

The NCI Program Director (cited in the INQUIRIES SECTION) will serve as
a resource available to the CNSC for scientific information with
respect to treatment regimens and clinical trial design.  The Cancer
Expert, RRP, will serve as a resource for specific scientific
information with respect to radiation therapy and diagnostic imaging of
CNS tumors.  The NCI Program Director will assist the CNSC as
appropriate in developing information concerning the scientific basis
for specific trials and also will be responsible for advising the CNSC
of the nature and results of relevant trials being carried out
nationally or internationally. The NCI Program Director will sponsor an
initial strategy meeting with the awardees to review the research plans
proposed to ensure that they are compatible with the overall goals of
the RFA, to ensure avoidance of duplication of effort, and to ensure
the most effective use of available resources, including
investigational agents. The NCI Program Director will also sponsor
strategy meetings semi-annually or as needed, to be attended by
investigators in the CNSC and other investigators as appropriate.

At these meetings relevant information will be reviewed, national
research goals discussed, and the outstanding research questions
established and prioritized by the CNSC investigators.  The Program
Director will also provide updated information on the efficacy and
toxicity of investigational new agents supplied to the CNSC under an
Investigational New Drug (IND) Application sponsored by the DCT.

2.  CTEP Assistance in Protocol Development

The protocol must be a detailed written plan of a clinical experiment
mutually acceptable to the proposing CNSC and to the CTEP Protocol
Review Committee (PRC).  Communication at the various stages of
protocol development is encouraged as necessary to promote protocol
development and implementation.  All protocols should be preceded by a
written Letter of Intent (LOI) from the CNSC declaring interest in
conducting a particular study.  The LOI should be sent to the CTEP LOI
Coordinator who receives, logs in and schedules LOIs for review by the
PRC (see Section -  Responsibilities of Awardees).   The PRC will
formally review the LOI.  Following review, the NCI Program Director
will provide a Program response to the CNSC and will address the
following issues:  (a) the existence and nature of concurrent clinical
trials in the area of research, pointing out possible duplication of
effort; (b) information including relevant pharmacokinetic and
pharmacodynamic data concerning investigational agents; (c)
availability of investigational agents, including biologic response
modifiers; (d) the scientific rationale and value of the proposed
study, the design, the statistical requirements; and (e) the
implementation of the study, if indicated.  The LOI mechanism is
designed for preliminary review and is recommended to expedite protocol
development and implementation and to facilitate agreement on study
priority and design (see the DCT Investigator's Handbook, pp 32-35,
available on request from Dr. Richard Kaplan at the address below, for
further discussion of these mechanisms).

3.  CTEP Review of Proposed Protocols

CNSC protocols will be reviewed by the PRC which meets weekly. It is
chaired by the Associate Director, CTEP.  Ad hoc reviewers, external to
NCI, will be utilized when deemed appropriate by the PRC chairperson.
Following the review of the protocol by the PRC, the NCI Program
Director will provide the CNSC with a consensus review that describes
recommended modifications and other suggestions, as appropriate (see
the DCT Investigator's Handbook, for further information regarding
protocol review at CTEP).

The major considerations relevant to Protocol Review by CTEP include:
(a) the strength of the scientific rationale supporting the study; (b)
the medical importance of the question being posed; (c) the avoidance
of unnecessary duplication with other ongoing studies; (d) the
appropriateness of study design; (e) consistency with development plans
for particular IND agents; (f) a satisfactory projected accrual rate
and follow-up period; (g) patient safety; (h) compliance with federal
regulatory requirements; (i) adequacy of data management; (j)
appropriateness of patient selection, evaluation, assessment of
toxicity, response to therapy and follow-up; and (k) method of
monitoring to be used.

