Full Text DE-95-003

ORAL CANCER RESEARCH CENTERS

NIH GUIDE, Volume 24, Number 11, March 24, 1995

RFA:  DE-95-003

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Oral Diseases 
  Epidemiology 
  Immunology 
  Viral Studies (Virology) 


National Institute of Dental Research

Letter of Intent Receipt Date:  May 15, 1995
Application Receipt Date:  August 22, 1995

PURPOSE

The National Institute of Dental Research (NIDR) invites applications
from United States institutions for the support of Oral Cancer
Research Centers.  The goal of these centers is to support
multidisciplinary basic and clinical research incorporating the range
of parameters and academic disciplines necessary for reducing the
morbidity and mortality due to oral cancer (e.g., epidemiology,
behavioral sciences, nutrition, immunology, molecular biology,
toxicology, and virology).  Multifactorial, multistep approaches will
be encouraged.  Proposed centers should take full advantage of
combined institutional strengths in various geographic locations.

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 Application (RFA), Oral Cancer Research Centers, is related to
the priority area of oral health.  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 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit,
public and private organizations, such as dental and medical schools,
universities, research institutions, hospitals, laboratories, units
of state and local governments, and eligible agencies of the federal
government.  Applications from foreign institutions are not eligible.
However, domestic applications may include international components.
Although an application must be submitted from a single institution,
it may include consortia arrangements with other institutions
provided these arrangements are clearly delineated and confirmed.
Applications with key personnel such as center directors or principal
investigators who are members of a minority group and/or women are
encouraged.  To be eligible for a center grant under this program,
the potential applicant institution must have an ongoing,
independently supported basic and/or clinical research program in the
area of oral cancer or the capacity and infrastructure to support
such research.  The current application must propose new research in
this area including human clinical oral cancer research.

MECHANISM OF SUPPORT

Centers will be supported by the National Institutes of Health
Specialized Center grant (P50) mechanism for a period of not more
than five years.  The earliest possible award date is April 1, 1996.
Responsibility for the planning, direction, and execution of the
proposed center will be solely that of the applicant.  This RFA is a
one-time solicitation.  Issuance of a subsequent request for new and
competing continuation applications will be contingent upon program
needs and the availability of funds.

FUNDS AVAILABLE

Two to three awards are planned and up to $2,250,000 in total costs
will be committed for the first year of support if sufficient
applications of high scientific merit are received.  Although this
program is provided for in the financial plans of the NIDR, the award
of grants pursuant to this RFA is also contingent upon the
availability of funds for this purpose.

Applicants may request up to $500,000 in direct costs for the first
year.  Where indirect costs are assigned to a subcontract and counted
as direct costs on the parent grant, the direct cost maximum of
$500,000 may be exceeded by the amount of indirect costs assigned to
the subcontract.  Applications that exceed these limits will be
returned without review.  Budget increases of no more than four
percent per year for recurring costs may be requested for each of the
subsequent four years.

RESEARCH OBJECTIVES

Background

The International Classification of Diseases defines oral cancer as
cancer of the oral cavity and pharynx, including cancer of the lip,
tongue, salivary glands, gum, floor and other areas of the mouth,
oropharynx, nasopharynx, hypopharynx, pharynx and other buccal areas.
The Programs Advisory Committee (PAC) of the NIDR has stressed the
need for research exploring a range of factors involved in oral
cancer.  Research topics in the area of oral cancer include: studies
on herpes simplex virus; tobacco and alcohol as potential synergistic
etiological agents; head and neck radiation studies; environmental
causes of oral cancer; the effect of nutrition on  survival following
treatment for cancer; the role of human papilloma virus in the
development of oral cancer; molecular mechanisms of oral cancer; the
synergistic roles of both x-rays and chemicals in the development of
cancer; smoke and smokeless tobacco products; the role of
antioxidants in preventing cancer; and the role of transforming
growth factor alpha (TGF-alpha).

Although there has been a reduction in total mortality over the past
two decades, the five-year relative cancer survival rate for oral and
pharyngeal cancer is one of the lowest.  As reported by the NCI
Surveillance Epidemiology and End Result (SEER) Program for
1983-1989, only 33 percent of black patients and 54 percent of white
patients survive the five year period after detection of oral cancer.
This five year survival rate falls far below the survival for many
other cancers including cancers of the testis, skin melanoma, breast,
colon, rectum and kidney.  At the same time, the annual number of new
cases for all cancers has increased, rising from an estimated 625,000
new cases and 331,000 deaths in 1970 to an estimated 1,170,000 cases
and 526,000 deaths in 1993.  A large portion of this increase is due
to a 50 percent increase in the size of the population since 1970
coupled with an increase in the number of older Americans.  The
number of people 85 and older has more than doubled during this time.
However, during the time period 1973-1990 the incidence of cancer of
the oral cavity and pharynx has decreased slightly from approximately
five percent to about four percent of all cancers for men and two
percent for women while mortality has decreased by about 18 percent.
It is reasonable to hypothesize that early detection and/or treatment
have played a role in the greater reduction of mortality over
incidence.  As with other forms of cancer, both the mortality and
incidence data reflect higher rates among men than women and blacks
than whites.

