DEVELOPMENT AND APPLICATION OF IMAGING IN THERAPEUTIC STUDIES

Release Date:  August 14, 1998

RFA:  CA-98-024

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  October 14, 1998
Application Receipt Date:  November 18, 1998

PURPOSE

The Diagnostic Imaging Program and the Cancer Therapy Evaluation Program of
the Division of Cancer Treatment and Diagnosis, National Cancer Institute
(NCI) invite applications to apply imaging technologies in the assessment of
investigational cancer therapeutic agents.  Imaging studies have traditionally
provided valuable anatomic tumor information pre- and post-treatment.  With
new drug-development methods producing ever increasing numbers of molecules
for investigation, there is an important opportunity to integrate and exploit
imaging techniques in the assessment of this process, in either clinical and
pre-clinical settings.  This Request for Applications (RFA) is designed to
support research projects that address the development and application of
labeled therapeutic agents as compounds for imaging studies, and/or the
development and application of imaging agents as metabolic markers of response
to newly-developed therapeutic agents.

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, Development and Application of
Imaging in Therapeutic Studies, 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 and foreign, 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.  Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as Principal
Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project
grant (R01).  Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The total project
period for an application submitted in response to this RFA may not exceed 4
years.  The anticipated award date is August 1, 1999.  Because the nature and
scope of the research proposed in response to this RFA may vary, it is
anticipated that the size of an award will vary also.  This RFA is one-time
solicitation.  Future unsolicited competing continuation applications will
compete with all investigator-initiated applications and be reviewed according
to the customary peer review procedures.  Awards will be administered under
PHS grants policy as stated in the Public Health Service Grants Policy
Statement DHHS Publication No. (OASH) 94-50,000 (Rev.) April 1, 1994.

FUNDS AVAILABLE

Approximately $2.8 million per year in total costs for four years will be
committed by the NCI to specifically fund applications submitted in response
to this RFA.  The expected number of awards is six to eight.  This funding
level is dependent on the receipt of a sufficient number of applications of
high scientific merit and the availability of funds.

RESEARCH OBJECTIVES

Background

The identification of therapeutic agents with high tumor specificity and low
toxicity is a continuing challenge.  In addition to traditional drug discovery
and development approaches, the implementation of rational drug design,
combinatorial chemistry techniques and high-throughput screening have led to
large numbers of new agents to study.  Regardless of the technique used to
identify a novel drug, extensive research is required before it can be widely
introduced into the clinic.  Determination of the intra-tumoral
pharmacokinetic and pharmacodynamic parameters is necessary in defining the
response endpoints in clinical trials.  The ability to track altered
biodistribution and washout would improve the understanding of drug
bioavailability and address drug-target issues.  Other critical parameters
include the degree of success of therapeutic delivery, toxic and efficacious
dose concentrations and measurement of tumor response to therapy. 
Pharmacokinetic studies of cancer therapies have made great contributions in
predicting the range of dose concentrations for Phase I trials and the
schedule of administration of these doses.  However, these measurements are
still largely determined indirectly through the analysis of metabolic products
in blood and urine samples, or through the invasive analysis of biopsy
tissues.

Advances in technology have now made imaging a potentially important non-
invasive tool for the functional or quantitative assessment of biochemical,
genetic, or pharmacologic activity   Imaging modalities such as Magnetic
Resonance Spectroscopy (MRS), Positron Emission Tomography (PET) and Single
Photon Emission Computed Tomography (SPECT) are uniquely suited to this
challenge.  In addition, optical, electron spin resonance (ESR) and
sonographic technologies also have some potential to contribute similar
information in certain applications.  These techniques are ready to be
incorporated into early clinical trails of therapeutic agents.  Effective
collaborations within multi-disciplinary research teams that include imaging
scientists, oncologists, chemists, molecular biologists, pharmacologists, and
mathematical model experts will be necessary to translate new imaging
technologies into clinical trials research.

Objectives and Scope

The purpose of this RFA is to encourage investigators to apply imaging
technologies in the assessment of investigational cancer therapeutic agents. 
The following are 2 general categories of interest:

1.  Development and application of labeled therapeutic agents as compounds for
imaging studies.

Imaging agents can be used as tracers to monitor the metabolism and
distribution of therapeutic agents in both the tumor and normal tissue. These
techniques can be applied to early clinical trials or pre-clinical studies in
animal model systems.  The evaluation of drug distribution and metabolism are
part of the standard studies that accompany drug development in early clinical
trials.  However, data on intra-tumoral uptake, distribution and metabolism
are usually lacking because obtaining such information usually requires
sequential biopsies.  Non-invasive imaging may prove useful for evaluating the
distribution kinetics and PK-PD relationships of certain antitumor agents for
which pharmacokinetics using standard pharmacological methods is particularly
problematic.