If a proposed protocol is disapproved, the specific reasons for lack of
approval will be communicated in writing by the NCI Program Director to
the CNSC as a consensus review within 30 days of protocol receipt by
the NCI.  NCI will not provide investigational drugs or permit
expenditure of NCI funds for a protocol that it has not approved.  The
NCI Program Director will be available to assist the CNSC in developing
a mutually acceptable protocol, consistent with the research interests,
abilities and strategic plans of the CNSC and of the NCI.

Disagreements arising pursuant to protocol approval will be submitted
to an arbitration panel to determine the suitability of a protocol that
has been disapproved.  An arbitration panel composed of one CNSC
nominee, one NCI nominee, and a third member with oncologic clinical
trials expertise chosen by the other two nominees will be formed to
review the CTEP decision and recommend an appropriate course of action
to the Director, DCT.  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 CNSC will not expend NCI funds to conduct any study disapproved by
CTEP unless CTEP's disapproval has been modified by the arbitration
process outlined above.

4.  CTEP Review of Quality Control and Study Monitoring

The Head, Quality Assurance and Compliance Section (QACS), Regulatory
Affairs Branch (RAB), CTEP will review and provide advice, through the
NCI Program Director, regarding mechanisms established by the CNSC for
quality control of therapeutic and diagnostic modalities employed in
its trials.  (See RESPONSIBILITIES OF AWARDEES).  The Head, QACS will
review the CNSC procedures and policies for study monitoring including
the awardees' on-site monitoring program (See 8. CTEP Review of
Federally Mandated Regulatory Requirements).

5.  CTEP Review of Data Management and Analysis

The Chief, Biometrics Research Branch (BRB), CTEP will review CNSC
mechanisms for data management and analysis.   (See RESPONSIBILITIES OF
AWARDEES).  When deemed appropriate, The Chief, BRB will make
recommendations to the CNSC, through the NCI Program Director, to
ensure that data collection and management procedures 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) sufficiently uniform
across the CNSC participants.

6.  CTEP Involvement in Protocol Closure

The NCI Program Director will monitor protocol progress.  When a study
involves a DCT IND agent, the Head , QACS and the Investigational Drug
Branch (IDB) Physician (Drug Monitor) who is assigned to each DCT IND
agent to coordinate its development will also monitor progress.  The
NCI Program Director may request that a protocol study be closed to
accrual for reasons including:  (a) insufficient accrual rate; (b)
accrual goal met; (c) poor protocol performance; (d) patient safety and
regulatory concerns; (e) study results are already conclusive; and (f)
emergence of new information that diminishes the scientific importance
of the study question.  NCI will not provide investigational agents or
permit expenditures of NCI funds for a study after requesting closure
(except for patients already on-study).  For any study, whether
involving an investigational drug or not, NCI will establish an
arbitration process for investigators who wish to appeal protocol
closure.  This process will be identical to that described above for
protocol disapproval.

7.  CTEP involvement in Investigational New Drug Applications

a.  The NCI will have the option to cross file or independently file an
IND on investigational drugs evaluated in the Phase I and II Clinical
Trials.  This would apply to drugs not developed in the NCI drug
development program.

b.  The NCI Program Director assisted by the Chief, RAB, CTEP will
advise investigators of specific requirements and changes in
requirements concerning IND sponsorship that the FDA may mandate.
Investigators performing trials under cooperative agreements will be
expected, in cooperation with the NCI, to comply with all FDA
monitoring and reporting requirements for investigational agents.

c.  Investigators performing NCI funded Phase I and II Clinical Trials
will be advised by the NCI Program Director of potential studies that
will be relevant to new avenues of cancer therapy. When this involves
investigational agents, the NCI Program Director assisted by the Chief,
RAB, CTEP will advise the investigators of the specific clinical
information that will be needed from the clinical trials for that
information to be acceptable to the FDA for inclusion in a new drug
application (NDA).

