PILOT STUDIES: ORAL COMPLICATIONS OF CANCER THERAPIES
RELEASE DATE: July 27, 2004
PA NUMBER: PA-04-134
March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date,
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using
the electronic SF424 (R&R) application. Accordingly, this funding opportunity
expires on the date indicated below. A replacement R21 (PA-06-212) funding
opportunity announcement has been issued for the submission date of June 1, 2006
and submission dates thereafter.
See NOT-OD-06-048 for information on May 1, 2006 Submission Date for AIDS and
AIDS-related R03 and R21 Applications.
EXPIRATION DATE: March 2, 2006
Department of Health and Human Services (DHHS)
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
(http://www.nih.gov)
COMPONENTS OF PARTICIPATING ORGANIZATION:
National Institute of Dental and Craniofacial Research (NIDCR)
(http://www.nidcr.nih.gov)
National Cancer Institute (NCI)
(http://www.nci.nih.gov)
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S) 93.121 Oral Diseases
and Disorders Research, 93.395 Cancer Treatment Research
THIS PA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this PA
o Research Objectives
o Mechanism(s) of Support
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS PA
The National Institute of Dental and Craniofacial Research (NIDCR) and
the National Cancer Institute (NCI) invite applications for clinical
research directed at reducing the incidence and severity of oral
complications from cancer therapies. The NIDCR and NCI recognize that
developmental, exploratory, and/or pilot studies in epidemiology,
behavioral/social sciences or other areas of clinical research may be
needed to accelerate scientific progress in addressing this topic. The
purpose of these studies would be to collect preliminary data to
establish an adequate foundation that may lead to R01 level clinical
research grants.
Oral complications from cancer therapies are common and can
substantially impair the comfort and function of patients during and
after treatment for cancer. In addition, these complications may impact
on a patient’s willingness to adhere or complete with the prescribed
therapies. The goal of this PA is to stimulate the submission of
developmental/exploratory studies related to lesions and symptoms that
occur in the oral cavity as a result of cancer therapies. Also,
responsive to this PA would be developmental and exploratory studies
that design and evaluate appropriate ways to assess mucositis and to
incorporate quality of life assessments in evaluating clinical outcomes
of preventive and treatment strategies for patients with acute or
chronic oral complications of cancer therapies.
RESEARCH OBJECTIVES
Background
In 2004, approximately 1.3 million Americans will be diagnosed with
cancer and many will receive one or more types of therapies for this
disease. Cancer therapies could include surgery, radiation,
chemotherapy, immunotherapy and/or cell transplantation. The type of
therapy will depend on the specific diagnosis, site and staging of the
malignancy.
A range of side effects accompanies the different types of cancer
therapy. These side effects may be mild and transient (e.g. alopecia,
nausea, neutropenia), chronic (e.g. fatigue, lymphedema) and/or late
and potentially life threatening (e.g. cardiomyopathy). Also, a number
of side effects or complications can be seen in the oral cavity. The
frequency of oral complications varies with about 40% of those
receiving chemotherapy, 80% of those having bone marrow
transplantation, and 100% of those with high-dose radiation to the head
and neck. The most common complications of the oral cavity include
mucositis, infection, salivary gland dysfunction, taste dysfunction and
pain. Radiation therapy for cancer in the head and neck area can
result in xerostomia, rampant dental caries, soft tissue necrosis and
osteonecrosis.
Ulcerative oral mucositis occurs in about 40% of patients receiving
cancer chemotherapy and it usually occurs within two weeks after
beginning therapy. Other oral complications include bacterial and viral
infections. Relatively little is known about the risk factors for
chemotherapy induced mucositis or infection.
Ulcerative and non-ulcerative mucositis also is a common side effect of
radiation therapy. Other complications related to head and neck
radiation include damage to the vasculature, connective tissue,
salivary glands and bone. These complications may be divided into
acute complications that occur during therapy and late complications
that occur after completion of radiation therapy. Acute complications
include oropharyngeal mucositis, sialdenitis and xerostomia, infections
(primary candidiasis) and taste dysfunction. Occasionally tissue
necrosis can be seen late during therapy. Chronic complications
include mucosal atrophy; mucosal, cutaneous and muscular fibrosis;
xerostomia and associated caries; osseous and mucosal necrosis,
secondary infection; and alterations in taste.
