PEDIATRIC BRAIN TUMOR CLINICAL TRIALS CONSORTIUM

Release Date:  February 20, 1998

RFA:  CA-98-007

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

National Cancer Institute

Letter of Intent Receipt Date: May 1, 1998
Application Receipt Date: July 10, 1998

PURPOSE

The Cancer Therapy Evaluation Program (CTEP) of the Division of Cancer Treatment
and Diagnosis (DCTD) at the National Cancer Institute (NCI) invites applications
for cooperative agreements (U01) from institutions to participate in establishing
a multidisciplinary network of highly specialized investigators to efficiently
evaluate technically challenging and innovative treatment approaches for children
with brain tumors.  This Pediatric Brain Tumor Clinical Trials Consortium
(PBTCTC) will conceive, develop, and conduct collaborative Pilot and Phase I and
II clinical evaluations of promising new therapeutic agents or approaches for the
treatment of primary central nervous system (CNS) malignancies in pediatric
patients. The Consortium will consist of up to 8 Participant Member Institutions
selected by peer review for their documented ability to develop and conduct
clinical trials of innovative treatment approaches and for their
multidisciplinary expertise in supporting innovative brain tumor clinical
research.  The consortium is to have a single Operations, Statistics, and Data
Management Center, also selected by peer review.  The PBTCTC will be constituted
from these separate funded awardees. Participant Member Institutions will be
responsible jointly for proposing and conducting clinical evaluations of new
treatment approaches, while the Operations, Statistics, and Data Management
Center will be responsible for providing operational and data management/analysis
support to implement Consortium protocols in a timely manner.  The ultimate
objective of the proposed awards is to stimulate collaborative efforts to
evaluate technically challenging treatment approaches that have promise in terms
of improving outcome for children with brain tumors.

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 Applications (RFA),
Pediatric Brain Tumor Clinical Trials Consortium, is related to the priority area
of cancer.  Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202/512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic non-profit and for-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of the
Federal government.  Applications from minority individuals, women, and persons
with disabilities are encouraged.

Eligible institutions may apply for either of the following types of awards: (1)
Participant Member Institutions; and/or (2) Operations, Statistics, and Data
Management Center.  Participant Member Institution and Operations, Statistics,
and Data Management Center applications must be submitted separately. Participant
Member Institutions must document their multidisciplinary expertise in conducting
innovative brain tumor clinical research and the ability to develop and conduct
clinical trials of innovative treatment approaches (including the application of
sophisticated imaging technologies for response and toxicity analysis). 
Operations, Statistics, and Data Management Center applicants must document their
ability to coordinate multi-institutional clinical trials of children with
cancer.  Detailed requirements are listed below in Terms and Conditions of Award,
Awardee Rights and Responsibilities.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program will be a
cooperative agreement (U01), an "assistance" mechanism, in which substantial NCI
scientific and/or programmatic collaboration with the awardee is anticipated
during performance of the activity.  Under the cooperative agreement, the NCI
purpose is to support and/or stimulate the recipient's activity by working
jointly with the award recipient in a partner role, but is not to assume
direction, prime responsibility, or a dominant role in the activity.  Details of
the responsibilities, relationships, and governance of the study to be funded
under cooperative agreements(s) are discussed later in this document under the
section "Terms and Conditions of Award".

Awards and level of support depend on receipt of a sufficient number of
applications of high scientific merit. Although this program is provided for in
the financial plans of the NCI, awards pursuant to this RFA are contingent upon
the availability of funds for this purpose.  The total project period for each
application submitted in response to the RFA may not exceed five years.  The
earliest anticipated award date is April 01, 1999.  At this time, the NCI has not
determined whether or how this solicitation will be continued beyond the present
RFA.  If there is sufficient continuing program need, NCI may invite the
recipients of awards under this RFA to submit competitive continuation
cooperative agreement applications for review.

FUNDS AVAILABLE

Approximately $2,000,000 in total costs per year for five years will be committed
to specifically fund applications submitted in response to this RFA.  It is
anticipated that awards will be made to up to eight Participant Member
Institution applicants and to a single Operations, Statistics, and Data
Management Center applicant. Approximately $1,000,000 total costs will be
allocated for support of 8 anticipated Participant Member Institutions.  It is
anticipated that one award for the Operations, Statistics, and Data Management
Center will be made for approximately $1,000,000.  In that award, it is expected
that $150,000 will be restricted for a Discretionary Fund for laboratory studies
including pharmacokinetic evaluations and the shipping of patient specimens.  It
is also expected that approximately $400,000 will be restricted for partial
support of research procedures required to meet study objectives (e.g.,
specialized imaging studies), with these funds provided to the Operations,
Statistics, and Data Management Center for distribution to Participant Member
Institutions based on patient accrual.

DEFINITIONS

AWARDEE - The organization to which a cooperative agreement is awarded and which
is responsible and accountable to NCI for the use of funds provided and for
performance of the cooperative agreement-supported project.

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

CTEP PROTOCOL REVIEW COMMITTEE - A committee composed of the professional staff
of the CTEP and additional consultants from other NCI divisions, and chaired by
the Associate Director, CTEP, that reviews and approves every protocol supported
through Cooperative Agreements with CTEP as well as protocols involving DCTD
investigational drugs.

DISCRETIONARY FUND - A fixed portion ($150,000) of the award to the Operations,
Statistics, and Data Management Center that will be allocated according to the
instructions of the Steering Committee.  Appropriate uses may include funding for
laboratory projects (e.g., pharmacokinetic studies, tumor biology studies).  When
appropriate expertise for protocol-required laboratory projects is not available
among PBTCTC Participant Member Institutions, Discretionary Funds may be provided
to non-member investigators to support the required work.

NCI IMAGING RESEARCH COORDINATOR - The Diagnostic Imaging Program, DCTD, NCI
staff member who interacts scientifically with the Applicant/Awardee Institutions
concerning imaging research opportunities.

NCI PROGRAM DIRECTOR - The CTEP extramural Program staff member (cited in the
INQUIRIES SECTION) who will coordinate DCTD interactions and provide guidance for
the overall program within the NCI.  He/she is available for consultation during
preparation of applications, as well as throughout the course of the research
conducted under these cooperative agreements.  He/she also serves in a back-up
role for the NCI Scientific Coordinator.

NCI RADIATION ONCOLOGY RESEARCH COORDINATOR - The Radiation Research Program,
DCTD, NCI staff member who interacts scientifically with the Applicant/Awardee
Institutions concerning radiation oncology research opportunities.

NCI SCIENTIFIC COORDINATOR - The Clinical Investigations Branch, CTEP, DCTD, NCI
staff member who interacts scientifically with the Applicant/Awardee
Institutions.

OPERATIONS, STATISTICS AND DATA MANAGEMENT CENTER -  The administrative unit that
coordinates all the Consortium activities.  Responsibilities include
administrative management, committee management and coordination, protocol
development and submission, study conduct, implementing a quality assurance
program including quality control, statistical analyses, adherence to
requirements regarding NCI drug accountability and FDA, OPRR, and HHS
regulations, and monitoring protocol and institutional performance.  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 Center may
be separate from the sites for the Participant Member Institutions, or may be
located at one of these sites.  Additionally, the Center may have the
statistics/data management center located at an institution different from the
Operations Center, but the award itself will be made to a single institution.