8.  CTEP Review of Federally Mandated Regulatory Requirements

The Head, QACS, through the NCI Program Director, will advise the CNSC
regarding mechanisms to meet FDA regulatory requirements for studies
involving DCT-sponsored investigational agents and the Office for
Protection from Research Risks (OPRR) requirements for the protection
of human subjects by the CNSC institutions.  (See RESPONSIBILITIES OF
AWARDEES, below)

For specific Phase I and II trials with NCI-sponsored investigational
agents, the NCI has contracted for a Clinical Trials Monitoring Service
(CTMS) to document regulatory compliance, to maintain a computerized
data base and to produce periodic routine reports of the results, and
special reports as necessary.  For Phase I studies, CTEP determines
that the CTMS monitoring described above is necessary using the
following guidelines:  (a) Introduction of drug into humans for the
first time; (b) Early Phase I studies using a single agent; (c) Concern
for safety of patients; (d) PRC expresses concern with excessive
toxicity.  Phase II studies may also be monitored as noted above if PRC
expresses concern with excessive toxicity.  For these trials, awardees
may be visited by the CTMS contractor three times a year.  Phase II
studies may also be monitored if PRC expresses concern with excessive
toxicity.  For these Phase I and II trials, awardees may be visited by
the CTMS contractor three times a year.  The required biweekly data
submissions to the CTMS are described under RESPONSIBILITIES OF
AWARDEES Section 9.d.

For Phase II trials with DCT IND agents not requiring the above
described monitoring, NCI will delegate to the awardee the task of
providing an independent audit of each research study.  The NCI's
Clinical Trials Monitoring Service (CTMS) contractor shall be used to
conduct these audits.  The staff of QACS will perform random audits of
the awardee to assure that the awardee is performing the delegated
audit duties.  Audit schedules and final audit reports will be provided
to QACS, CTEP.  Institutional responsibilities for monitoring are
described below under RESPONSIBILITIES OF AWARDEES Section 9.c.

9.  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 NCI's Drug Master File
Agreement with the FDA relative to the responsibility of the NCI as an
IND agent sponsor.  The awardee will retain custody and primary rights
to the data consistent with current HHS, PHS and NIH policies.

10.  CTEP Review of Progress

Performance of each CNSC will be reviewed at least annually by the NCI
Program Director on the basis of the information provided at the CTEP
sponsored Meetings, in the annual progress reports and in the data
summary reports submitted to the IDB Drug Monitor or by CTMS reports.
In addition, periodic accrual information may be requested from the
CNSC by the NCI Program Director for all active studies when deemed
appropriate.

Insufficient patient accrual or progress, or noncompliance with the
terms of award, including these Terms of Cooperation, may result in a
reduction of budget, withholding of support, suspension or termination
of the award.

RESPONSIBILITIES OF AWARDEES

It is the responsibility of the CNSC to develop the details of the
clinical and laboratory research design, including definition of
objectives and approaches, planning, implementation, analysis, and
publication of results, interpretations and conclusions of studies.
The CNSC shall, with CTEP assistance, develop Phase I and II protocols
for clinical cancer research in accord with the research interests of
the CNSC, abilities and goals, and submit them to CTEP (either to the
LOI Coordinator or to the CTEP Protocol and Information Office, the
receiving office for all protocols sent to CTEP) for review as
appropriate prior to their implementation.

1.  Protocol Development

It is anticipated that decisions in all CNSC activities will be reached
by consensus of the collaborating member institutions under the
leadership of the CNSC Project Leader.  The Project Leader shall
designate a Protocol Chairperson for each proposed study.  The Project
Leader along with coordinating Central Operations Office/Coordinating
Center staff will be responsible for communication with the appropriate
CTEP staff.

2.  The CNSC Central Operations Office/Coordinating Center

The CNSC Central Operations Office/Coordinating Center, under the
leadership of the Project Leader and with CTEP assistance, is
responsible for coordinating protocol development, protocol submission,
study conduct, quality control and study monitoring, drug ordering,
data management, statistical analysis, protocol amendments/status
changes, adherence to requirements regarding investigational drug
management and federally mandated regulations and protocol and
performance reporting.  All the scientific and administrative decisions
related to the CNSC funded activities and made by the CNSC institutions
or affiliates will be coordinated by the Project Leader with the
assistance of the CNSC Central Operations Office/Coordinating Center.