A number of studies have used protective mucosal coatings such as
sucralfate, alone or in combination with antibiotics and analgesics, to
reduce mucositis and its associated pain and discomfort. Anti-
inflammatory drugs, such as triclosan and indometacin have been found
to reduce the duration and severity of mucositis in some cases and
topical applications of vitamin A and E also have been used in attempts
to reduce mucositis. The use of low-energy laser therapy has been
reported to reduce the incidence of mucositis and to enhance
epithelial healing.
Saliva is a lubricant in the oral cavity and provides a barrier against
bacteria and viral infections. It also helps to moisten food and aids
in swallowing. The use of amifostine prior to radiation therapy to the
head and neck region has been shown to help in preserving salivary
output. Similarly, pilocarpine can be used to stimulate saliva
production, provided that functional glands remain after cancer
therapy. In addition, salivary substitutes can be given to lubricate
and facilitate oral function.
Research is necessary on the development and evaluation of new methods
or tools for assessing mucositis and other oral complications of cancer
therapy so that patients at high-risk for these complications are
identified, and targeted for appropriate preventive treatment.
Behavioral studies on the diffusion and adoption of presently
recommended strategies for the prevention and management of oral
symptoms within various communities and health care settings also are
needed.
Objectives and Scope
The goal of this PA is to stimulate research on the prevention and/or
management of symptoms and lesions in the oral cavity and pharynx
resulting from cancer therapies. Applications responsive to this PA
are for developmental/exploratory studies that may lead to R01 type
research grants. Applications for small clinical trials will not be
responsive to this PA
(http://grants.nih.gov/grants/guide/notice-files/NOT-DE-04-002.html).
The list of research topics below is for illustrative purposes and
applications on topics not explicitly listed that fall within the goal
of this PA also are welcomed.
o Studies to develop and standardize measurements of acute and chronic
oral complications of cancer therapy
o Studies to develop effective screening tools for early identification
of oral complications, such as mucositis or associated pain
o Studies that clarify the time course of oral complications and
differential risks within patient subgroups
o Studies of the effect of mucositis or other oral complications on
nutrition, communication, or other clinical outcomes directly related
to oral function or quality of life
o Studies to document the prevalence, severity, and time course of
mucositis and other oral complications associated with various cancer
therapies
o Studies to investigate novel approaches to expand the adoption and
implementation of effective measures for preventing and managing oral
complications of cancer therapies
o Studies identifying key characteristics of patients, treatments, or
health care environment that influence the effectiveness of the
prevention/management of oral complications from cancer therapies
o Studies to document long term effects of oral cancer complications of
cancer therapies among survivors
MECHANISM OF SUPPORT
This PA will use the NIH Exploratory/Developmental (R21) award mechanism
for the submission of exploratory and/or development research grants. As
an applicant you will be solely responsible for planning, directing, and
executing the proposed project.
Applicants may request a project period of up to two years with a
combined budget for direct costs of up to $275,000 for the two-year
period. For example, the applicant may request $100,000 in the first
year and $175,000 in the second year. The request should be tailored to
the needs of the project. Normally, no more than $200,000 may be
requested in any single year.
This PA uses just-in-time concepts. It also uses the modular budgeting
formats (see http://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, if you are submitting an application with direct costs in
each year of $250,000 or less, use the modular budget format. This
program does not require cost sharing as defined in the current NIH
Grants Policy Statement at
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the
following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges,
hospitals, and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic and foreign institutions/organizations
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to
conduct the proposed research is invited to work with their institution
to develop an application in response to this PA. Individuals from
underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH programs.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this PA and welcome the opportunity
to answer questions from potential applicants. Inquiries may fall into
two areas: scientific/research, and financial or grants management
issues:
o Direct your questions about scientific/research issues to:
Maria Teresa Canto, DDS, MPH
Director, Epidemiology Research Program
Clinical Research Branch
Division of Clinical Research and Health Promotion
National Institute of Dental & Craniofacial Research
National Institutes of Health
45 Center Drive, Room 4AS43B
Bethesda, MD 20892-6401
Telephone:(301) 594-5497
Fax: (301) 480-8319
E-mail: maria.canto@nih.gov
Dr. Roy S. Wu
Clinical Grants & Contracts Branch
Cancer Therapy Evaluation Program
Division of Cancer Treatment & Diagnosis
National Cancer Institute
Executive Plaza North, Room 7009
6130 Executive Boulevard
Bethesda, MD 20892-7432
Phone: 301-496-8866
Fax: 301-480-4663
E-mail: rw51j@nih.gov
o Direct your questions about financial or grants management matters
to:
Mary Daley
Chief Grants Management Officer
National Institute of Dental
and Craniofacial Research, NIH, HHS
45 Center Drive MSC 6402
Bldg. 45, Rm. 4AN44B
Bethesda, MD 20892-6402
Phone: 301-594-4808
Fax: 301-480-3562
email: md74u@nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant
application instructions and forms (rev. 5/2001). Applications must
have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS)
number as the Universal Identifier when applying for Federal grants or
cooperative agreements. The D&B number can be obtained by calling (866)
705-5711 or through the web site at http://www.dunandbradstreet.com/.