PARTICIPANT MEMBER INSTITUTION - An institution that submits an individual
cooperative agreement application for conducting clinical trials as part of the
PBTCTC. The Participant Member Institution may conduct clinical trials and
participate in correlative laboratory studies.

PATIENT STUDIES RESEARCH FUND - A restricted portion (approximately $400,000) of
the award to the Operations, Statistics, and Data Management Center that will be
allocated according to the instructions of the Steering Committee and are to be
disbursed on a capitation basis.  These funds are to support special clinical
research costs for patients accrued onto Consortium clinical trials and are to
be disbursed on a capitation basis.  It is anticipated that for each Consortium
protocol, the capitation formula for institutional reimbursement required to
offset specific research expenses will be developed by the Steering Committee. 
The capitation formula will be subject to NCI review and approval prior to
implementation.  A primary anticipated use of these funds is to supplement
Participant Member Institutions for costs related to specialized imaging studies
required to meet Consortium protocol study endpoints.  Other specialized clinical
research studies are also appropriate uses for these funds (e.g., institutional
costs related to sample collection and shipping required for pharmacokinetic
studies and for correlative biology studies on tumor tissues, provide supplements
for additional patient accrual and for auditing of clinical trials).

PEDIATRIC BRAIN TUMOR CLINICAL TRIALS CONSORTIUM (PBTCTC) - The consortium of
Participant Member Institutions  and the Operations, Statistics and Data
Management Center that have been awarded separate cooperative agreement (U01s).

PRINCIPAL INVESTIGATOR - The single individual designated by the awardee
institution who is responsible for the scientific and technical direction of the
project.  The Principal Investigator (PI) provides the scientific leadership for
the Participant Member Institution and coordinates the Consortium-required
efforts of other investigators from his/her institution.

PROJECT COORDINATOR -  The person who submits the application for the Operations,
Statistics, and Data Management Center and who is responsible for the operational
activities of the consortium through his/her role as PI of the Operations,
Statistics, and Data Management Center.  The Project Coordinator will be expected
to have substantial pediatric oncology clinical trials experience.

PROTOCOL CHAIRPERSON - The person who is primarily responsible for the
development, coordination and monitoring of a specific clinical protocol.

PROTOCOL COMMITTEE - The committee composed of the requisite multi-disciplinary
expertise that is responsible for development, implementation, and reporting of
the individual clinical trials of the PBTCTC.

STEERING COMMITTEE - The committee that will be the main oversight body of the
PBTCTC.  It will be composed of at least the following:  Participant Member
Institution PIs, representatives from the Operations, Statistics, and Data
Management Center (to include the Project Coordinator and a statistical/data
management representative), a patient/family representative, and a non-voting
representative of each of the brain tumor committees of the pediatric Cooperative
Groups.  NCI advisory members to the Steering Committee will include the NCI
Program Director, the NCI Scientific Coordinator, the NCI Imaging Research
Coordinator, the NCI Radiation Oncology Research Coordinator, and the NCI Adult
CNS Consortium Scientific Coordinator.

STEERING COMMITTEE CHAIRPERSON - A member of the Steering Committee (cannot be
the NCI Program Director or the NCI Coordinator) elected by the Steering
Committee who will coordinate the activities of the Consortium with the
Operations, Statistics, and Data Management Center, and chair the biannual
meetings of the Consortium (after the first meeting, which will be convened by
the NCI) to be held at the NCI.  The chairperson shall prepare and distribute the
agendas for each meeting.

TUMOR AND TISSUE REPOSITORY - A central resource supported by funds from the
Operations, Statistics, and Data Management Center for the storage of tumor
specimens and biological fluids from patients entered onto PBTCTC clinical trials
for future correlative studies. The location(s) of the repository will be
determined by the Steering Committee, and concepts such as "virtual tumor banks"
may be employed by the Consortium (provided that there is central decision making
concerning use of all stored materials).

RESEARCH GOALS AND SCOPE

Background

In the 1980s, pediatric brain tumors surpassed childhood acute lymphoblastic
leukemia as the primary cause of cancer-related deaths among children.  During
the past 20 years therapeutic advances resulting in improved survival for
children with brain tumors have been limited, with 5-year survival rates
increasing only slightly from 54% to 60%.  Furthermore, for some specific
pediatric brain tumor diagnoses (e.g., brain stem gliomas and glioblastoma
multiforme) long-term survival rates remain below 20%, and even for those
diagnoses for which curative therapy exists, long-term sequelae (especially 
neuropsychological) are troubling.

New clinical research opportunities exist for evaluation in children with brain
tumors.  These include novel cytotoxic drugs, drug resistance inhibitors,
radiation enhancers, radiosurgery techniques, antiangiogenic agents, signal
transduction inhibitors, antisense oligonucleotides, differentiating agents,
immune modulators, antibody-based approaches, regional delivery techniques,
oncolytic viruses, and new approaches to gene therapy.  However, timely
evaluations of emerging therapeutic and diagnostic technologies for children with
brain tumors are difficult because no single institution sees enough children
with brain tumors to conduct timely clinical studies of these new therapeutic
concepts (implying the need for multi-institutional collaborations). The NIH-
supported pediatric Clinical Trials Cooperative Groups are well-positioned to
provide definitive evaluations of treatment approaches that use technologies that
have been disseminated to both large and small centers. However, evaluations of
new agents and innovative treatment approaches for children with brain tumors
present challenges that call for exceptional expertise and coordination which are
achievable in only a limited number of institutions.  For example, new radiation
therapy and neurosurgical approaches often require special equipment and skills
that are currently not widely available.  Additionally, sophisticated neuro-
imaging studies are becoming increasingly important in evaluating response to
treatment as well as treatment-associated toxicity (e.g., MR spectroscopy to
evaluate cellular response to therapy, PET imaging for evaluation of drug
distribution and metabolism, PET imaging for evaluation of treatment-associated
changes in tumor metabolism, and specialized methods for noninvasive imaging of
gene therapy and cellular therapies).  An additional complexity for new drug
evaluation in children with brain tumors are the interactions among
investigational anti-cancer agents and anticonvulsants and/or corticosteroids,
since these interactions virtually mandate pharmacokinetic monitoring and dose-
finding within the context of phase II studies. Given the above, clinical trial
designs of innovative treatment strategies for children with brain tumors should
include extensive patient analyses to understand the mechanism of action of
agents under investigation and to evaluate patient responses.

This RFA will address these challenges to progress in childhood brain tumor
clinical research by establishing a consortium of institutions with the requisite
multimodality and research expertise to rapidly conduct the initial clinical
trials of novel treatment approaches for children with brain tumors, prior to
definitive evaluations of these approaches by the pediatric Cooperative Groups.