3.  Protocol Submission

The CNSC Central Operations Office/Coordinating Center, under the
leadership of the Project Leader, will submit CNSC protocols to the
CTEP Protocol and Information Office in a timely fashion for review and
approval by NCI.  All protocols should be preceded by a written Letter
of Intent (LOI) from the CNSC to the CTEP LOI Coordinator declaring
interest in conducting a particular study. The LOI shall describe the
hypothesis to be investigated, the general design of the contemplated
trial plus relevant information on accrual capabilities to document
feasibility. Protocols will be developed and submitted and studies will
be conducted in accordance with the "DCT GUIDELINES FOR MULTICENTER
INVESTIGATIONAL AGENT STUDIES" (available upon request from Dr. Richard
Kaplan at the address below).  The Project Leader, with the assistance
of the Central Operations Office/Coordinating Center staff, will
communicate the results of the NCI review of protocols to the CNSC
participating institutions.

4.  Prioritization of Studies

The CNSC Project Leader and the Principal Investigators of the
participant institutions will develop, together with the NCI Program
Director, mutually acceptable plans for prioritization of clinical
protocols, laboratory studies, and distribution of clinical specimens
and tissues.

5.  Quality Control

The CNSC will establish mechanisms for quality control of therapeutic
and diagnostic modalities employed in its trials. Quality control at a
minimum must consist of:

a) Pathology:  Verification of pathologic diagnosis in cases where
known variability in the accuracy of histologic diagnosis is a
potentially serious problem and where pathology data may provide
important prognostic information.

b) Radiation Therapy:  Review (either concurrent or retrospective) of
port films and compliance with protocol-specified doses for individual
patients, where relevant.

Determination of adequacy of radiation delivery with the assistance of
the Radiological Physics Center (RPC), whose functions usually include
equipment dosimetry, periodic institutional visits and other aspects of
physics review.

c) Chemotherapy:  Review of flow sheets with determination of protocol
compliance in dose administration and dosage modification.

d) Neurosurgery:  Assessment of adequacy of protocol-specified surgical
procedures (where relevant) through review of operative notes and
study-specific surgical forms.

e) Diagnostic Imaging:  Central review of claimed responses and
adequacy of imaging.

6.  Study Monitoring

The CNSC will establish mechanisms for study monitoring.  The CNSC is
responsible for assuring accurate and timely knowledge of the progress
of each study through:

a) establishing procedures for assigning dose level at the time a new
patient is entered, and assuring that the required observation period
has elapsed before beginning a higher dose level;

b) tracking and reporting of patient accrual and adherence to defined
accrual goals;

c) ongoing assessment of case eligibility and evaluability;

d) timely medical review and assessment of patient data;

e) rapid reporting of treatment-related morbidity (adverse drug
reactions) and measures to ensure communication of this information to
all parties;

f) interim evaluation and consideration of measures of outcome, as
consistent with patient safety and good clinical trials practice;

g) timely communication of results of studies; and

h) an on-site monitoring program  (see 9c below).

i) establishing data management support capabilities which assure that
data will be submitted via electronic transfer to the NCI's Clinical
Trials Monitoring Service (CTMS) when required.  (See 9d below)

7.  Data Management and Analysis

The CNSC will develop procedures to ensure that data collection and
management are:  (1) adequate for quality control and analysis; (2) as
simple as appropriate in order to encourage maximum participation of
physicians entering patients and to avoid unnecessary expense; and (3)
sufficient across the participating institutions.