This RFA indicates a renewed and increased interest on the part of
the NIDR in supporting research on oral cancer.  Because of the
interest and familiarity of dental professionals with the oral
cavity, they may be the first to recognize and diagnose oral cancers.
Oral cancers and precancerous lesions can often be visualized by the
health care professional and are often easier than cancers in other
sites to biopsy, treat, and follow during treatment.

Goals of the Centers

The primary goal of the centers is to accelerate and expand the
development of basic, clinical, epidemiological and behavioral
research as well as to translate research findings into improved
clinical methods for prevention, early detection and therapy of oral
cancer.  Multifactorial, multidisciplinary and multistep approaches
will be encouraged.  It is assumed that the proposed centers will
take full advantage of combined institutional strengths in various
geographic locations.

The following areas of research in oral cancer are encouraged but are
not meant to be exclusive:

o  determination of molecular events that lead to the conversion of a
normal oral epithelial cell to a malignant cell;

o  prospective and retrospective analysis of tissue samples to
determine events that lead to oral cancer;

o  genetic basis for susceptibility to cancer development including
gene changes, production of gene products, incorporation of a virus
in the genome, and chromosomal alterations;

o  continued development of specific markers or probes that can
enhance early detection and provide a better prognosis for
premalignant oral lesions;

o  tobacco, alcohol, and candidiasis as risk factors for cancer of
the buccal epithelium and other parts of the oral cavity;

o  studies of premalignant lesions in an effort to enhance early
prevention, detection, and treatment;

o  use of animals or other experimental approaches to develop better
means of prevention and treatment of mucosal diseases including oral
cancer;

o  the nature and mode of action of antitumor agents including gene
therapy;

o  enhance naturally occurring anticancer therapies including
biological modifiers and salivary antivirals;

o  improvement in the understanding of the effects of anticancer
therapies on oral mucosa and salivary glands;

o  development of procedures for reducing the untoward oral side
effects (e.g., destruction of salivary gland) resulting from
chemotherapy and radiation of oral and other cancers;

o  effects of nutrition or nutritional supplements on precancerous
lesions and on recovery from radiation and chemotherapy; and

o  development and testing of interventions designed to reduce risk
behavior factors (e.g., tobacco and alcohol use) for oral cancer and
precancerous lesions;

Center Characteristics

Each research center must be a clearly defined organizational entity
within a larger research institution with a director responsible for
management of the center.  Strong and effective scientific leadership
must be provided.  The application should specify provisions that
will be made for replacement of the director with a suitably
qualified alternative should circumstances require.  The director
will be responsible for the organization and operation of the center
and for communication with the center internal and external advisory
panels and with the NIDR on scientific and administrative matters.
Directors will be responsible for maintaining high-quality research
efforts and for ensuring effective collaboration among collaborating
scientists.  The center will consist of a cluster of related research
projects, some of which may be basic while others may involve
clinical and small epidemiological studies.  These projects must not
constitute a collection of individual, unrelated investigations more
appropriately supported by individual research project grants or
small grants, rather they should be related by a common research
theme.

Each center must include core units, each of which is shared by at
least two research projects.  One unit must be an administrative
core.  Funds for the center director and administrative staff will be
provided.  This core unit should ensure that participants are
provided with shared support services that enhance their research.
The director will be responsible for monitoring the overall quality
and the scope of center activities.  The administrative core may
provide limited funds, not to exceed $25,000 in direct costs and not
lasting for more than two years, to support pilot research projects.
The goals of the pilot and feasibility studies are to provide
start-up funds for new projects, to develop new investigators under
the direction of experienced basic and clinical scientists, and to
encourage established investigators to utilize recent research
techniques in addressing novel areas of oral cancer concerns.
Research plans for pilot and feasibility projects to be carried out
during the first and second years of the award and detailed
procedures for the review and selection of future such projects by
advisory panels and the center director must be included in the
application.

The director will convene an advisory panel of experts from outside
the applicant institution at least once a year to review center
activities and provide a written report on the progress of the
center.  This report may be included in the center's annual progress
report to the NIDR.

A biostatistics, experimental design, data management and analysis
core is also mandatory, although this function can be incorporated
into the administrative core.  The biostatistics core will provide
the staff with resources needed to enhance research programs through
the application of epidemiology, sampling, biostatistics, and related
support methodologies.  Specifically, it should foster and strengthen
biostatistician-clinical investigator interaction in the design and
conduct of clinical research.  Evidence should be presented of the
role played by proposed key staff from this core in the development
of the application, in particular the design of the research and
pilot projects.

