ADVANCED TECHNOLOGY RADIATION THERAPY CLINICAL TRIALS SUPPORT

Release Date:  May 11, 1998

RFA:  CA-98-006

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  July 7, 1998
Application Receipt Date:  August 11, 1998

PURPOSE

This Request for Applications (RFA) is to solicit applications to generate a
resource that will facilitate the conduct of National Cancer Institute (NCI)
sponsored clinical trials in 3-dimensional radiation therapy treatment planning
and delivery (3D-CRT), stereotactically directed radiation therapy, intensity
modulated radiation therapy (IMRT), and brachytherapy in both pediatric and adult
patients.

The Radiation Research Program, Division of Cancer Treatment and Diagnosis of the
NCI invites applications for projects to generate a resource for support of high
technology radiation therapy clinical trials.  Such support should include
credentialing of institutions to participate in these trials, developing basic
technical and quality assurance criteria for each protocol assessed, providing
prospective review of treatment plans to assure that  they are within protocol
specifications. Such support should also include development and maintenance of
a comprehensive database of diagnostic images, dose-volume histograms, tumor and
normal structure definitions to be correlated with treatment outcomes.

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, Advanced Technology Radiation
Therapy Clinical Trials Support, 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 for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and Local governments, and eligible agencies of the
Federal Government. Foreign organizations are not eligible. Single applications
from multi institutional consortia may be submitted. Racial/Ethnic minority
individuals, women and persons with disabilities are encouraged to apply as
Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program will be a
Resource Related Support cooperative agreement (U24), an "assistance" mechanism
(rather than an "acquisition" mechanism), in which substantial NCI scientific
and/or programmatic involvement with the awardee is anticipated during
performance of the activity.  Under the cooperative agreement, the NCI purpose
is to support and/or stimulate the activity of recipient(s), to generate a high
quality resource by involvement in and otherwise working jointly with the award
recipient(s) in a partner role, but it is not to assume direction, prime
responsibility, or a dominant role in the activity. NCI staff will also be
involved with the coordination of different groups, should there be more than one
award recipient (e.g., with one PI focused on adult clinical trials and one PI
focused on pediatric trials). Details of the responsibilities, relationships and
governance of the study to be funded under cooperative agreement(s) are discussed
later in this document under the section "Terms and Conditions of Award."

The total project period for applications submitted in response to the present
RFA may not exceed 3 years. The anticipated award date is April, 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 reissue the RFA for recompetition. If the NCI does not continue the
program, awardees may submit grant applications through the usual investigator
initiated grant program.

Because the nature and scope of projects proposed in response to this RFA may
vary, it is anticipated that the sizes of awards will vary also.  The number of
awards and level of support depend on receipt of a sufficient number of
applications of high scientific merit.

FUNDS AVAILABLE

It is anticipated that approximately one million dollars in total cost per year
for 3 years will be awarded to fund applications that are submitted in response
to this RFA.  NCI anticipates one or more awards.  The funding level is dependent
on the receipt of a sufficient number of applications of high scientific merit.
Although this program is provided for in the financial plans of NCI, the award
of cooperative agreements in response to this RFA is also contingent upon the
availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

The use of image based radiation teletherapy treatment planning has grown
substantially over the past few years.  The rapid growth in computer processing
power and concomitant decrease in cost has made this possible.  This allows the
radiation oncologist to visualize the radiation treatment plan directly on the
patients diagnostic CT or MRI with the tumor and critical normal structure in
place.  Fashioning a three dimensional view of any single structure is also
possible.  Diagnostic imaging can also be used to guide placement of
brachytherapy sources.  Once the digital images and treatment parameters are
available they may be centrally archived for a quantitative analysis of dose
volume relationships for long term outcomes of both tumor control and normal
tissue toxicity.

Planning and delivering radiation with these advanced technologies is not as
straight forward as with conventional techniques.  More precise definition of
tumor and normal tissue is necessary as is the need to evaluate all aspects of
the treatment plan in three dimensions instead of the more familiar two
dimensions.  Multi-institutional clinical trials require a consistent quality
assurance program for 3D CRT and brachytherapy treatment plans.