The D&B number should be entered on line 11 of the face page of the PHS
398 form. The PHS 398 document is available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an
interactive format. For further assistance contact GrantsInfo,
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.
The title and number of this program announcement must be typed on line
2 of the face page of the application form and YES box must be marked.
SUPPLEMENTARY INSTRUCTIONS: All instructions for the PHS 398 (rev.
5/2001) must be followed, with these exceptions:
o Research Plan
Items a - d of the Research Plan (Specific Aims, Background and
Significance, Preliminary Studies, and Research Design and Methods) may
not exceed a total of 15 pages. No preliminary data is required but may
be included if it is available. Please note that a Progress Report is
not needed; competing continuation applications for an
exploratory/developmental grant will not be accepted.
Appendix. Use the instructions for the appendix detailed in the PHS 398
except that no more than 5 manuscripts, previously accepted for
publication, may be included.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: All investigator
initiated R21 applications must be submitted in a modular grant format.
The modular grant format simplifies the preparation of the budget in
these applications by limiting the level of budgetary detail.
Applicants request direct costs in $25,000 modules. Section C of the
research grant application instructions for the PHS 398 (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants. Additional information
on modular grants is available at
http://grants.nih.gov/grants/funding/modular/modular.htm.
APPLICATION RECEIPT DATES: Applications submitted in response to this
program announcement will be accepted at the standard application
deadlines, which are available at
http://grants.nih.gov/grants/dates.htm. Application deadlines also are
indicated in the PHS 398 application kit.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original
of the application, including the checklist, and five 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)
APPLICATION PROCESSING: Applications must be mailed on or before the
receipt dates described at
http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR
will not accept any application in response to this PA 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
unfunded version of an application already reviewed, but such
application must include an Introduction addressing the previous
critique.
Although there is no immediate acknowledgement of the receipt of an
application, applicants are generally notified of the review and funding
assignment within 8 weeks.
PEER REVIEW PROCESS
Applications submitted for this PA will be assigned on the basis of
established PHS referral guidelines. Appropriate scientific review
groups convened in accordance with the standard NIH peer review
procedures (http://www.csr.nih.gov/refrev.htm) will evaluate
applications for scientific and technical merit.
As part of the initial merit review, all applications will:
o Undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of the applications
under review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by an 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.
In the written comments, reviewers will be asked to evaluate the
application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals. The
scientific review group will address and consider each of the following
criteria in assigning the application’s overall score, weighting them
as appropriate for each application.
o Significance
o Approach
o Innovation
o Investigator
o Environment
The application does not need to be strong in all categories to be
judged likely to have 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.
SIGNIFICANCE: Does this approach address the goals of this PA? If the
aims of the application are achieved, how will scientific knowledge be
advanced?
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?
INNOVATION: Does the project employ novel concepts, approaches or
methods? Are the aims original and innovative?
INVESTIGATOR: Are the investigators 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?
ENVIRONMENT: Does the scientific environment in which the work will be
done contribute to the probability of success? Is there evidence of
institutional support?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the
following items will be considered in the determination of scientific
merit and the priority score:
PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of
human subjects and protections from research risk relating to their
participation in the proposed research will be assessed. (See criteria
included in the section on Federal Citations, below).
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy
of plans to include subjects from both genders, all racial and ethnic
groups (and subgroups), and children as appropriate for the scientific
goals of the research. Plans for the recruitment and retention of
subjects will also be evaluated. (See Inclusion Criteria in the
sections on Federal Citations, below).