Other proposed cores must directly relate to ongoing and planned oral
health research activities of the center:

o  A Diagnostics Core may provide and develop methods and/or
instrumentation to detect early signs or markers of oral disease or
dysfunction and to monitor the efficacy of treatments.

o  A Laboratory Core may provide resources and scientific expertise
to carry out adjunct studies on clinical trial patients or general
population samples.  Animal resources may be included where
appropriate.  Laboratory cores could, for example, include:
behavioral/social sciences, biomaterial sciences, pharmacology,
microbiology, immunology, nutrition, or molecular biology.  Core
resources, such as animal facilities, computer services and equipment
to be shared by investigators will be provided, although budgetary
constraints preclude expenditures for very expensive items of
equipment or major renovations.

o  A Unique Clinical Facilities Core may provide resources to
facilitate research that cannot be carried out in conventional
health-care settings, such as the use of mobile units for clinical
studies involving elderly or physically disabled individuals or
work-site based dental operatories for preventive interventions with
employed adults.  Any costs associated with patient care must be
limited to procedures included in research protocols.

The above descriptions are not intended to include the full range of
possible activities.  Cores may provide support for personnel,
including the necessary expertise to direct cores, equipment,
supplies, services, facilities, and limited travel.  In addition,
they may provide funds for the integration of activities with other
research centers in the same or related biomedical or
behavioral/social science areas for purposes of program enrichment.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the 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 should be included with
the application.

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 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion  of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.
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 reprinted
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 May 15, 1995, a letter
of intent that includes a descriptive title for the oral cancer
research center, each research project and each pilot and feasibility
project and core; give the name, address, and telephone number of the
center director; the identity of other key personnel and
participating institutions and departments; and this RFA by number
and title.

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 is helpful in planning for the timely
review of applications.  It allows NIDR staff to estimate the
potential review workload and to avoid possible conflict of interest
in the review.

The letter of intent is to be addressed to Dr. Norman S. Braveman at
the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are due no later than close of business on August 22,
1995.  Applications received after that time will be returned to the
applicant without further consideration.

Prospective applicants are encouraged to communicate with program and
grants management staff of the NIDR's Extramural Program as early as
possible in the planning phase of application preparation.  Advice
and suggestions by staff may materially assist applicants to ensure
that the cancer center's objectives and structure and the budget
format are acceptable.

Applications are to be submitted on the grant application form PHS
398 (rev. 9/91), available at most institutional offices of sponsored
research and from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 5333 Westbard Avenue,
Room 449, Bethesda, MD 20892, telephone 301/435-0714.  The RFA label
available in the PHS 398 application form kit must be affixed to the
bottom of the face page of the original and the original must be
placed on top of the entire package.  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, in order
to identify the application as a response to this RFA, the RFA title
"Oral Cancer Research Centers" and number "RFA DE-95-003" must be
typed in item 2a of the face page of the application form and the YES
box must be checked.

The instructions accompanying form PHS 398 must be followed to the
extent possible, but some modification will be necessary.  For
example, a new Table of Contents must be prepared giving page numbers
for all items in the application.  Pagination must be consecutive
throughout the application.  Each project, pilot feasibility project,
and core unit must be identified by number and investigator.  A
consolidated budget for the complete oral cancer center for the
entire project period must be presented (use page 5, form PHS 398).
Separate detailed, annual and total budgets for the entire project
period for each project and core must be presented (use pages 4-5,
form PHS 398).  In addition, a summary table must be included
providing budget totals for each project and core and for the entire
program, for all years of support.  Direct and indirect costs are to
be given.  Funds may be requested for professional, technical, and
administrative personnel, consultant services, equipment, supplies,
travel, patient costs directly related to the research, minor
renovations and other costs.  Detailed justification of the budget
requests will be required.

Specific attention must be given to efforts to contain costs and
ensure cost-competitive implementation of center goals.  Accordingly,
provide a summary of additional financial support from non-NIDR
sources for activities that will complement and expand the program
proposed for support by the NIDR.  Explain how these activities will
further the goals of the cancer center and make it more
cost-effective.  Awardees will be expected to update this information
on an annual basis.

Under Research Plan, describe the goals of the center and explain how
each proposed research project, core and pilot/feasibility project
will contribute toward achieving those goals.  Describe the
administrative structure, the responsibilities of the center
director, individual investigators, advisory groups, and the proposed
mechanisms for monitoring scientific progress.  Describe the
relationship of all existing and pending institutional research
projects that may be relevant to the oral cancer center regardless of
funding source.

