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.

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