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)
National Institutes of Health (NIH)

National Institute of Dental and Craniofacial Research (NIDCR)
National Cancer Institute (NCI)

and Disorders Research, 93.395 Cancer Treatment Research

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


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.


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 

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 

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 

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 

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 
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

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 
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


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.   


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 

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 

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 

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) 435-0714, 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. 

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 

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 

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.


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.

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 
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: 

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).
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).


BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.


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.

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

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 
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 

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 

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-

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 

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.

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 

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 

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.


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, 

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
NIH Funding Opportunities and Notices

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
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