Each project and core unit must be presented as in a research grant
application, that is, the instruction pages 19-24 of form PHS 398
must be followed.  The 25-page limitation will apply to each core
unit.  Each pilot/feasibility study must be presented as in a small
grant application, so that, the Research Plan may not exceed ten
pages.  Additional instructions and guidelines, in this connection,
are to be found in the NIDR Small Grant Program announcement
PA-91-36:  NIH GUIDE, Vol. 20, No. 12, March 22, 1991, and in its
modification by the notice that appeared in the NIH GUIDE, Vol. 22,
No. 1, January 8, 1993.  Abstracts (page 2, form PHS 398) must be
completed for the entire application, each research project and core
unit, and for each pilot and feasibility study proposed for
initiation during the first two years of the award.

Whenever appropriate, the application must: (a) delineate all
consortia arrangements and formally and officially confirm them by
signed statements from the responsible official(s) of each
institution; (b) be accompanied by firm funding commitments that
ensure that appropriate clinical research projects will be active at
the time of the award; and (c) include a letter of agreement from
either the GCRC program director or principal investigator should the
applicant identify a GCRC as a resource for conducting the proposed
research.

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

Division of Research Grants
National Institutes of Health
6705 Rockledge Drive, Suite 1040 - MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express or courier service)

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

Dr. H. George Hausch
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN-44F
45 Center Drive MSC 6402
Bethesda, MD  20892-6402

Applications must be received by August 22, 1995.  If an application
is received after that date, it will be returned to the applicant
without review.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NIDR.  Incomplete applications or those
that exceed the first year budget limit of $500,000 will be returned
to the applicant without further consideration. Waivers of the
receipt deadline and budget limitation will not be granted.  If NIDR
staff find that the application is not responsive to the RFA, it will
be returned without further consideration.

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 NIDR in accordance with the review
criteria stated below.  As part of the initial merit review, a
process (triage) may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be
competitive will be discussed and assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the principal investigator/program director
and the official signing for the applicant organization will be
promptly notified.  Secondary review of the applications will be
conducted by the National Advisory Dental Research Council.

Major factors to be considered in the evaluation of the applications
include:

o  The extent to which the center will promote advances in the area
of oral cancer that could not be achieved or would be achieved more
slowly if the component projects were funded separately.

o  The institutional environment, its commitment to the center, and
evidence of an organizational structure that will promote
multidisciplinary, collaborative research.  The potential of the
center to provide an environment for interaction between
investigators including the opportunity to learn new technology and
for investigators supported by other public and private funds.

o  The scientific merit, originality and feasibility of each project,
the soundness of the methodology proposed, and the competence of the
investigators. Availability of statistical and data analysis
resources and evidence of their use in developing the research
protocols.

o  The technical merit and justification for core resources
requested.

o  The adequacy of laboratory and clinical facilities, and the
availability of appropriate populations in clinical studies.

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

o  The inclusion of clinical and basic research projects that are
interrelated with adequate plans for interaction and communication of
information and concepts among the collaborating investigators.

o  The scientific and administrative qualifications, experience and
commitment of the center director and his/her ability to provide
effective leadership.  The arrangements for an assistant director to
administer the center in the director's absence and replace the
director should it become necessary.

o  Plans for monitoring research, and for reviewing changes in
research direction.  The composition and use of internal and external
reviewing committees and future pilot studies.

o  Appropriateness of the period and budget requested for each
project, core, pilot project and the entire center.

The inclusion of projects deemed to have limited scientific merit or
that are considered peripheral to the oral cancer center's objectives
may be considered a reflection of the center director's judgement and
may adversely affect the rating of the application.  Component pilot
projects lacking significant and substantial merit will not be
recommended for further consideration.  Pilot projects or cores with
only adequate merit that are not deemed essential to success of the
oral cancer center may be recommended for deletion.

AWARD CRITERIA

The earliest anticipated date of award is April 1,
1996.

Applicants should be aware that, in addition to scientific merit,
program priorities and program balance, the total cost of the Oral
Cancer Center to the NIDR will be considered by NIDR staff and the
National Advisory Dental Research Council in making funding
recommendations.  One consideration will be the extent to which
complementary projects, supported from non-NIDR funds, will
contribute to the cost-effectiveness of the proposed Oral Cancer
Center.  In circumstances in which applications have similar
scientific merit, but vary in cost-competitiveness, the NIDR is
likely to select the more cost-competitive application for funding.

Funded oral cancer centers may undergo an interim peer review by NIDR
to evaluate progress.

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. Norman S. Braveman
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN 24B
45 Center Drive MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-2089
FAX:  (301) 480-8318
Email:  BravemanN@de45.nidr.nih.gov

Direct inquiries regarding grants management issues to:

Ms. Theresa Ringler
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AS-55
45 Center Drive  MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.121.  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.  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 routing 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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