Objectives and Scope

The purpose of the proposed awards is to establish a Pediatric Brain Tumor
Clinical Trials Consortium for the expeditious evaluation of innovative therapies
in children with brain tumors.  The NCI is seeking multidisciplinary and multi
institutional teams of exceptionally skilled clinical investigators from non-
profit and for-profit research organizations who will interact with CTEP in a
concerted way to conceive, create, and evaluate new approaches to therapy of
pediatric CNS malignancies.  It is anticipated that the pilot studies and phase
I and II clinical trials conducted by the Consortium will require the specialized
abilities of experienced neurosurgeons, neuro-oncologists, radiation oncologists,
and neuro-imagers with access to the latest generation of imaging equipment.  The
novel treatment approaches studied by the Consortium will be selected by the
Steering Committee based on research opportunities identified by Consortium
investigators.  These opportunities may have been developed within institutions
participating in the PBTCTC, within the NCI, by other academic investigators, or
by the pharmaceutical/ biotechnology sector.  Laboratory studies to monitor
patients (e.g., pharmacokinetics, pharmacodynamics) or to measure a particular
biological response that may provide information relevant to the success or
failure of the therapy administered are encouraged.  It is anticipated that these
studies will be included in the protocols to be created by the PBTCTC.  Tissue
specimens or biological fluids should be collected by the Participant Member
Institutions for use in patient monitoring studies or donation to the PBTCTC
Tumor and Tissue Repository for future correlative laboratory studies.

The Pediatric Brain Tumor Clinical Trials Consortium will consist of
approximately 8 Participant Member Institutions and an Operations, Statistics,
and Data Management Center, each funded through separate cooperative agreements
(see Definitions).  The Consortium will be expected to accrue 80-100 patients per
year to 3-4 clinical trials evaluating innovative and technically challenging
therapeutic strategies.  Thus, each applicant to be a Participant Member
Institution must demonstrate the ability to recruit a minimum of 10-12 patients
per year with childhood brain tumors to the innovative treatment studies that
will be sponsored by the Consortium.  In addition, applicants should describe
areas of clinical and laboratory expertise resident at their institution that
could serve as a basis for the development of clinical protocols by the
Consortium.

In the period immediately following the award of funds, NCI will sponsor a
meeting at which the Principal Investigators of each awarded U01 (Participant
Member Institutions and Operations, Statistics, and Data Management Center) and
NCI staff will meet to discuss the operational features of the PBTCTC, including
development of by-laws, organizational structure, and standard operating
procedures (to be based on the proposed procedures and by-laws drafted by the
Operations, Statistics, and Data Management Center).  The ideas for clinical
trials provided in the cooperative agreement applications as well as ideas
generated after the formation of the Consortium will be presented, discussed and
prioritized.  Protocols will then be created, reviewed by the Steering Committee
and submitted to the NCI for review and approval to ensure they are within the
scope of peer review and for safety considerations, as required by Federal
regulations. Such high priority clinical trials will begin after receiving final
NCI approval.

SPECIAL REQUIREMENTS

A.  Terms and Conditions of Award

The administrative and funding instrument used for this program is a cooperative
agreement (U01), an "assistance" mechanism in which substantial NIH scientific
and/or programmatic involvement with the awardee is anticipated during
performance of the activity.  Under the cooperative agreement, the NIH purpose
is to support and/or stimulate the recipient's activity by involvement in and
otherwise working jointly with the award recipient in a partner role, but it is
not to assume direction, prime responsibility, or a dominant role in the
activity.  Consistent with this concept, the dominant role and prime
responsibility for the activity resides with the awardee(s) for the project as
a whole, although specific tasks and activities in carrying out the studies will
be shared among the awardees and the NCI staff.  The role of the NCI staff as
described throughout these terms and conditions of award is to facilitate and
assist 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
NCI staff listed below has very specific and well defined responsibilities in
terms of investigational agent development and the role of DCTD as a drug sponsor
as defined in CFR 21 part 312.

Under the cooperative agreement, a relationship will exist between the recipient
of these awards and the NCI, in which the performers of the activities are
responsible for the requirements and conditions described below, and agree to
accept program assistance from the NCI Program Director and/or the NCI
Coordinator in achieving project objectives.  Failure of an awardee to meet the
performance requirements, including these special terms and conditions of award,
or significant changes in the level of performance, may result in a reduction of
budget, withholding of support, suspension and/or termination of the award.

These Terms and Conditions of Award 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.

B.  Awardee Rights and Responsibilities

It is the responsibility of the PBTCTC 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 PBTCTC shall, with CTEP assistance, develop
Pilot and Phase I and II protocols for clinical cancer research relating to
childhood brain tumors in accord with the research interests, abilities and goals
of the PBTCTC, and submit them to CTEP for review as appropriate prior to their
implementation.  The first responsibility of successful PBTCTC Participant Member
Institution Applicants and the successful Operations, Statistics, and Data
Management Center applicant will be to participate in a meeting convened by NCI
staff to establish by-laws and standard operating procedures for the PBTCTC and
to identify the initial clinical trials to be conducted by the PBTCTC.  Specific
Rights and Responsibilities for the Operations, Statistics, and Data Management
Center and for the Participant Member Institutions are separately described
below.

Operations, Statistics, and Data Management Center Rights and Responsibilities:

The PBTCTC Operations, Statistics, and Data Management Center, under the
leadership of the Project Coordinator and with CTEP assistance, is responsible
for coordinating protocol development, protocol submission, study conduct,
quality assurance including quality control and study monitoring, data
management, statistical analysis, protocol amendments/status changes, adherence
to requirements regarding investigational drug management and federally mandated
regulations and protocol and performance reporting.  The Project Coordinator from
the PBTCTC Operations, Statistics, and Data Management Center will assist the
Steering Committee Chairperson in seeing that the PBTCTC is able to fulfill its
clinical research mission and to meet its administrative and regulatory
obligations. Specific responsibilities of the Operations, Statistics, and Data
Management Center include:

1.  Preparation of an initial proposal for an organizational structure for the
Consortium, including a draft charter/by-laws for the Consortium.  The
organizational structure should include the Scientific Committees that the
Consortium will need to support its research objectives (e.g., Neuro-imaging
Committee, Neuro-oncology Committee, Neuro-pathology Committee, Neurosurgical
Committee, Radiation Oncology Committee).  Following the development or
modification of the proposed organizational structure and Consortium by-laws for
the PBTCTC and its ratification at the initial meeting of the Steering Committee,
the Operations, Statistics, and Data Management Center will be responsible for
maintaining these and for submitting approved amendments/revisions to NCI and to
PBTCTC Participant Member Institutions.

2.  Establishment of procedures for submission of PBTCTC protocols to the CTEP
Protocol and Information Office in a timely fashion for review and approval by
NCI.  Protocols involving NCI sponsored agents should be preceded by a written
Letter of Intent (LOI) from the PBTCTC 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 DCTD
"Investigator's Handbook" (available upon request from the Program Director at
the address below or available at the CTEP Web page at the following URL:
http://ctep.info.nih.gov/handbook/index.html).  The Operations,
Statistics, and Data Management Center staff will communicate the results of the
NCI review of protocols to the PBTCTC Participant Member Institutions and to
relevant PBTCTC Committees.  The PBTCTC will not expend NCI funds to conduct any
study disapproved by CTEP unless CTEP's disapproval has been modified by the
arbitration process outlined below.

