CLINICAL TRIALS: ORAL COMPLICATIONS OF CANCER THERAPY RELEASE DATE: July 27, 2004 PA NUMBER: PAR-04-133 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 (PAR-06-213) 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) invites applications for clinical research directed at reducing the incidence and severity of oral complications from cancer therapies. The purpose of this PA for pilot data grants would be to collect preliminary data to establish an adequate foundation for Phase III clinical trials. 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. Moreover, scientific data are incomplete and inconsistent regarding the effectiveness of various forms currently used to prevent and treat these complications. Therefore, the goal of this PA is to stimulate the submission of pilot data grants for clinical trials targeted to the prevention and management of lesions and symptoms, which occur in the oral cavity as a result 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. Although several interventions are available and they have shown some benefit at preventing or reducing the severity of oral complications related to cancer therapy, well-designed clinical trials are needed to determine which interventions are most efficacious for different categories of patients and cancer therapies. These interventions should be tailored to the specific therapy protocols, as well as the health and immune status of the patient. 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 pilot data grants leading to Phase III clinical trials. Applications for small clinical trials will not be responsive to this PA (see http://grants.nih.gov/grants/guide/notice-files/NOT-DE-04-002.html). The pilot data grant applications to be supported under this award may involve limited pilot testing of novel experimental hypotheses, design- driven development of new or novel techniques or technologies, and/or the acquisition of a body of data that has potentially high-impact on the reduction of mucositis and other oral complications related to chemotherapy, radiation or other cancer therapies. Also, data collected under this PA may include but is not limited to: collection of preliminary data for establishing measures of effectiveness and/or safety; testing and documenting recruitment mechanisms and their effectiveness; short-term studies to address questions to optimize the design of the Phase III clinical trial; small studies to refine an intervention strategy (e.g., dosage, duration, delivery system, etc.); and, the development and testing of participant inclusion criteria and data collection and outcome instruments. MECHANISM OF SUPPORT This PA will use the NIH Exploratory/Developmental (R21) award mechanism for clinical pilot data grants. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. The pilot data grant from the NIDCR Clinical Program is described in the following website (see http://grants1.nih.gov/grants/guide/pa-files/par-03-043.html). 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 institutions/organizations o Foreign institutions are not eligible to apply. 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. SPECIAL REQUIREMENTS Before submitting an application for an NIDCR Clinical Pilot Data Grant responsive to this PA, the investigator may wish to submit a brief description of the proposed Phase III clinical trial to the NIDCR for review for programmatic relevance. See http://www.nidcr.nih.gov for details or contact Dr. Canto listed in WHERE TO SEND INQUIRIES under scientific/research issues. The brief description is optional for submissions to NCI. WHERE TO SEND INQUIRIES Inquiries are encouraged early in the development of a NIDCR Clinical Pilot Data Grant responsive to this PA. The opportunity to clarify any issues or questions from potential applicants is welcome and highly encouraged. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Dr. Maria Teresa Canto Division of Clinical research and Health Promotion National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4As43B, MSC 6401 Bethesda, MD 20892-6401 Telephone: (301) 594-5497 FAX: (301) 480-8322 Email: 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 peer review issues to: Dr. H. George Hausch Division of Extramural Activities National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4An-44F, MSC 6401 Bethesda, MD 20892-6401 Telephone: (301) 594-2904 o Direct your questions about financial or grants management matters to: Chris Myers Grants Management Specialist Grants Management Branch Division of Extramural Activities National Institute of Dental and Craniofacial Research Building 45, Room 4AS51 45 Center Drive Bethesda, Maryland 20892-6402 Phone: 301-594-4799 Fax: 301-480-3562 E-mail: Chris.Myers@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Appendices will be accepted in applications responsive to this PA. 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 types on line 2 of the face page of the application form and YES box must be marked. 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. SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget grant format. The modular budget 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. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and three 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) In order to facilitate the review of applications assigned to the NIDCR, the applicant must, at the same time, mail or deliver two copies of the application to: Dr. H. George Hausch Division of Extramural Activities National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-44F - MSC 6402 Bethesda, MD 20892-6402 APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL INSTITUTES OF HEALTH AND THE NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e., FED EX, UPS, DHL, etc.). This policy for applications addressed to the Center for Scientific Review was published in the NIH Guide to Grants and Contracts at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. 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. An appropriate scientific review group convened by NIDCR 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 selection process in which only those applications deemed to have the highest scientific merit, generally the top half of 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 discuss the following aspects of your 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 these criteria in assigning your application's overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment Your 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of the proposed pilot activities on the concepts or methods that drive this field? Will a successful outcome from this pilot work lead directly to the development of a definitive Phase III clinical trial that would likely advance the field of craniofacial, oral, or dental research? (2) Approach: Are the conceptual framework, design, and methods adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: In general, pilot data grants leading to a Phase III clinical trial are not expected to be innovative. For pilot data grants leading to a Phase III clinical trial, innovation will be evaluated on the basis of whether the pilot data grant tests new paradigms of public health policy or standards of clinical practice. (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers, if any? Is the principal investigator an independent researcher? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed planned activities take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be 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_2001.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://grants.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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