Information on gene therapy delivery and distribution is of particular
interest.  Biological endpoints in cancer gene therapy trials, including the
determination of gene transfer efficiency/expression and of tumor cell
apoptosis, are important for the optimization of these therapies.  It is often
difficult to perform the invasive procedures that are necessary for tissue
procurement, and the sites of gene transduction may be missed by the biopsy
needle.  Non-invasive imaging technologies could greatly facilitate the
development of cancer gene therapies.

2.  Development and application of imaging agents as metabolic markers of
response to newly-developed therapeutic agents.

Imaging agents may be utilized as substrates or analogues of substrates for
the biochemical pathway of action of the therapeutic agents.  Since some
antitumor agents target specific enzyme systems (e.g., dihydropyrimidine
dehydrogenase, thymidylate synthase), the development of technologies that
image those enzyme systems may prove valuable tools to evaluate
pharmacokinetic-pharmacodynamic relationships.  These markers of drug action
could be used to monitor metabolic response to the drug both in vitro and in
vivo.

The proposed projects will be required to integrate the development and
utilization of a novel imaging agent into the investigation of a specific
therapeutic agent (or the defined biochemical pathway in which it acts). 
Applications to study or develop new imaging agents that are not specifically
involved in a pathway that is a direct target for current drug development
will not be considered responsive to this initiative.

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.

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

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are clear and compelling scientific and ethical reasons not
to include them.  This policy applies to all initial (Type 1) applications
submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by October 14, 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.  Although a
letter of intent is not required, is not binding, and does not enter into the
review of a subsequent application, the information that it contains allows
NCI staff to estimate the potential review workload and avoid conflict of
interest in the review.

The letter of intent is to be sent to:

Anne E. Menkens, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 800
Bethesda, MD  20892
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-9531
FAX:  (301) 480-5785
Email:  [email protected]

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in
applying for these grants.  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 PHS 398 application kit is also
available on the web at:
https://grants.nih.gov/grants/funding/phs398/forms_toc.html.

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 be
sent to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892-7399
Rockville, MD  20850 (for express/courier service)

Applications must be received by November 18, 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 substantial
revisions of applications already reviewed, but such applications must include
an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

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.  If the application is not responsive
to the RFA, CSR staff may contact the applicant to determine whether to return
the application to the applicant or submit it for review in competition with
unsolicited applications at the next review cycle.

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the NCI in accordance with the standard NIH peer review procedures.  As part
of the initial merit review, all applications will receive a written critique
and undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of applications under review,
will be discussed, assigned a priority score, and receive a second level
review by the appropriate national advisory council or board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
reviewers will comment on the following aspects of the application in their
written critiques in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered by the reviewers in assigning the
overall score weighting them as appropriate for each application.  Note that
the application does not need to be strong in all categories to be judged
likely to have a major scientific impact and thus deserve a high priority
score.  For example, an investigator may propose to carry out important work
that by its nature is not innovative but is essential to move a field forward.

1.  Significance.  Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?

2.  Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

3.  Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

4.  Investigator.  Is the investigator appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?

5.  Environment.  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of institutional support?

In addition to the above criteria, the applications will also be assessed for
the strength and appropriateness of the collaborations required for the
implementation of these ambitious projects.  These collaborations may already
be in place in a limited number of institutions.  However, new teams of
investigators that have not previously been scientifically interactive are
also encouraged.

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders,
minorities and their subgroups, and children as appropriate for the scientific
goals of the research, or justification for exclusion, and plans for the
recruitment and retention of subjects; the provisions for the protection of
human and animal subjects; and the safety of the research environment.

AWARD CRITERIA

Award criteria that will be used to make award decisions include: scientific
merit (as determined by peer review), availability of funds, and programmatic
priorities.

Schedule

Letter of Intent Receipt Date:  October 14, 1998
Application Receipt Date:       November 18, 1998
Review by NCAB Advisory Board:  May 1999
Anticipated Award Date:         August 1, 1999

INQUIRIES

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:

Anne E. Menkens, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 800
Bethesda, MD  20892
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-9531
FAX:  (301) 480-5785
Email:  [email protected]

Direct inquiries regarding NCI agents available for clinical trials to:

Ms. Diane Bronzert
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 734, MSC 7432
Bethesda, MD  20892-7432
Telephone:  (301) 496-8866
FAX:  (301) 480-4663
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Mr. E. C. Melvin
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, Ext. 258
FAX:  (301) 496-8601
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.395.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99- 158, 42 USC
241 and 285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74 and 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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