8.  Investigational Drug Management

Investigators performing trials under cooperative agreements must be
NCI registered investigators (form 1572) and will be expected to
implement CTEP requirements described in the DCT Investigators'
Handbook for storage and accounting for investigational agents, to
abide by NCI/HHS Drug Accountability Records (DAR) procedures, and to
comply with all FDA requirements for investigational agents.

9.  CNSC Compliance with Federally Mandated Regulatory Requirements

The CNSC is responsible for establishing procedures for all
participating institutions to comply with FDA regulations for studies
involving investigational agents and OPRR requirements for the
protection of human subjects.  These procedures are:

a) methods for assuring that each institution where investigators are
conducting CNSC trials has a current, approved assurance on file with
the OPRR; that each protocol is reviewed and approved by the
responsible Institutional Review Board (IRB) prior to patient entry;
that each protocol is reviewed at least annually by the IRB so long as
the protocol is active; that each investigator is registered with the
Drug Management and Authorization Section (DMAS), CTEP, with a current
1572 form on file; and that each patient (or legal representative)
gives written informed consent prior to entry on study.

b) a system for assuring timely reporting of all serious and unexpected
toxicities to the IDB, CTEP according to CTEP guidelines (mailed
annually to all registered investigators). This requires reporting
Adverse Drug Reactions (ADRs) by telephone to the IDB Drug Monitor
within 24 hours of the event and requires a written report to follow
within 10 working days.

c) an on-site monitoring program which assures that a sampling of
records at each participating institution is audited at least two times
during the cooperative agreement period.  The on-site audit will
address issues of data verification and compliance with regulatory
requirements for the protection of human subjects and investigational
agent accountability.  Any serious problems with data verification or
compliance with Federal regulations must be reported to the Head, QACS
immediately.  Otherwise, written reports must be submitted within six
weeks of each audit.  All audit schedules are to be provided to the
Head, QACS at least four weeks prior to the date of the audit.

d) For the specific Phase I and Phase II trials that require monitoring
by the CTMS three times a year, information must be provided via
electronic transfer to the CTMS at two week intervals and includes:
notification of each patient entered onto a Phase I or II protocol
within the previous two week period, and all data obtained on each
registered patient within the previous two weeks as specified by the
NCI/DCT Standard Case Report Form and the individual protocol.

e) implementation of the CTEP requirements described in the DCT
Investigators Handbook for storage and accounting for investigational
agents provided under DCT sponsorship.

10.  Progress Review

The CNSC will establish a mechanism for assessing performance of its
members, with particular attention to accrual of adequate number of
eligible patients onto consortium trials, timely submission of required
data, conscientious observance of protocol requirements, authorship and
participation in group leadership. This mechanism will include a
procedure for recommending an adjustment of institutional funds within
the consortium as appropriate for the level of participation in
consortium activities, including (but not limited to) accrual.

11.  Attendance at Meetings

The CNSC Project Leader and appropriate representative(s) of the CNSC
participating institutions, shall meet twice a year with the NCI
Program Director to review CNSC progress, establish priorities, and
plan future activities.  Additional meetings between the NCI Program
Director and the Project Leader will be held if necessary.

12.  Reporting Requirements

Reporting requirements will be in agreement with FDA regulations and
NCI procedures.  Annual progress reports will be submitted to the NCI
and will include at a minimum summary data on protocol performance by
the awardee and each participating institution. In addition, data
summary reports will be requested prior to the due date of the annual
report to the FDA required of IND sponsors.  The types of reports
required are determined by CTEP at the time of protocol review.  They
are: (a) Quarterly Data Updates (QDA) for late Phase I trials not CTMS
monitored; (2) Annual Data Updates (ADU) for late Phase I/Phase II
combination studies sent to Protocol Chairman to summarize clinical
data and progress; (3) Study summaries sent annually to summarize
clinical data for Phase II studies.  A system for providing such
information in a timely manner must be in place.