3.  Establishment of mechanisms for study monitoring.  The PBTCTC is responsible
for assuring accurate and timely knowledge of the progress of each study through:

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

b) registration, tracking and reporting of patient accrual and adherence to
defined accrual goals; appropriate attempts to accrue patients who fulfill NIH
Guidelines for accrual of women and minorities to clinical trials with
appropriate documentation and reporting of accrual as specified by NIH
Guidelines;

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 for pilot and phase I and
II studies;

4.  Establishment of mechanisms for quality assurance and quality control of
therapeutic and diagnostic modalities employed in PBTCTC 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 submitted data with determination of protocol
compliance in dose administration and dosage modification.

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

e) Diagnostic Imaging:  Central review of claimed responses and adequacy of
imaging.  During the 5-year award period, a program for electronic submission,
storage, and review of imaging studies should be developed and implemented by the
Operations, Statistics, and Data Management Center.

e) On-site Auditing:  Establishment of an on-site monitoring program utilizing
the NCI audit guidelines as a model which assures that a sampling of records at
each Consortium institution participating in the clinical trials is audited at
least once during each 3 year period.  The on-site audit will address issues of
data verification, protocol compliance, 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 NCI Program Director immediately.  Otherwise,
written reports must be submitted within four weeks of each audit to the NCI
Program Director.  Audit schedules are to be provided to the NCI Program Director
annually in the non-competing continuation (Type 5) applications.

5.  Establishment of procedures to ensure that data collection and management
are:  (i) adequate for quality control and analysis; (ii) as simple as
appropriate in order to encourage maximum participation of physicians entering
patients and to avoid unnecessary expense; and (iii) coordinated across the
participating institutions.  Clinical trials data should be submitted
electronically, where feasible.

6.  Establishment of procedures for the effective interaction of the statistical
expertise of the Operations, Statistics, and Data Management Center with Study
Committee investigators such that appropriate Statistical plans for PBTCTC pilot
and phase I and II studies are developed.

7.  Establishment of procedures for assuring that PBTCTC investigators performing
trials involving DCTD Investigational Agents are NCI-registered investigators
(Form 1572) and for assuring that the PBTCTC is in compliance with CTEP
requirements described in the DCTD Investigators' Handbook for storage and
accounting for investigational agents {including NCI/HHS Drug Accountability
Records (DAR) procedures}, and is in compliance with FDA requirements for
investigational agents.

8.  Establishment of procedures to meet the Office for Protection from Research
Risks (OPRR) requirements for the protection of human subjects.  These include
methods for assuring that each institution at which investigators are conducting
Consortium trials has a current, approved assurance on file with the OPRR; that
each protocol is reviewed by the responsible Institutional Review Board (IRB)
prior to patient entry; that each protocol is reviewed annually by the IRB so
long as the protocol is active; and that each patient (or legal representative)
gives written informed consent prior to entry on study.  These should be reviewed
at the time of each audit.

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

10.  Maintaining and managing the Discretionary Fund including dispensing the
funds for Steering Committee and NCI approved laboratory studies accompanying
clinical protocols.

11.  Managing and coordinating the acquisition and shipping of protocol-specified
tumor specimens and biological fluids (with relevant clinical data) to the
appropriate laboratories for testing.

12.  Managing and coordinating the PBTCTC Tumor and Tissue Repository for storing
specimens for future correlative laboratory studies approved by the Steering
Committee.

13.  Maintaining and managing the Patient Studies Research Fund to support
special clinical research costs for patients accrued onto Consortium clinical
trials.  Funds will be disbursed on a capitation basis.  It is anticipated that
for each Consortium protocol, the capitation formula for institutional
reimbursement required to offset specific research expenses will be developed by
the Steering Committee.  The capitation formula will be subject to NCI review and
approval prior to implementation.

14.  Establishment of policies and procedures, in collaboration with the PBTCTC
Steering Committee and NCI program staff, for assessing performance of PBTCTC
member institutions, with particular attention to accrual of adequate number of
eligible patients onto consortium trials, timely submission of required data,
conscientious observance of protocol requirements, study development and
leadership, authorship and participation in group leadership. This mechanism will
include a procedure for recommending to NCI Program staff an adjustment of
institutional funds within the consortium as appropriate for the level of
participation in consortium activities, including (but not limited to) accrual.

15.  Submitting annual progress reports to the NCI that will describe activities
and accomplishments during the previous year of the Consortium in general and of
the Operations, Statistics, and Data Management Center.  The report should
include summary data on protocol performance by each Consortium member as well
as plans and proposed budget for the coming year.

16.  Establishment of procedures for the timely publication of major findings.
Publication or oral presentation of work done under this agreement will require
appropriate acknowledgment 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.

17.  Working with the Steering Committee Chairperson to organize biannual
meetings of the consortium to review PBTCTC progress, establish priorities, and
plan future activities. Relevant responsibilities include: (i) arranging for
appropriate meeting space and accommodations for Consortium attendees;  (ii)
developing and distributing meeting agendas; and (iii) preparing summaries after
each meeting to be sent to Consortium members and NCI program staff. Additional
meetings between NCI staff and the Project Coordinator and Steering Committee
Chairperson (and other PBTCTC members as appropriate) will be held if necessary.

18.  Establishment of procedures for routine electronic communication between the
Operations, Statistics, and Data Management Center and PBTCTC members at
Participant Member Institutions to facilitate protocol development and study
monitoring and to facilitate the work of the various discipline Committees of the
PBTCTC.

19.  Serving as the liaison between the NCI program staff and the Participant
Member Institutions.

Participant Member Institutions Rights and Responsibilities Include:

1.  Participating in the Pediatric Brain Tumor Clinical Trials Consortium, as
evidenced by participating in research design and protocol development,
participating in the scientific Committees of the Consortium, accruing eligible
patients to PBTCTC studies, and by following and implementing the operating
procedures of the Consortium.

2.  Serving as Protocol Chairs.  For each specific clinical protocol, a single
Protocol Chairperson from a Participant Member Institution will be selected to
function as the scientific coordinator for that protocol.  He/she will assume
responsibility for the development of the protocol and for monitoring the
protocol during the actual performance of the clinical trial in accordance with
PBTCTC policies and procedures.

3.  Service on the Scientific Committees for the various disciplines that the
PBTCTC will need to support its research objectives (e.g., Neuro-imaging 
Committee, Neuro-oncology Committee, Neuro-pathology Committee, Neurosurgical
Committee, Radiation Oncology Committee).

4.  Implementing the core data collection method and strategy collectively
developed by the PBTCTC Steering Committee.  It is the responsibility of each
Participant Member Institution to ensure that protocol-specified data are
submitted in a timely manner to the Operations, Statistics, and Data Management
Center.  Clinical trials data will be submitted electronically, where feasible.