The purpose of the development of a central quality assurance resource  is to
eliminate the need for individual clinical trials groups to assemble a resource-
intensive quality assurance center which each individual group may not be able
to use optimally. A centralized resource will ensure that appropriate personnel
and equipment are available when needed and that appropriate procedures and
criteria are developed. With the availability of full digital data for tumor and
normal tissue volumes, it will be necessary to establish a database for that
information that may be made available to the research community for outcome
analysis.

Objectives and Scope

The primary objective of this RFA is to solicit applications for projects that
will generate a resource to use state-of-the- art methods to develop quality
assurance criteria for NCI sponsored high technology radiation therapy clinical
trials, and to implement those criteria for selected clinical protocols when
applicable, including credentialing of participating institutions and treatment
plan review . This resource should also develop and maintain a database of
treatment parameters for correlating with clinical outcomes.

Applicants should discuss in their applications the rationale for their approach. 
Some examples of items that may be included in the application, for purposes of
illustration only, are the following:

--Criteria for deciding which anatomic sites are important to study and examples
of such sites --Criteria for deciding which clinical trials should be monitored -
-Methods for choosing which quality assurance criteria may be chosen for each
high technology modality and criteria for modifying them as the project
progresses
--Manner of interacting with the clinical trials groups
--Methods of transferring digital data between and among institutions --Proposed
plans for timely communication of  results of protocol quality assurance to the
clinical trials group --Sample quality assurance protocols for representative
anatomic sites and treatment modalities --Proposed design parameters for database
archiving and criteria for allowing outside investigator access The following
terms and conditions will be incorporated into the award statements(s).

Terms and Conditions of Award

A.  Applicability

These special Terms of Award are in addition to and not in lieu of otherwise
applicable OMB administrative guidelines, HHS Grant Administration Regulations
at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration
policy statements.

The administrative and funding instrument used for this program is a Resource
Related Support Cooperative Agreement (U24), an "assistance" mechanism (rather
than an "acquisition" mechanism) in which substantial NCI scientific and/or
programmatic involvement 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 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 between the awardees
and the NCI Program Director.

B.  Awardee Rights and Responsibilities

1)  Awardees will have primary and lead responsibilities for  the project as a
whole, including research design and the actual performance of the project and
preparation of publications, as well as collaboration with other awardees, with
assistance from the NCI Program Director.  The Principal Investigator(s) is
expected to make any necessary adjustments in the overall research strategies to
accommodate the changing environment resulting from improved technologies during
the course of the project period.

2) Awardees will be expected to work with the NCI funded clinical trials
cooperative groups to provide technical quality assurance expertise. The nature
of the cooperation will vary depending upon the particular clinical protocol
under consideration, and upon the needs of the individual group. This
relationship will be arrived at by mutual agreement among the awardee,
cooperative group radiation oncology committee, and cooperative group chairman
with the NCI providing any needed input regarding allocation of available
resources.

3) If there is more than one awardee, they will be expected to collaborate in
sharing techniques, experience in the application of standards, etc. in order to
avoid duplication of efforts.

4) The NCI reserves the right to require transfer of all data, or true copies of
such data, acquired and/or generated as a result of participation in this award
to an eligible third party in order to preserve the data and/or to continue the
research. Third parties supported under this award must be informed of this
right, and this requirement must be included in agreements with third parties
under the award. This provision does not remove the initial investigator's access
to the data. Under data archiving and sharing, initial investigators still
benefit from first and continuing use, but not from prolonged exclusive use.

5)  Awardees will retain custody of and have primary rights to the data developed
under these awards, subject to Government rights of access consistent with
current HHS, PHS, and NIH policies.

C.  NIH Staff Responsibilities

1) The NCI Program Director will have substantial scientific programmatic
involvement during the conduct of this activity, through technical assistance,
advice and coordination above and beyond normal program stewardship for grants,
as described below.

--Participation in the Steering Committee and any subcommittee meetings that may
be called.