ADDITIONAL REVIEW CONSIDERATIONS
BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that
applications and proposals involving human subjects must be evaluated
with reference to the risks to the subjects, the adequacy of protection
against these risks, the potential benefits of the research to the
subjects and others, and the importance of the knowledge gained or to
be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy
of the NIH that women and members of minority groups and their sub-
populations must be included in all NIH-supported clinical research
projects unless a clear and compelling justification is provided
indicating 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 clinical research should read the "NIH
Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research - Amended, October, 2001," published in the NIH Guide
for Grants and Contracts on October 9, 2001
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a
complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_20
01.htm). The amended policy incorporates: the use of an NIH
definition of clinical research; updated racial and ethnic categories
in compliance with the new OMB standards; clarification of language
governing NIH-defined Phase III clinical trials consistent with the new
PHS Form 398; and updated roles and responsibilities of NIH staff and
the extramural community. The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or
proposals and/or protocols must provide a description of plans to
conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN
SUBJECTS: The NIH maintains a policy 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 scientific and
ethical reasons not to include them.
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 is available at
http://grants.nih.gov/grants/funding/children/children.htm
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:
NIH policy requires education on the protection of human subject
participants for all investigators submitting NIH proposals for
research involving human subjects. You will find this policy
announcement in the NIH Guide for Grants and Contracts Announcement,
dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-
files/NOT-OD-00-039.html.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:
The Office of Management and Budget (OMB) Circular A-110 has been
revised to provide public access to research data through the Freedom of
Information Act (FOIA) under some circumstances. Data that are (1)
first produced in a project that is supported in whole or in part with
Federal funds and (2) cited publicly and officially by a Federal agency
in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has
provided guidance at
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this PA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application
should include a description of the archiving plan in the study design
and include information about this in the budget justification section
of the application. In addition, applicants should think about how to
structure informed consent statements and other human subjects
procedures given the potential for wider use of data collected under
this award.
STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:
The Department of Health and Human Services (DHHS) issued final
modification to the Standards for Privacy of Individually Identifiable
Health Information , the Privacy Rule, on August 14, 2002. The
Privacy Rule is a federal regulation under the Health Insurance
Portability and Accountability Act (HIPAA) of 1996 that governs the
protection of individually identifiable health information, and is
administered and enforced by the DHHS Office for Civil Rights (OCR).
Decisions about applicability and implementation of the Privacy Rule
reside with the researcher and his/her institution. The OCR website
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule,
including a complete Regulation Text and a set of decision tools on Am
I a covered entity? Information on the impact of the HIPAA Privacy
Rule on NIH processes involving the review, funding, and progress
monitoring of grants, cooperative agreements, and research contracts
can be found at
http://grants1.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and
proposals for NIH funding must be self-contained within specified page
limitations. Unless otherwise specified in an NIH solicitation, Internet
addresses (URLs) should not be used to provide information necessary to
the review because reviewers are under no obligation to view the
Internet sites. Furthermore, we caution reviewers that their anonymity
may be compromised when they directly access an Internet site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting priority
areas. This PA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.healthypeople.gov/.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject
to the intergovernmental review requirements of Executive Order 12372
or Health Systems Agency review. Awards are made under the
authorization of Sections 301 and 405 of the Public Health Service Act
as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52
and 45 CFR Parts 74 and 92. All awards are subject to the terms and
conditions, cost principles, and other considerations described in the
NIH Grants Policy Statement. The NIH Grants Policy Statement can be
found at http://grants.nih.gov/grants/policy/policy.htm
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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.
References
Clarkson JE, Worthington HV, Eden OB. Interventions for preventing oral
mucositis for patients receiving treatment (Cochrane Review). In: The
Cochrane Library, Issue 1, 2004. Chicheste, UK: John Wiley & Sons, Ltd.
Clarkson JE, Worthington HV, Eden OB. Interventions for treating oral
candidiasis for patients with cancer receiving treatment (Cochrane
Review). In: The Cochrane Library, Issue, 2004. Chichester, UK: John
Wiley & Sons, Ltd.
Duncan M, Grant G. Review article: oral and intestinal mucositis
causes and possible treatments. Aliment Pharmacol Ther 2003;18:853-74.
Jenal, A, Tiwari RC et. al. CA A Cancer Journal for Clinicians,
54(1):8-29.
Oral complications of chemotherapy and head/neck radiation (PDQ),
www.cancer.gov (date last modified 8/19/2003).
Peterson DE, Sonis ST. Executive Summary, Journal of the National
Cancer Institute Monographs 2001;29 3 5.
Weekly TOC for this Announcement
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