5.  Complying with mechanisms for quality assurance and quality control of
therapeutic and diagnostic modalities employed in PBTCTC trials. Institutional
responsibilities for quality control include, but are not limited to, the
following:

a) Pathology: Submission of appropriate materials to allow verification of
pathologic diagnosis, when relevant.

b) Radiation Therapy: Submission of appropriate materials to allow review (either
concurrent or retrospective) of port films and compliance with protocol-
specified doses for individual patients, when relevant.

c) Chemotherapy: Submission of appropriate data to allow determination of
protocol compliance in dose administration and dosage modification.

d) Neurosurgery: Submission of appropriate information to allow review of
protocol-specified neurosurgical procedures.

e) Diagnostic Imaging: Submission of appropriate imaging studies to allow central
review of claimed responses and adequacy of imaging.  During the 5-year award
period, a program for electronic submission, storage, and review of imaging
studies should be developed by the Operations, Statistics, and Data Management
Center and implemented within each Participant Member Institution.

e) On-site Auditing: Participation in the on-site monitoring program established
by the Operations, Statistics, and Data Management Center which assures that a
sampling of records at each Consortium institution participating in the clinical
trials is audited at least once during each 3 year period.

6.  Implementing the procedures established by the Operations, Statistics, and
Data Management Center for assuring that PBTCTC investigators performing trials
involving DCTD Investigational Agents are NCI registered investigators (Form
1572) and for assuring that the PBTCTC is in compliance with CTEP requirements
described in the DCTD Investigators' Handbook for storage and accounting for
investigational agents (including NCI/HHS Drug Accountability Records (DAR)
procedures), and is in compliance with FDA requirements for investigational
agents.

7.  Implementing the procedures established by the Operations, Statistics, and
Data Management Center to meet the Office for Protection from Research Risks
(OPRR) requirements for the protection of human subjects.  These include methods
for assuring that each institution at which investigators are conducting
Consortium trials has a current, approved assurance on file with the OPRR; that
each protocol is reviewed by the responsible Institutional Review Board (IRB)
prior to patient entry; that each protocol is reviewed annually by the IRB so
long as the protocol is active; and that each patient (or legal representative)
gives written informed consent prior to entry on study.

8.  Implementing the procedures established by the Operations, Statistics, and
Data Management Center for assuring timely reporting of all serious and
unexpected toxicities to the Investigational Drug Branch (IDB), CTEP.

9.  Acquisition and submission of protocol-specified tumor specimens, biological
fluids and relevant clinical data to the appropriate laboratories where these
specimens will be tested or stored for future studies.  When additional tumor
specimens or biological fluids are available, research specimens should be
maintained in the PBTCTC Tumor and Tissue Repository for future correlative
studies.

10.  Serving as a resource for the conduct of protocol-specified laboratory
projects (e.g., pharmacokinetic studies, tumor biology studies).  The PBTCTC
Steering Committee will establish a process for the selection of the laboratories
to perform these studies.  These projects may be supported using the
Discretionary Funds of the Operations, Statistics, and Data Management Center or
by independent funding.

11.  Participating in PBTCTC procedures for the timely publication of major
findings. Publication or oral presentation of work done under this agreement will
require appropriate acknowledgment 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.

12.  Appropriately participating in the biannual meetings of the PBTCTC (and in
other meetings as deemed necessary for performance of PBTCTC activities).

13.  Appropriately using Discretionary Funds awarded by the Operations,
Statistics, and Data Management Center to conduct laboratory studies accompanying
PBTCTC clinical protocols.

14.  Submitting an annual progress report to the NCI that describe activities and
accomplishments during the previous year, and that includes plans and proposed
budget for the coming year.

C.  NCI Staff Responsibilities

It is expected that the dominant role and prime responsibility for the activity
will reside with the awardee(s) for the project as a whole, although specific
tasks and activities in carrying out the studies will be shared among the
awardees and the NCI Program Director and NCI Scientific Coordinator.  The NCI
Program Director and Scientific Coordinator will be the main NCI contacts for all
facets of the scientific interaction with the awardees and will provide advice
to the awardee on specific scientific and/or analytic issues in addition to
programmatic issues.

NCI Program Staff Responsibilities will include:

1.  Convening a meeting after awards are made at which the Principal
Investigators of each awarded U01 (Participant Member Institutions and
Operations, Statistics, and Data Management Center) and NCI staff will meet to
discuss the operational features of the PBTCTC.  At this meeting, the Chair of
the Steering Committee will be selected, and a process will be identified for
rapid establishment of PBTCTC by-laws and standard operating procedures (based
on the proposed procedures and by-laws drafted by the Operations, Statistics, and
Data Management Center).  At this meeting, the initial clinical trials for PBTCTC
evaluation will be identified as well.

2.  Interacting with the Participant Member Institutions and Operations,
Statistics, and Data Management Center on a regular basis to monitor Consortium
progress.  Monitoring may include:  regular communications with the PIs and
staff, periodic site visits for discussions with awardee research teams, response
audits to confirm activity reported from a PBTCTC clinical trial, observation of
field data collection and management techniques, fiscal review, and attendance
at PBTCTC meetings.  The NCI retains, as an option, periodic external review of
progress.

3.  Serving as a resource with respect to other ongoing NCI activities that may
be relevant to the PBTCTC research efforts to identify promising new leads, to
facilitate compatibility with other NCI research projects, and to avoid
unnecessary duplication of effort.

4.  CTEP Assistance in Protocol Development:  The protocol must be a detailed
written plan of a clinical experiment mutually acceptable to the PBTCTC 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.  It is recommended that protocols utilizing NCI-
sponsored agents be preceded by a written Letter of Intent (LOI) from the PBTCTC
declaring interest in conducting a particular study. The PRC will formally review
the LOI.  Following review, the NCI Scientific Coordinator will provide a Program
response to the PBTCTC 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; (d) the PRC's assessment of the
scientific rationale and value of the proposed study, its design, and 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 (for further discussion of these mechanisms see the DCTD
Investigator's Handbook, pp 32-35: available on request from the NCI Program
Director at the address below, or available at the CTEP Web page at the following
URL: http://ctep.info.nih.gov/handbook/index.html).

5.  CTEP Review of Proposed Protocols:  All PBTCTC protocols, including protocols
utilizing agents not sponsored by NCI, will be reviewed by the PRC, which meets
weekly and 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 Scientific Coordinator
will provide the PBTCTC with a consensus review that describes recommended
modifications and other suggestions, as appropriate (see the DCTD 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 and reporting to NCI to be used.  If a
proposed protocol is disapproved, the specific reasons for lack of approval will
be communicated in writing by the NCI Scientific Coordinator to the PBTCTC 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 Scientific Coordinator will be available to
assist the PBTCTC in developing a mutually acceptable protocol, consistent with
the research interests, abilities and strategic plans of the PBTCTC and of the
NCI.

6.  CTEP Involvement in Imaging Research:  The NCI Imaging Research Coordinator
will advise the PBTCTC Steering Committee and the NCI Scientific Coordinator with
respect to ongoing NCI activities and research opportunities related to the
imaging of pediatric brain tumors.  He/she will participate in CTEP review of
PBTCTC protocols with imaging components and will assist the NCI Science
Coordinator in the overall review of PBTCTC imaging research activities and
accomplishments.

7.  CTEP Involvement in Radiation Oncology Research:  The NCI Radiation Oncology
Research Coordinator will advise the PBTCTC Steering Committee and the NCI
Scientific Coordinator with respect to ongoing NCI activities and research
opportunities related to radiation therapy for childhood brain tumors.  He/she
will participate in CTEP review of PBTCTC protocols with radiation therapy
components and will assist the NCI Science Coordinator in the overall review of
PBTCTC radiation oncology research activities and accomplishments.