--Serving as a resource with respect to other ongoing NCI activities that may be
relevant to this effort.

--Assisting, with the agreement of the Principal Investigator(s), in the design,
development, and coordination of the choice of anatomic sites to study, clinical
trials to monitor, and quality assurance parameters to review.

--Reviewing clinical protocols and quality assurance protocols to insure that
they are within the scope of this effort and within the scope of peer review.

2)  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 award will be shared among the
awardees and the NCI Program Director who will provide expert advice to the
awardee on specific scientific and/or analytic issues as described below. The NCI
Program Director will have overall programmatic responsibility for the award and
will be the contact point for all facets of interaction with the awardee related
to stewardship and monitoring of the award.

3)  The NCI reserves the right to terminate or curtail the study (or an
individual award) in the event of inadequate progress, data reporting, or
underutilization of this resource.

D.  Collaborative Responsibilities

1)  During the course of the award period, the awardee(s) will  be invited to
meet with the NCI Program Director, other Principal Investigators and/or other
uninvolved experts in Bethesda, MD, to review scientific progress.

2) A Steering Committee organized by the Principal Investigator(s) will be the
main oversight body for this cooperative agreement. The Steering Committee will
be composed of the Principal Investigator(s), the NCI Program Director,
representatives from the clinical trials groups, and external non-participating
professionals to provide expertise that may not be otherwise available. These may
be drawn from such organizations as the American Association of Physicists in
Medicine and the American Society of Therapeutic Radiology and Oncology. The
Steering Committee will meet twice yearly in Bethesda, Maryland to plan the
details of the project and to report progress. The chairman of the steering
committee will be chosen by consensus of the members, with the chair periodically
rotating. The NCI Program Director will be a member of and will attend and
participate in the Steering Committee and, if appropriate, its subcommittees but
will not be a voting member of any committee. The purpose of the Steering
Committee will be to periodically review resource needs, determine directions for
future needs, and to share experiences with implementation of this resource. It
is expected that decisions made or actions taken by the Steering Committee will
be by consensus and all awardees will be expected to implement them.

3) The Principal Investigator(s) will semiannually document progress in written
reports to the NCI Program Director and to the Chairperson of the Steering
Committee and will provide periodic supplementary reports upon request.

4)  Applicants are expected to be willing to redirect efforts if changes in the
technology or interim results of clinical trials so indicate.

E.  Arbitration

Any disagreement that may arise on scientific/programmatic matters (within the
scope of the award), between award recipients and the NCI may be brought to
arbitration.  An arbitration panel will be composed of three members -- one
selected by the Steering Committee (with the NCI member not voting) or by the
individual awardee in the event of an individual disagreement, a second member
selected by NCI, and the third member selected by the two prior selected members. 
This special arbitration procedure in no way affects the awardee's right to
appeal an adverse action that is otherwise appealable in accordance with the PHS
regulations at 42 CFR Part  50, Subpart D and HHS regulation at 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 new
policy results from the NIH Revitalization Act of 1993. All investigators
proposing research involving human subjects should read the "NIH Guidelines on
the Inclusion of Women and Minorities as Subjects in Clinical Research," which
has been printed in the Federal Register of March 28, 1994 and in the NIH GUIDE
FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the program staff or
contact person listed under INQUIRIES.  Program staff may also provide additional
relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by July 7, 1998 a letter of intent
that includes a descriptive title of the proposed research, name, address, and
telephone number of the Principal Investigator, identities of other key personnel
and participating institutions, and 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 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 L. Cumberlin
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Suie 800 - MSC 7440
Bethesda, MD  20892-7440
Telephone:  (301) 496-6111
FAX:  (301) 480-5785

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these projects.  Applications kits 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 301/710-0267, Email:
[email protected].

