CLINICAL CANCER THERAPY RESEARCH

Release Date:  January 22, 1999

PA NUMBER:  PA-99-046

P.T.

National Cancer Institute

This PA replaces PA-92-069, which was published in the NIH Guide, Vol. 21, No.
15, April 17, 1992.

PURPOSE

The National Cancer Institute (NCI) seeks grant applications to conduct clinical
therapeutic studies/trials of neoplastic diseases in humans.  Clinical research,
by definition, involves a clinician/patient-subject interaction with a
therapeutic intent.  This Program Announcement (PA) encompasses a full range of
therapeutic studies and clinical trials employing drugs, biologics, radiation,
and surgery.  The intent of the PA is to encourage clinical researchers to
translate insights in cancer biology and the development of new agents into
innovative cancer therapeutic studies.

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 PA, Clinical Cancer Therapy Research,
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),
or at http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and 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.  Racial/ethnic minority individuals, women, and persons with
disabilities as well as new clinical investigators are encouraged to apply as
principal investigators.  An application may include one or more institutions
(e.g., individual institutions, consortia, cancer centers) with established
clinical, laboratory, and statistical resources.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project grant
(R01) award mechanism.  Responsibility for the planning, direction, and execution
of the proposed research will be solely that of the applicant.  The total project
period for an application submitted in response to this PA may not exceed five
years.

Investigators interested in submitting R21 grant applications in this research
area are referred to PA-98-042, Exploratory Grants for Correlative Laboratory
Studies and Clinical Trials, which was published in the NIH Guide for Grants and
Contracts, March 20, 1998.

RESEARCH OBJECTIVES

Summary

Highly productive research efforts into understanding the basic biology of the
cancer cell have resulted in discoveries concerning the role of growth factors,
genes that promote and suppress neoplasia, mechanisms of treatment sensitivity
and resistance, and the biology of the immune systems have provided the basis for
the development of novel and improved cancer treatments.  The rate of progress
in the treatment of cancer depends upon the translation of these basic and
preclinical discoveries into clinical cancer therapies. The NCI supports an
extensive network of clinical and laboratory research studies related to cancer
therapy through contracts, grants, and cooperative agreements.  At present, the
traditional research grant mechanism (R01) is underutilized by clinical
investigators for the support of clinical research.  In December, 1997, the NIH
Director's Panel on Clinical Research, chaired by Dr. David Nathan, issued a
report elucidating the concerns of the clinical community related to the fairness
of the review of clinical research and patient-oriented research at the Center
for Scientific Review (CSR) (http://www.nih.gov/news/crp/97report/). 
In response to the report, CSR has recently formed a new Clinical Oncology
Special Emphasis Panel for the review of clinical oncology research.  NCI is 
committed to supporting clinical trials research and encourages clinical investigators 
to submit clinical therapeutic studies to move advances in basic biology and 
drug development into the clinical setting.

Objectives and Scope

The aims of this initiative are two-fold: (1) to stimulate development of
innovative therapeutic clinical trials with laboratory correlations to foster the
development of interactions between basic science laboratories and clinicians
performing these clinical trials and (2) to support innovative correlative
laboratory studies linked to therapeutic clinical trials.

Clinical studies/trials must involve human subjects and be therapeutic in design. 
The clinical studies must be based on a strong rationale and preclinical or
clinical data should support the underlying hypotheses.  The applications may
include single or multi-institutional research studies with appropriate
biological correlates linked to these studies.  New clinical therapeutic trials
may employ drugs, biologics, radiation, or surgery used as single
agents/modalities or in combination.  Biological correlative studies that have
clinical relevance to therapeutic study and are aimed at improving cancer
treatment are also appropriate.

Some examples of clinical therapeutic trials include:  (1) therapies based on
novel mechanisms of action and metabolic studies of antitumor agents; (2) studies
of mechanisms of hormone-, drug-, or radiation-resistance and reversal; (3)
mechanism of action of biological response modifiers in the treatment of cancer,
e.g., cancer immunotherapy (monoclonal antibodies, cytokines, antisense, and
vaccines) alone or in combination with chemotherapeutic agents; (4) mechanism of
action of new growth factor targeted therapies; (5) new radiation therapies or
radiation modifiers to enhance cell kill or protect normal tissue; (6) surgical
therapies in combination with therapeutic agents.

Some examples of biological correlative studies include:  (1) phenotypic or
genotypic alterations that appear to correlate with the development of therapy
resistance; (2) correlation of oncogenes, growth factors, and specific antigen
expression with response to therapies; (3) pharmacokinetic and pharmacodynamic
measurements; (4) characterization of immune response associated with new
immunotherapies; (5) imaging studies to assess efficacy of treatment; and (6)
alterations in cell cycle control.

Investigators are not limited to the above areas of potential studies.

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 492B 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 20, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994 available on the web at the following URL address:
http://www.nih.gov.grants/guide/1994/94.03.18/notice-nih-guideline008.html

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.

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:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

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

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines indicated in the
application kit.  Application 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 301-435-0714, Email:
grantsinfo@nih.gov.  Application kits also are available on the OER homepage at:
http://www.nih.gov/grants/forms.htm

Applicants planning to submit an investigator-initiated new (type 1), competing
continuation (type 2), competing supplement, or any amended/revised version of
the preceding grant application types requesting $500,000 or more in direct costs
for any year are advised that he or she must contact the Institute or Center (IC)
program staff before submitting the application, i.e, as plans for the study are
being developed.  Furthermore, the application must obtain agreement from the IC
staff that the IC will accept the application for consideration for award.
Finally, the applicant must identify, in a cover letter sent with the
application, the staff member and Institute or Center who agreed to accept
assignment of the application.  This policy requires an applicant to obtain
agreement for acceptance of both any such application and any such subsequent
amendment.  Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at
http://www.nih.gov/grants/guide/notice-files/not98-030.html

Applicants from institutions that have a General Clinical Research Center (GCRC)
funded by the NIH National Center for Research Resources are requested to
identify the GCRC as a source 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.

The title and number of the program announcement must be typed in Section 2 on
the face page of the application.

The completed original application and five legible copies must be sent or
delivered 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications will be evaluated for scientific and technical merit
by an appropriate scientific review group convened 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, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their subgroups,
and children as appropriate for the scientific goals of the research. Plans for
the recruitment and retention of subjects will also be evaluated.

o The reasonableness of the proposed budget and duration in relation to the
proposed research

o The adequacy of the proposed protection for humans, animals or the environment,
to the extent they may be adversely affected by the project proposed in the
application.

The initial review group will also examine the provisions for the protection of 
human subjects and the safety of the research environment.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions: 
Quality of the proposed project as determined by peer review, availability of
funds, and program priority.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Dr. Roy S. Wu or Ms. Diane Bronzert
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 734
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663
Email:  rw51j@nih.gov
Email:  db85g@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Sara Stone
Grants Management Branch
National Cancer Institute
Executive Plaza South, Room 242
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 266
FAX:  (301) 496-8601
Email: stones@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
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 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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