8.  CTEP Involvement in Protocol Closure: Protocol closure is primarily the
responsibility of the PBTCTC and the specific Protocol Committee.  The NCI
Program Director and Scientific Coordinator will also monitor protocol progress
and may request protocol closure to further patient accrual for the following
reasons:  (a) insufficient accrual rate; (b) accrual goal met; (c) poor protocol
performance; (d) patient safety or 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).

9.  PBTCTC meetings:  The NCI Scientific Coordinator, Program Director, Imaging
Research Coordinator, and Radiation Oncology Research Coordinator will attend
biannual PBTCTC meetings to discuss relevant scientific information, to discuss
progress in the clinical trials, and to discuss the status of newly available
investigational agents and other research opportunities in order to plan future
activities.

10.  CTEP involvement in Investigational New Drug Applications:

a.  The NCI will be willing to consider filing or cross-filing an IND for
investigational drugs evaluated in the Pilot and 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, Regulatory Affairs Branch
(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 Pilot and Phase I and II Clinical Trials
will be advised by the NCI Scientific Coordinator and Program Director of
potential studies that will be relevant to new avenues of cancer therapy. When
this involves investigational agents, the NCI Scientific Coordinator 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).

11.  CTEP Review of Federally Mandated Regulatory Requirements:  The Chief,
Clinical Trials Monitoring Branch (CTMB), through the NCI Scientific Coordinator,
will advise the PBTCTC regarding mechanisms to meet FDA regulatory requirements
for studies involving DCTD-sponsored investigational agents and the Office for
Protection from Research Risks (OPRR) requirements for the protection of human
subjects by PBTCTC institutions.  (See AWARDEE RIGHTS AND RESPONSIBILITIES,
above).  For specific Pilot and Phase I and II trials with NCI-sponsored
investigational agents selected by the CTEP Protocol Review Committee, 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.

12.  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. 
Data from studies of non-NCI-sponsored agents must be available for external
monitoring as described in the policies and procedures established by the PBTCTC
for on-site auditing of clinical trials data.  The awardee (and industry sponsor,
if any) will retain custody and primary rights to the data consistent with
current HHS, PHS and NIH policies.

13.  CTEP Review of Progress:  Performance of each PBTCTC will be reviewed at
least annually by the NCI Program Director and Scientific Coordinator on the
basis of the information provided at the semi-annual and other 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 PBTCTC by the NCI Scientific Coordinator for all active
studies when deemed appropriate.  Insufficient patient accrual or progress, or
noncompliance with the terms of award, including these Terms and Conditions of
Award, may result in a reduction of budget, withholding of support, suspension
or termination of the award.

D.  Collaborative Responsibilities

1.  Service on the Steering Committee:  The Steering Committee will be composed
of at least the following:  Participant Member Institution PIs, representatives
from the Operations, Statistics, and Data Management Center (to include the
Project Coordinator and a statistical/data management representative), the NCI
Program Director and NCI Coordinator, a patient/family representative, and a non-
voting representative of each of the brain tumor committees of the pediatric
Cooperative Groups.  The Steering Committee is responsible for the development
and approval of the PBTCTC organizational structure and Consortium by-laws.  The
Steering Committee will have primary responsibility to design research
activities, to establish priorities, and to develop and provide preliminary
approval of protocols (prior to submission to NCI and final NCI approval), and
to review progress.  The Steering Committee will also establish a process for the
selection of the laboratories to perform protocol-associated laboratory studies
and will authorize the spending of funds from the Discretionary Fund and the
Patient Studies Research Fund.  The Chairperson of the Steering Committee will
be selected from among the Principal Investigators of the Participant Member
Institutions at their initial meeting.  The Steering Committee Chairperson will
assist the Operations, Statistics, and Data Management Center in coordinating
Steering Committee activities, including preparing for PBTCTC meetings,
documenting actions taken and progress in written reports to the NCI Program
Director, and providing periodic supplementary reports to designated NCI staff
upon request.

E.  Arbitration

Any disagreement that may arise on scientific/programmatic matters (within the
scope of the award), excluding patient safety issues or regulatory compliance,
between award recipients and the NCI may be brought to arbitration.  An
arbitration panel composed of one awardee nominee, one NCI nominee, and a third
member with 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, DCTD.  The arbitration procedures in no way affect the awardee's
right to appeal an adverse determination under the terms of 42 CFR Part 50,
Subpart D, and 45 CFR Part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 4928 of Public
Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

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

LETTER OF INTENT

Prospective applicants are asked to submit, by May 1, 1998, a letter of intent
that includes a descriptive title of the proposed research, the name, address,
and telephone number of the Principal Investigator, the identities of other key
personnel and participating institutions, and the number and title of the RFA in
response to which the application may be submitted.  The letter of intent should
indicate if an application is planned for the Operations, Statistics, and Data
Management Center or is planned for a Participant Member Institution.

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:

Ms. Diane Bronzert
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 734, MSC 7432
Bethesda, MD  20892-7432
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-8866
FAX:  (301) 480-4663
Email:  BRONZERTD@CTEP.NCI.NIH.GOV

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these cooperative agreements.  These forms are available at most
institutional offices of sponsored research and may be obtained from the Division
of Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301)
435-0714, email: asknih@od.nih.gov.  Line 2 of the application where the RFA is
identified must indicate if an application is for the Operations, Statistics, and
Data Management Center or is for a Participant Member Institution.

Because the Terms and Conditions of Award 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.

PBTCTC Operations, Statistics, and Data Management Center applicants must
demonstrate in their applications the ability to meet the RESEARCH OBJECTIVES of
the RFA.  For the PBTCTC Operations, Statistics, and Data Management Center, the
Research Plan (Items a-d, PHS 398 form) should not exceed 50 pages.  To promote
the development of a collaborative program among the award recipients and to
assure that issues related to the RESEARCH OBJECTIVES of the RFA are adequately
considered, a number of issues need to be addressed in their applications as
discussed below.

Applicants for the PBTCTC Operations, Statistics, and Data Management Center
should describe:

1.  the qualifications and pediatric oncology clinical research experience of the
Project Coordinator,  and the qualifications and experience of other key
personnel. Previous experience with the design and administration of multi-
institutional clinical trials with extensive data collection requirements should
be described.
2.  their ability  to support the design and conduct of clinical trials for
children with cancer, with emphasis on clinical trials for patients with brain
tumors (including documentation of previous experience), including the following:
A.  their plans for coordinating protocol development in a timely manner.
B.  their plans for data collection and management, including a description of
facilities and data management resources and personnel.  Electronic submission
of clinical trials data will be expected for Consortium studies, and plans for
electronic data submission should be detailed.
C.  their statistical approach for pilot and phase I and II clinical trials for
children with brain tumors, and for correlating research studies with treatment
outcomes in clinical trials.
D.  their experience with and plans for multi-institutional study monitoring and
for interactions with the Protocol Chair during the period that the studies are
being conducted.
E.  their experience with and plans for quality assurance and quality control,
including: pathology, neurosurgery, radiation therapy, chemotherapy delivery,
neuro-imaging, and plans for on-site monitoring.  Specifically concerning neuro-
imaging, applicants should describe their capabilities and plans for central
collection and review of neuro-imaging studies, including plans for electronic
submission and storage of neuro-imaging studies during the five year funding
period.
F.  their experience with and plans for compliance with regulatory requirements,
including: (i) reporting of adverse drug reports for clinical trials involving
investigational agents; (ii) establishment of procedures to meet the Office for
Protection from Research Risks (OPRR) requirements for the protection of human
subjects; (iii) and assuring that PBTCTC investigators performing trials
involving DCTD Investigational Agents are NCI registered investigators (Form
1572) and for assuring that the PBTCTC is in compliance with CTEP requirements
described in the DCTD Investigators' Handbook for storage and accounting for
investigational agents {including NCI/HHS Drug Accountability Records (DAR)
procedures}.
G.  their plans for assuring rapid publication of data obtained in PBTCTC
clinical trials and laboratory studies.
H.  their experience with and plans for administering correlative laboratory
studies, including: (i) coordinating the acquisition and shipping of protocol-
specified tumor specimens, biological fluids and relevant clinical data to the
appropriate laboratories; (ii) maintaining effective collaboration between
laboratory and clinical investigators and the Operations, Statistics, and Data
Management Center within the consortium; and (iii) evaluating and analyzing
laboratory data with respect to treatment delivered or treatment outcome.
3.  their ability for fiscal management of the Discretionary Fund and the Patient
Studies Research Fund.
4.  their plans for effective interaction and communication among Participant
Member Institutions within the consortium, with the pediatric Cooperative Groups,
and with the NCI (including plans for PBTCTC meetings and for effective
electronic communication between meetings).
5.  their plans for an organizational structure for the Consortium, including a
draft charter/by-laws (to be included in the Appendix of the application) for the
Consortium.  The organizational structure should include a description of the
mechanisms by which appropriate input will be obtained from representatives of
the various disciplines that the Consortium will need to support its research
objectives (e.g., Neuro-imaging, Neuro-oncology, Neuro-pathology, Neurosurgery,
Radiation Oncology, etc.).

The Operations, Statistics, and Data Management Center budget should include the
following:

o  Costs for protocol development and implementation (including required
personnel).
o  Costs for data collection and management (including required personnel).
o  Costs for statistical support and analysis.
o  Patient Studies Research Funds (approximately $400,000 total costs) to be
dispersed to support institutional research costs, including: (i) collection and
shipping of tissue specimens; (ii) performance of special neuro-imaging research
studies; (iii) additional patient accrual and data monitoring; and (iv) other
protocol-specified laboratory tests to be performed at accruing institutions.
o  Costs for quality assurance, including: pathology review, radiation therapy
review, neurosurgical review, neuro-imaging review (using electronic submission
and storage of protocol-mandated neuro-imaging studies), and on-site auditing.
o  Travel funds for 2-3 representatives from the Operations, Statistics, and Data
Management Center to attend the biannual PBTCTC meetings.
o  Travel funds for the Steering Committee patient/family representative and the
Cooperative Group representatives to attend the biannual PBTCTC meetings (6 trips
total).
o  A Discretionary Fund (approximately $150,000 total costs) for laboratory
studies including correlative molecular studies on tumor specimens and
pharmacokinetic evaluations.

PBTCTC Participant Member Institution applicants must demonstrate in their
applications the ability to meet the RESEARCH OBJECTIVES of the RFA.  To promote
the development of a collaborative program among the award recipients and to
assure that issues related to the RESEARCH OBJECTIVES of the RFA are adequately
considered, a number of issues need to be addressed in their applications as
discussed below.

1.  Applicants should describe the clinical and/or basic research experience,
training, time availability, research competence, and commitment to PBTCTC
participation of the PI and investigators in the following disciplines:
A.  pediatric neuro-oncology;
B.  radiation oncology;
C.  neurosurgery;
D.  neuro-imaging; and
E.  neuropathology,
as evidenced by past clinical research contributions and current research efforts
relating to childhood (and/or adult) brain tumors.

Relating to the above disciplines, applicants should also address the following
topics:
A.  plans for institutional neuropathology support for tumor classification and
for banking and distribution of patient specimens for concurrent and future
studies.  Ability to collect and ship patient specimens (e.g, tumor and
biological fluids) to other members of the PBTCTC for the conduct of protocol-
mandated tests or to a central tumor repository under the guidelines established
by the PBTCTC should be described.  Institutional neuropathology research
projects relevant to childhood brain tumors should be described.
B.  the institutional availability of state-of-the-art imaging such as MRI,
functional MRI, MRS, SPECT, and PET and the institutional commitment for
utilizing these methodologies in the conduct of PBTCTC studies when such imaging
studies are required.  Institutional imaging research projects relevant to
childhood brain tumors should be described.
C.  the institutional availability of state-of-the-art radiotherapy (e.g., for
delivery of stereotactic radiotherapy and brachytherapy) and the institutional
commitment to utilize these techniques in the conduct of PBTCTC studies when
required.  Institutional radiotherapy research projects relevant to childhood
brain tumors should be described.
D.  the institutional availability of state-of-the-art neurosurgical facilities
and expertise, and the institutional commitment to utilize these in the conduct
of PBTCTC studies when required.  Institutional neurosurgery research projects
relevant to childhood brain tumors should be described.

2.  Patient Accrual:
o  Applicants should document their ability to recruit a minimum of 10-12
evaluable patients per year with brain tumors who would be candidates for pilot
and phase I and II clinical trials.  Recent institutional accrual of children
with brain tumors to pilot and phase I and II clinical trials should be provided. 
o  Applicants should state their commitment to enter eligible patients onto
clinical trials being performed through the Consortium and acknowledge that these
clinical trials have the highest priority.  Applicants should describe their
plans to prioritize patients with brain tumors between Consortium studies and
other trials.

3.  Applicants should document their ability to meet the data collection and
regulatory requirements necessary for clinical research for children with brain
tumors, including:
o  institutional data management resources and plans for utilizing these
resources for the conduct of PBTCTC clinical trials.  Specific documentation of
their institutions's ability to comply with electronic submission of clinical
trials data should be included.
o  provisions for the protection of human subjects.
o  plans for inclusion of females and minorities.
o  drug control procedures as required for utilization of NCI-supplied
experimental agents.

4.  Applicants should describe the clinical and laboratory areas of scientific
expertise resident at their institution that are applicable to innovative
therapies for pediatric brain tumors, discuss and document the expertise (funded
grants, publications, etc.), and describe the unique research contributions that
the applicant would bring to the Consortium.  Applicants should indicate in which
of these research areas they would be willing to either lead Consortium clinical
studies or would be willing to conduct correlative studies (e.g., pharmacokinetic
and pharmacodynamic monitoring or imaging research studies) for Consortium
protocols.

5.  Applicants should describe the availability of appropriate facilities and
equipment including clinical, computer and data management, laboratory
facilities, and facilities for processing patient specimens for PBTCTC laboratory
studies and for the PBTCTC Tumor and Tissue Repository.  Note: Applicants from
institutions that have a General Clinical Research Center (GCRC) funded by the
NIH National Center for Research Resources may wish to identify the GCRC as a
resource for conducting the proposed research.  If so, a letter of agreement from
either the GCRC Program Director or Principal Investigator must be included with
the application.