The RFA label available in the PHS 398 (rev.5/95) application form must be
affixed to the bottom of the face page of the application. Failure to use this
label could result in delayed processing of the application such that it may not
reach the review committee in time for review.  In addition, the RFA title and
number must be typed on line 2 of the face page of the application form and the
YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed 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
Bethesda, MD  20892-7399
Rockville, MD  20852 (for express/courier service)

Applications must be received by August 11, 1998.  If an application is received
after that date, it will be returned to the applicant without review.  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 a substantial revision of an application already
reviewed, but such an application must follow the guidance in the PHS Form 398
application instructions for the preparation of revised applications, including
an introduction addressing the previous critique.

Budget and Related Issues

Applicants are expected to provide a detailed breakdown of the proposed budget
to include categorical breakdown of such items as personnel, supplies,
consultants, etc.  Applicants should include travel funds for the Principal
Investigator and the other key investigators on the grant to meet with the NCI
Program Director, and other awardees. Applicants should plan on two meetings  per
year to be held in Bethesda, MD.

REVIEW CONSIDERATIONS

General Considerations

All applications will be judged on the basis of the scientific merit of the
proposed project and the documented ability of the investigators to meet the
RESEARCH OBJECTIVES of the RFA.  The technical merit of the proposed approach for
developing the quality assurance and data archiving resource is extremely
important, although it will not be the sole criterion for evaluation of an
application.  Other considerations, such as the qualifications of the Principal
Investigator, key personnel, support staff,  and the quality of the proposed
facilities in which this work will be carried out.

Review Method

Upon receipt, applications will be reviewed for completeness by the CSR and for
responsiveness by the NCI.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.  Applications may
receive a preliminary scientific review by an NCI peer review group to determine
their relative competitiveness. The NCI will withdraw from further competition
those applications judged to be noncompetitive for an award and notify the
applicant Principal Investigator and institutional official.  Those applications
that are complete and responsive and judged to be competitive will undergo
further scientific merit review in accordance with the criteria stated below for
scientific/technical merit by an appropriate peer review group convened by the
NCI.  The second level of review will be provided by the National Cancer Advisory
Board (NCAB).

Review Criteria

Applicants are encouraged to submit and describe their own ideas about how best
to meet the goals of the RFA.

The review group will assess the scientific merit of the application and related
factors, including:

--scientific and technical merit of the proposed work, including the
appropriateness and adequacy of the approach and methodology proposed to develop
and apply quality assurance criteria to anatomic sites that have not been
previously studied with these advanced technology modalities.

--qualifications and experience of the Principal Investigator and staff,
particularly, but not exclusively, in the project area, including the
qualifications and experience of the personnel at subcontracting institutions (if
any).

--demonstrated capability for monitoring the technical performance of 3D- CRT
clinical studies.

--demonstrated capability for monitoring the technical performance of
brachytherapy studies

--familiarity with the design and coordination of multidisciplinary,
multimodality, multi-institutional clinical trials

--availability of the resources/scientific environment necessary to perform the
research in a cost effective manner;

- demonstrated willingness to work with the NCI clinical trials groups and with
the NCI  Program Director;

--adequacy of the proposed protection for human subjects;

--appropriateness of the proposed budget and duration in relation to the proposed
resource.

AWARD CRITERIA

Applications will be considered for award based upon (1) overall scientific and
technical merit as determined by peer review, and (2) availability of funds.

Schedule

Letter of Intent Receipt Date:  July 7, 1998
Application Receipt Date:       August 11, 1998
Review by NCAB                  February, 1999
Anticipated Award Date:         April 1999

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged. The
opportunity to clarify any issues or questions from potential applicants is
welcome.

Direct inquiries regarding programmatic issues to:

Dr. Richard L. Cumberlin
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Suite 800 - MSC 7440
Bethesda, MD  20892-7440
Telephone:  (301) 496-6111
FAX:  (301) 480-5785

Direct inquiries regarding fiscal matters to:

Ms. Crystal Wolfrey
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 243
Bethesda, MD 20892
Telephone:  (301) 496-7800 Ext. 282
FAX:  (301) 496-8601
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.396.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241
and 285) and administered under PHS grants policies and Federal Regulations 42
CFR Parts 52 and 45 CFR Part 74 and Part 92. This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health Systems
Agency review.

The PHS strongly encourages all grant 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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