13.  Publication of Data

Timely publication of major findings is encouraged.  Publication or
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 and
primary rights to the data consistent with current HHS, PHS and NIH
policies.

SPECIAL INSTRUCTIONS FOR PREPARATION OF COOPERATIVE AGREEMENT
APPLICATIONS

The grant application form PHS 398 (rev. 9/91) is to be used for the
cooperative agreement application.  The general instructions, e.g., for
format and budget issues, included in the application packet must be
followed.

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 staff involvement.

All costs required for these studies must be included in the
application and must be fully justified.  These costs include the
additional costs of clinical research associated with Phase I and Phase
II studies including costs for patient accrual, sample handling,
laboratory studies, quality assurance, data management and data
analysis, study monitoring, travel, an on-site audit program and the
biweekly electronic data submissions to the NCI's Clinical Trials
Monitoring Service when required.  For Phase II trials with DCT IND
agents for which the awardee is responsible for providing the on-site
monitoring, the awardee shall contract with the NCI's Clinical Trials
Monitoring Service for the performance of audits.  The awardee(s) will
be expected to provide two audits per institution during the
cooperative period and to request funding accordingly.  Funds requested
for the audit program will be restricted for this purpose only.  The
on-site audit requirements are described in the above section entitled
SPECIAL REQUIREMENTS, TERMS OF COOPERATION, RESPONSIBILITIES OF
AWARDEE.

Each CNSC should anticipate the need to attend two meetings per year to
share data and to coordinate activities.  Travel funds for two
representatives from the Central Operations Office/Coordinating Center
and one or two representative(s) from each participant clinical and/or
laboratory member institution should be included in the budget.

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 should 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.  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 in
Section 1-4 of the Research Plan AND summarized in Section 5, Human
Subjects.  Applicants/offerors 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 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 15, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Project
Leader, 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 subsequent applications, the information
is helpful in planning for the review of applications.  It 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. Richard Kaplan
Cancer Therapy Evaluation Program
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 734
6130 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663

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, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD
20892, telephone (301) 496-7441; and from the NCI Program Director
named below.

The Central Operations Office/Coordinating Center as lead institution
should submit a research grant application in which they should list
the anticipated participant institutions, and include proposed clinical
protocols in the Appendix.  (The Central Operations Office/Coordinating
Center application must be a separate document from any application
from a participant institution; if a single institution will be
applying for both participation in clinical and/or laboratory studies
and as the Central Operations Office/Coordinating Center, two
applications will be necessary.)  Each participant institution should
submit an individual research grant application and should indicate the
Central Operations Office/Coordinating Center of the CNSC consortium in
which they intend to participate.   Participant institutions conducting
clinical trials should include copies of the proposed CNSC clinical
protocols in the Appendix.  The grant application should describe the
nature of their participation and justify budget requests for the
protocols.

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
and the YES box must be marked.

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

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

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

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

Applications must be received by March 10, 1993.  If an application is
received after that date, it will be returned.  The Division of
Research Grants (DRG) will not accept any application in response to
this announcement 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
substantial revisions of applications already reviewed, but such
applications must include an introduction addressing the previous
critique.

REVIEW CONSIDERATIONS

A.  REVIEW PROCEDURES

Upon receipt, applications will be reviewed for completeness by DRG and
responsiveness by the NCI.  Incomplete applications will be returned to
the applicant without further consideration.  Applications that are
judged non-responsive will be returned by the NCI.  An application
judged to be non-responsive to this RFA may be submitted as an
investigator initiated regular research grant (R01) or program project
grant (P01) at the next receipt date.  The application would require
modification in accordance with either the R01 or P01 guidelines.  The
new application would not be considered an application for a
Cooperative Agreement, nor would it be considered a response to an RFA.
Questions concerning the relevance of proposed research to the RFA may
be directed to program staff as described in the INQUIRIES section
below.

Applications may be triaged by an NCI peer review group on the basis of
relative competitiveness.  The NCI will withdraw from further
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, using 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 provided by the National Cancer Advisory Board.