6.  Applicants should include as an Appendix a description of a clinical research
project congruent with the Research Objectives of the RFA and based upon
expertise and research findings from their institution.  The description should
be limited to no more than 5 pages, and the CTEP Letter of Intent format should
be used.  This format is described in Appendix VII of the DCTD "Investigator's
Handbook" (available upon request from the Program Director at the address below
or available at the CTEP Web page at the following URL:
http://ctep.info.nih.gov/handbook/index.html).

All costs required for these studies must be included in the applications and
must be fully justified.  These costs include the additional costs of clinical
research associated with Pilot and Phase I and Phase II studies including costs
for patient accrual, sample handling, laboratory studies, quality assurance, data
management and data analysis, study monitoring, and travel.

Each Participant Member Institution budget should include the following:

o  Support for personnel from the requisite participating subspeciality areas
(Neuro-imaging, Neuro-oncology,  Neuro-pathology, Neurosurgery, and Radiation
Oncology).
o  Support for institutional data management activities.
o  Support for travel to the PBTCTC biannual meeting (approximately eight
individual trips per year to be divided between the two PBTCTC biannual
meetings). It is likely that one meeting each year will include representatives
of multiple disciplines from each Participant Member Institution, while the other
meeting will be restricted to 1 or 2 attendees from each Participant Member
Institution.

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.

The Social Security Number (SSN) of the Principal Investigator should be provided
along with the applicant's name at the top of the Personal Data form page only
(PHS Form 398, page KK).  The SSN should not be listed on the face page of the
application, nor provided elsewhere in the application, e.g., top of each
application page.  When submitting competing renewal applications using the PHS
398 grant application kit, do not complete or submit the Personnel Report form
page (JJ).  This form page will be requested, if necessary, at the time of award.

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

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

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636, MSC 7401
Bethesda, MD  20892
Rockville, MD  20852 (for express/courier service)

Applications must be received by July 10, 1998.  If an application is received
after that date, it will be returned.

The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The CSR
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 follow the guidance in
the PHS 398 application instructions for the preparation of revised applications,
including an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

All applications will be judged on the basis of the documented ability of the
investigators to meet the RESEARCH OBJECTIVES of the RFA as listed under Review
Criteria.

A.  Review Procedures

Upon receipt, applications will be reviewed for completeness by CSR 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.

Applications will be reviewed 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

Applications for the Operations, Statistics, and Data Management Center will be
reviewed on the basis of the following criteria:

o  Qualifications and research experience of the Project Coordinator and the key
personnel including, but not limited to, previous experience with design and
administration of multi-institutional clinical trials (particularly for children
with cancer) with extensive data collection requirements.
o  Adequacy of plans for the timely development and implementation of multi-
institutional clinical trials for children with brain tumors.
o  Adequacy of the available facilities and data management and statistical
resources and personnel.
o  Evidence of competence with regard to clinical trials administration, to
include: experimental design and statistical analysis; quality assurance and
quality control;  study monitoring;  data collection and management (including
plans for electronic submission of clinical trials data); and compliance with
regulatory requirements. Specifically concerning neuro-imaging, the adequacy of
plans for central collection and review of neuro-imaging studies using electronic
submission and storage.
o  Evidence of competence with regard to fiscal administration for distribution
and management of funds involving multi-site studies.
o  Adequacy of experience with and plans for administering correlative laboratory
studies, including  coordination of the acquisition and shipping specimens,
maintenance of effective collaboration between laboratory and clinical
investigators and the Operations, Statistics, and Data Management Center within
the consortium, evaluation and analysis of laboratory data with respect to
treatment delivered or treatment outcome.
o  Adequacy of plans for effective communication and coordination between the
Participant Member Institutions and the Operations, Statistics and Data
Management Center and with the NCI.
o  Plans for the organizational structure of the Consortium, including its draft
charter/by-laws.

Applications for Participant Member Institutions will be reviewed on the basis
of the following criteria:

o  The overall qualifications of applicant institutions to meet the requirements
for participation listed under APPLICATION PROCEDURES.
o  Clinical and/or basic research experience, training, time availability, and
research competence and commitment of the PI and investigators in the following
disciplines:
a) pediatric neuro-oncology;
b) radiation oncology;
c) neurosurgery;
d) neuro-imaging; and
e) neuropathology,
as evidenced by past clinical research contributions and current research efforts
relating to childhood (and/or adult) brain tumors.
o  Availability of sufficient numbers of evaluable patients with brain tumors for
the conduct of pilot and phase I and II clinical trials, and adequacy of
institutional commitment to enter eligible patients onto PBTCTC clinical trials.

o  Adequacy of plans for pathology support for tumor classification and for
submission of tumor specimens for banking for concurrent or future correlative
studies.
o  Availability of state-of-the-art imaging such as MRI, functional MRI, MRS,
SPECT, and PET and ability to appropriately utilize these methodologies in the
conduct of PBTCTC studies.
o  Adequacy of state-of-the-art radiotherapy (e.g., for delivery of stereotactic
radiotherapy and brachytherapy) and ability to appropriately utilize these
techniques in the conduct of PBTCTC studies.
o  Adequacy of state-of-the-art neurosurgical facilities and expertise, and 
ability to appropriately utilize these in the conduct of PBTCTC studies.
o  Adequacy of data management resources and facilities.
o  Adequacy of provisions for the protection of human subjects.
o  Adequacy of the plans for inclusion of females and minorities.
o  Submitted clinical protocol proposals will be reviewed as examples of ideas
and/or research designs of applicant Institutions.  These may be commented upon
by peer reviewers as they illustrate the overall capability of the applicant to
contribute to the research objectives of the Consortium.  The specific proposals
themselves will not be considered major elements in the evaluation, since PBTCTC
protocols will reflect the input and expertise of investigators from multiple
institutions, including those at the Operations, Statistics and Data Management
Center.

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

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

Letter of Intent Receipt Date:             May 1, 1998
Application Receipt Date:                  July 10, 1998
Review by National Cancer Advisory Board:  February 1999
Anticipated Award Date:                    April 1999

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.  The opportunity to clarify any issues or questions from
potential applicants is welcome.

Direct inquiries regarding scientific issues to:

Dr. Malcolm Smith
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 741, MSC 7436
Bethesda, MD  20892-7436
Telephone:  (301) 496-2522
FAX:  (301) 402-0557
Email:  smithm@CTEP.NCI.NIH.GOV

For programmatic information:

Ms. Diane Bronzert
Division of Cancer Treatment Diagnosis and Centers
National Cancer Institute
6130 Executive Boulevard, Room 734, MSC 7432
Bethesda, MD 20892-7432
Telephone:  (301) 496-8866
FAX:  (301) 480-4663
Email:  BRONZERTD@CTEP.NCI.NIH.GOV

Direct inquiries regarding fiscal matters to:

Ms. Crystal Wolfrey
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 243, MSC 7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, ext. 282
FAX:  (301) 496-8601
Email:  WOLFREYC@GAB.NCI.NIH.GOV

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,
Public Law 99-158, 42 USC 241 and 285) and administered under HHS grants
policies.  This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.


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