B.  REVIEW CRITERIA

1.  Applications for the Central Operations Office/Coordinating Center
will be reviewed on the basis of the following criteria:

o  Scientific, technical, and medical significance and originality of
proposed research as reflected in the protocols, research plans and
strategies that address the clinical and laboratory considerations in
the CNSC as a whole.

o  Qualifications and research experience of the Project Leader,
Principal Investigators, and the key personnel including, but not
limited to, previous experience with design and administration of
multi-institutional clinical trials and correlative laboratory studies.

o  Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the CNSC objectives including:

o  adequacy of plans for the development, implementation and analysis
of multi-institutional clinical trials

o  adequacy of plans for correlative laboratory studies and evaluation
of the data with respect to treatment administration or treatment
outcome

o  adequacy of statistical approach for correlating research studies
with treatment outcomes in clinical trials

o  Adequacy of plans for effective collaboration between laboratory and
clinical investigators and the Central Operations Office/Coordinating
Center within the consortium.  Documentation of commitment of the
Program Leader and each Principal Investigator and of key personnel to
the goals of the CNSC.

o  Adequacy of the available facilities and data management resources
and personnel.  Evidence of the competence of the Central Operations
Office/Coordinating Center with regard to the mechanisms for CNSC
administration, experimental design, quality control, study monitoring,
data management and reporting, statistical analysis, and compliance
with regulatory requirements.

o  Demonstration of access to sufficient numbers of evaluable patients
for Phase I and II clinical trials and followup by the CNSC (see
Eligibility Requirements) and access to adequately processed tissue
samples from a proportion of these patients.

o  Plans for effective interaction and coordination among participant
institutions within the consortium, with other consortia working on CNS
tumors, and with the NCI.

2.  Applications for participant institutions will be reviewed on the
basis of the following criteria:

o  The overall qualifications of applicant institutions to meet the
eligibility requirements for participant institutions (see Eligibility
Requirements)

o  Scientific merit and feasibility of the proposed research.

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

o  Demonstration of availability of and access to sufficient numbers of
evaluable patients for the conduct of phase I and II clinical trials.
Evidence of ability to accrue patients to clinical trials.

o  Clinical and/or basic research experience, training, time
availability, and research competence of the investigators involved.

o  Adequacy of plans for pathology support for tumor classification and
for banking and distribution of patient specimens for concurrent and
future studies.

o  Availability of state-of-the-art imaging equipment, especially MRI.
The availability of MRS, SPECT, PET and other imaging techniques will
be considered favorable additional assets.

o  Adequacy of state-of-the-art radiotherapy equipment.  The
availability of equipment for stereotactic radiosurgery and
brachytherapy is not required, but would also be considered as assets
to the application.

o  Adequacy of the available facilities and data management resources.

o  Adequacy of provisions for the protection of human subjects.

o  Adequacy of the plans for inclusion of females and minorities.

The reviewers will also judge the appropriateness of the proposed
budget and duration in relation to the scientific merit and feasibility
of the proposed research.

AWARD CRITERIA

The anticipated date of award is September 1993.  In addition to the
technical merit of the application, NCI will consider how well the CNSC
and participant institution met the goals and objectives of the program
as described in the RFA.

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 strongly encouraged and should be directed to
program staff listed below.  The program staff welcome the opportunity
to clarify any issues or questions from potential applicants.

Direct inquiries regarding programmatic issues to:

Dr. Richard Kaplan, Senior Investigator
Cancer Therapy Evaluation Program
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 734
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663

Direct inquiries regarding fiscal matters to:

Ms. Katharine Schulze
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 242
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 16
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 Sections 301,
410, and 411, Part A (Public Law 78-410, 42 USC 241 as amended, Public
Law 99-158, 42 USC 285a) and administered under PHS grants policies and
Federal Regulations at 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.